|
1
|
Morimoto S, Ogawa T. Exploration of candidate biomarkers for hypertension via transcriptomic studies in rats. Hypertens Res 2025:10.1038/s41440-025-02246-4. [PMID: 40490492 DOI: 10.1038/s41440-025-02246-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2025] [Accepted: 05/11/2025] [Indexed: 06/11/2025]
Affiliation(s)
- Satoshi Morimoto
- Department of Medicine, Tokyo Women's Medical University Adachi Medical Center, Tokyo, Japan.
| | - Tetsuya Ogawa
- Department of Medicine, Tokyo Women's Medical University Adachi Medical Center, Tokyo, Japan
| |
Collapse
|
|
2
|
Ben Salem A, Ezzidi I, Ben Abdennebi H, Mtiraoui N, Sarray S. A novel link between KCNQ1 genetic variants and polycystic ovary syndrome susceptibility. Biomed Rep 2025; 22:104. [PMID: 40322554 PMCID: PMC12046284 DOI: 10.3892/br.2025.1982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 04/02/2025] [Indexed: 05/08/2025] Open
Abstract
Genome-wide association studies (GWAS) have identified the potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene, as a potential contributor to the pathogenesis of type 2 diabetes (T2D). Given the known genetic overlap between T2D and polycystic ovary syndrome (PCOS), the present study aimed to investigate the potential association between KCNQ1 gene variants and PCOS susceptibility in a population of Tunisian women. A total of 230 patients and 230 healthy controls were recruited for this case control study. The Rotterdam consensus criteria were used to diagnose patients with PCOS. Genotyping of three KCNQ1 variants (rs231361, rs151290 and rs2237895), was performed using allelic discrimination (real-time PCR). After excluding false positive associations using the false discovery rate adjustment and ensuring statistical power >80%, the present results suggested that the KCNQ1 gene may play a role in PCOS susceptibility. Specifically, the rs231361 variant showed a significant association with an increased risk of PCOS through multiple genetic inheritance models. Additionally, the A/A genotype of the rs231361 variant displayed a correlation with increased levels of triglycerides compared with those with the G/G wild-type and the G/A heterozygous genotypes. To the best of our knowledge, this is the first study to identify the KCNQ1 rs231361 variant as a potential genetic risk factor for PCOS. These findings have important implications for risk assessment and the development of personalized treatment approaches for affected women.
Collapse
Affiliation(s)
- Assila Ben Salem
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, 5000 Monastir, Tunisia
| | - Intissar Ezzidi
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, 5000 Monastir, Tunisia
- Higher Institute of Biotechnology of Monastir, University of Monastir, 5000 Monastir, Tunisia
| | - Hassen Ben Abdennebi
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, 5000 Monastir, Tunisia
| | - Nabil Mtiraoui
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, 5000 Monastir, Tunisia
- Higher Institute of Biotechnology of Monastir, University of Monastir, 5000 Monastir, Tunisia
| | - Sameh Sarray
- College of Medicine and Health Sciences, Arabian Gulf University, 0329 Manama, Kingdom of Bahrain
- Faculty of Sciences, University of Tunis EL Manar, 2092 Tunis, Tunisia
| |
Collapse
|
|
3
|
Ali M, Javeriya S, Ahmad MH, Babar I, Rehan MMB, Iman H, Saeed H. Jervell and Lange-Nielsen Syndrome (JLNS) in a 13-Year-Old Girl: A Rare Case Report. Clin Case Rep 2025; 13:e70426. [PMID: 40248607 PMCID: PMC12003554 DOI: 10.1002/ccr3.70426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 03/10/2025] [Accepted: 04/03/2025] [Indexed: 04/19/2025] Open
Abstract
JLNS is a rare genetic disorder characterized by congenital sensorineural hearing loss and a prolonged QTc interval, leading to life-threatening arrhythmias. Early diagnosis, beta-blocker therapy, lifestyle modifications, and consideration of ICD surgery are critical in managing sudden cardiac death risk.
Collapse
Affiliation(s)
- Masab Ali
- Department of Internal MedicinePunjab Medical CollegeFaisalabadPakistan
| | - Sana Javeriya
- Department of MedicineJiius Indian Institute of Medical Science and ResearchJalnaMaharashtraIndia
| | - Muhammad Husnain Ahmad
- Department of MedicineTentishev Satkynbai Memorial Asian Medical InstituteGagarinaKantKyrgyzstan
| | - Ilsa Babar
- Department of Internal MedicineKing Edward Medical UniversityLahorePakistan
| | | | - Hafiza Iman
- Department of Internal MedicinePunjab Medical CollegeFaisalabadPakistan
| | - Humza Saeed
- Department of Internal MedicineRawalpindi Medical UniversityRawalpindiPakistan
| |
Collapse
|
|
4
|
Mkrtchyan L, Sahakyan H, Eldstrom J, Karapetyan T, Abrahamyan A, Nazaryan K, Schwarz JR, Kneussel M, Fedida D, Vardanyan V. Ion permeation through a narrow cavity constriction in KCNQ1 channels: Mechanism and implications for pathogenic variants. Proc Natl Acad Sci U S A 2024; 121:e2411182121. [PMID: 39671184 DOI: 10.1073/pnas.2411182121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 11/12/2024] [Indexed: 12/14/2024] Open
Abstract
KCNQ1 potassium channels play a pivotal role in the physiology and pathophysiology of several human excitable and epithelial tissues. The latest cryo-electron microscopy (cryo-EM) structures provide unique insights into channel function and pharmacology, opening avenues for different therapeutic strategies against human diseases associated with KCNQ1 mutations. However, these structures also raise fundamental questions about the mechanisms of ion permeation. Cryo-EM structures thought to represent the open state of the channel feature a cavity region not wide enough for accommodation of hydrated K+. To understand how K+ passes through the cavity constriction, we utilized microsecond-scale molecular dynamics (MD) simulations using the KCNQ1/KCNE3 cryo-EM structure, characterized mutants at the G345 residue situated at the narrowest point of the cavity, and recorded single channels. The findings indicate that ions become partially dehydrated at the constriction, which enables permeation. MD simulations demonstrate that the constriction can impede the flow of ions through the channel's pore, a finding that is corroborated by mutational screening and single-channel recordings. Reduced channel conductance is the key mechanism underlying reported pathological KCNQ1 mutations at or near the constriction site.
Collapse
Affiliation(s)
- Liana Mkrtchyan
- Molecular Neuroscience Group, Institute of Molecular Biology, Yerevan 0014, Armenia
| | - Harutyun Sahakyan
- Laboratory of Computational Modeling of Biological Processes, Institute of Molecular Biology, Yerevan 0014, Armenia
| | - Jodene Eldstrom
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Tatev Karapetyan
- Molecular Neuroscience Group, Institute of Molecular Biology, Yerevan 0014, Armenia
| | - Astghik Abrahamyan
- Molecular Neuroscience Group, Institute of Molecular Biology, Yerevan 0014, Armenia
| | - Karen Nazaryan
- Laboratory of Computational Modeling of Biological Processes, Institute of Molecular Biology, Yerevan 0014, Armenia
| | - Jürgen R Schwarz
- Institute for Molecular Neurogenetics, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
| | - Matthias Kneussel
- Institute for Molecular Neurogenetics, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
| | - David Fedida
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Vitya Vardanyan
- Molecular Neuroscience Group, Institute of Molecular Biology, Yerevan 0014, Armenia
| |
Collapse
|
|
5
|
Sweat ME, Pu WIT. Genetic and Molecular Underpinnings of Atrial Fibrillation. NPJ CARDIOVASCULAR HEALTH 2024; 1:35. [PMID: 39867228 PMCID: PMC11759492 DOI: 10.1038/s44325-024-00035-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 11/02/2024] [Indexed: 01/28/2025]
Abstract
Atrial fibrillation (AF), the most common sustained arrhythmia, increases stroke and heart failure risks. Here we review genes linked to AF and mechanisms by which they alter AF risk. We highlight gene expression differences between atrial and ventricular cardiomyocytes, regulatory mechanisms responsible for these differences, and their potential contribution to AF. Understanding AF mechanisms through the lens of atrial gene regulation is crucial to improving AF treatment.
Collapse
Affiliation(s)
- Mason E. Sweat
- Department of Cardiology, Boston Children’s
Hospital, Boston, MA 02115, USA
| | - WIlliam T. Pu
- Department of Cardiology, Boston Children’s
Hospital, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge,
MA 02138, USA
| |
Collapse
|
|
6
|
Stowe RB, Bates A, Cook LE, Dixit G, Sahu ID, Dabney-Smith C, Lorigan GA. Dynamic protein-protein interactions of KCNQ1 and KCNE1 measured by EPR line shape analysis. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2024; 1866:184377. [PMID: 39103068 PMCID: PMC11610511 DOI: 10.1016/j.bbamem.2024.184377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 07/09/2024] [Accepted: 08/02/2024] [Indexed: 08/07/2024]
Abstract
KCNQ1, also known as Kv7.1, is a voltage gated potassium channel that associates with the KCNE protein family. Mutations in this protein has been found to cause a variety of diseases including Long QT syndrome, a type of cardiac arrhythmia where the QT interval observed on an electrocardiogram is longer than normal. This condition is often aggravated during strenuous exercise and can cause fainting spells or sudden death. KCNE1 is an ancillary protein that interacts with KCNQ1 in the membrane at varying molar ratios. This interaction allows for the flow of potassium ions to be modulated to facilitate repolarization of the heart. The interaction between these two proteins has been studied previously with cysteine crosslinking and electrophysiology. In this study, electron paramagnetic resonance (EPR) spectroscopy line shape analysis in tandem with site directed spin labeling (SDSL) was used to observe changes in side chain dynamics as KCNE1 interacts with KCNQ1. KCNE1 was labeled at different sites that were found to interact with KCNQ1 based on previous literature, along with sites outside of that range as a control. Once labeled KCNE1 was incorporated into vesicles, KCNQ1 (helices S1-S6) was titrated into the vesicles. The line shape differences observed upon addition of KCNQ1 are indicative of an interaction between the two proteins. This method provides a first look at the interactions between KCNE1 and KCNQ1 from a dynamics perspective using the full transmembrane portion of KCNQ1.
Collapse
Affiliation(s)
- Rebecca B Stowe
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA
| | - Alison Bates
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA
| | - Lauryn E Cook
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA
| | - Gunjan Dixit
- Cell, Molecular and Structural Biology Program, Department of Chemistry & Biochemistry, Miami University, Oxford, OH 45056, USA
| | - Indra D Sahu
- Division of Natural Sciences, Campbellsville University, Campbellsville, KY 42718, USA
| | - Carole Dabney-Smith
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA
| | - Gary A Lorigan
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA.
| |
Collapse
|
|
7
|
Edmond MA, Hinojo-Perez A, Efrem M, Yi-Chun L, Shams I, Hayoz S, de la Cruz A, Perez Rodriguez ME, Diaz-Solares M, Dykxhoorn DM, Luo YL, Barro-Soria R. Lipophilic compounds restore function to neurodevelopmental-associated KCNQ3 mutations. Commun Biol 2024; 7:1181. [PMID: 39300259 DOI: 10.1038/s42003-024-06873-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 09/10/2024] [Indexed: 09/22/2024] Open
Abstract
A major driver of neuronal hyperexcitability is dysfunction of K+ channels, including voltage-gated KCNQ2/3 channels. Their hyperpolarized midpoint of activation and slow activation and deactivation kinetics produce a current that regulates membrane potential and impedes repetitive firing. Inherited mutations in KCNQ2 and KCNQ3 are linked to a wide spectrum of neurodevelopmental disorders (NDDs), ranging from benign familial neonatal seizures to severe epileptic encephalopathies and autism spectrum disorders. However, the impact of these variants on the molecular mechanisms underlying KCNQ3 channel function remains poorly understood and existing treatments have significant side effects. Here, we use voltage clamp fluorometry, molecular dynamic simulations, and electrophysiology to investigate NDD-associated variants in KCNQ3 channels. We identified two distinctive mechanisms by which loss- and gain-of function NDD-associated mutations in KCNQ3 affect channel gating: one directly affects S4 movement while the other changes S4-to-pore coupling. MD simulations and electrophysiology revealed that polyunsaturated fatty acids (PUFAs) primarily target the voltage-sensing domain in its activated conformation and form a weaker interaction with the channel's pore. Consistently, two such compounds yielded partial and complete functional restoration in R227Q- and R236C-containing channels, respectively. Our results reveal the potential of PUFAs to be developed into therapies for diverse KCNQ3-based channelopathies.
Collapse
Affiliation(s)
- Michaela A Edmond
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA
- Texas A&M University Health Science Center, Department of Neuroscience & Experimental Therapeutics, Bryan, USA
| | - Andy Hinojo-Perez
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Mekedlawit Efrem
- Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA
| | - Lin Yi-Chun
- Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA
| | - Iqra Shams
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Sebastien Hayoz
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Physiology, University of Arizona, Tucson, USA
| | - Alicia de la Cruz
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA
- Linkoping University, Department of Biomedical and Clinical Sciences (BKV), Linkoping, Sweden
| | | | - Maykelis Diaz-Solares
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Derek M Dykxhoorn
- John P. Hussman Institute for Human Genomics, John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Yun Lyna Luo
- Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA
| | - Rene Barro-Soria
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA.
| |
Collapse
|
|
8
|
Morgenstern TJ, Darko-Boateng A, Afriyie E, Shanmugam SK, Zhou X, Choudhury P, Desai M, Kass RS, Clarke OB, Colecraft HM. Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.28.596281. [PMID: 38854018 PMCID: PMC11160594 DOI: 10.1101/2024.05.28.596281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Targeted recruitment of E3 ubiquitin ligases to degrade traditionally undruggable proteins is a disruptive paradigm for developing new therapeutics. Two salient limitations are that <2% of the ~600 E3 ligases in the human genome have been exploited to produce proteolysis targeting chimeras (PROTACs), and the efficacy of the approach has not been demonstrated for a vital class of complex multi-subunit membrane proteins- ion channels. NEDD4-1 and NEDD4-2 are physiological regulators of myriad ion channels, and belong to the 28-member HECT (homologous to E6AP C-terminus) family of E3 ligases with widespread roles in cell/developmental biology and diverse diseases including various cancers, immunological and neurological disorders, and chronic pain. The potential efficacy of HECT E3 ligases for targeted protein degradation is unexplored, constrained by a lack of appropriate binders, and uncertain due to their complex regulation by layered intra-molecular and posttranslational mechanisms. Here, we identified a nanobody that binds with high affinity and specificity to a unique site on the N-lobe of the NEDD4-2 HECT domain at a location physically separate from sites critical for catalysis- the E2 binding site, the catalytic cysteine, and the ubiquitin exosite- as revealed by a 3.1 Å cryo-electron microscopy reconstruction. Recruiting endogenous NEDD4-2 to diverse ion channel proteins (KCNQ1, ENaC, and CaV2.2) using a divalent (DiVa) nanobody format strongly reduced their functional expression with minimal off-target effects as assessed by global proteomics, compared to simple NEDD4-2 overexpression. The results establish utility of a HECT E3 ligase for targeted protein downregulation, validate a class of complex multi-subunit membrane proteins as susceptible to this modality, and introduce endogenous E3 ligase recruitment with DiVa nanobodies as a general method to generate novel genetically-encoded ion channel inhibitors.
Collapse
Affiliation(s)
- Travis J. Morgenstern
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY
| | - Arden Darko-Boateng
- Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY
| | - Emmanuel Afriyie
- Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY
| | - Sri Karthika Shanmugam
- Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY
| | - Xinle Zhou
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY
| | - Papiya Choudhury
- Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY
| | | | - Robert S. Kass
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY
| | - Oliver B. Clarke
- Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY
| | - Henry M. Colecraft
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY
- Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY
| |
Collapse
|
|
9
|
Ricardo PC, Arias MC, de Souza Araujo N. Decoding bee cleptoparasitism through comparative transcriptomics of Coelioxoides waltheriae and its host Tetrapedia diversipes. Sci Rep 2024; 14:12361. [PMID: 38811580 PMCID: PMC11137135 DOI: 10.1038/s41598-024-56261-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 03/04/2024] [Indexed: 05/31/2024] Open
Abstract
Cleptoparasitism, also known as brood parasitism, is a widespread strategy among bee species in which the parasite lays eggs into the nests of the host species. Even though this behavior has significant ecological implications for the dynamics of several species, little is known about the molecular pathways associated with cleptoparasitism. To shed some light on this issue, we used gene expression data to perform a comparative analysis between two solitary neotropical bees: Coelioxoides waltheriae, an obligate parasite, and their specific host Tetrapedia diversipes. We found that ortholog genes involved in signal transduction, sensory perception, learning, and memory formation were differentially expressed between the cleptoparasite and the host. We hypothesize that these genes and their associated molecular pathways are engaged in cleptoparasitism-related processes and, hence, are appealing subjects for further investigation into functional and evolutionary aspects of cleptoparasitism in bees.
Collapse
Affiliation(s)
- Paulo Cseri Ricardo
- Departamento de Genética e Biologia Evolutiva - Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
| | - Maria Cristina Arias
- Departamento de Genética e Biologia Evolutiva - Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
| | | |
Collapse
|
|
10
|
Borowicz-Reutt K, Czernia J, Krawczyk M. Genetic Background of Epilepsy and Antiepileptic Treatments. Int J Mol Sci 2023; 24:16280. [PMID: 38003469 PMCID: PMC10671416 DOI: 10.3390/ijms242216280] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/01/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Advanced identification of the gene mutations causing epilepsy syndromes is expected to translate into faster diagnosis and more effective treatment of these conditions. Over the last 5 years, approximately 40 clinical trials on the treatment of genetic epilepsies have been conducted. As a result, some medications that are not regular antiseizure drugs (e.g., soticlestat, fenfluramine, or ganaxolone) have been introduced to the treatment of drug-resistant seizures in Dravet, Lennox-Gastaut, maternally inherited chromosome 15q11.2-q13.1 duplication (Dup 15q) syndromes, and protocadherin 19 (PCDH 19)-clusterig epilepsy. And although the effects of soticlestat, fenfluramine, and ganaxolone are described as promising, they do not significantly affect the course of the mentioned epilepsy syndromes. Importantly, each of these syndromes is related to mutations in several genes. On the other hand, several mutations can occur within one gene, and different gene variants may be manifested in different disease phenotypes. This complex pattern of inheritance contributes to rather poor genotype-phenotype correlations. Hence, the detection of a specific mutation is not synonymous with a precise diagnosis of a specific syndrome. Bearing in mind that seizures develop as a consequence of the predominance of excitatory over inhibitory processes, it seems reasonable that mutations in genes encoding sodium and potassium channels, as well as glutamatergic and gamma-aminobutyric (GABA) receptors, play a role in the pathogenesis of epilepsy. In some cases, different pathogenic variants of the same gene can result in opposite functional effects, determining the effectiveness of therapy with certain medications. For instance, seizures related to gain-of-function (GoF) mutations in genes encoding sodium channels can be successfully treated with sodium channel blockers. On the contrary, the same drugs may aggravate seizures related to loss-of-function (LoF) variants of the same genes. Hence, knowledge of gene mutation-treatment response relationships facilitates more favorable selection of drugs for anticonvulsant therapy.
Collapse
Affiliation(s)
- Kinga Borowicz-Reutt
- Independent Unit of Experimental Neuropathophysiology, Department of Toxicology, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (J.C.); (M.K.)
| | | | | |
Collapse
|
|
11
|
Julian CG, Houck JA, Fallahi S, Lazo-Vega L, Matarazzo CJ, Diamond B, Miranda-Garrido V, Krause BJ, Moore LG, Shortt JA, Toledo-Jaldin L, Lorca RA. Altered placental ion channel gene expression in preeclamptic high-altitude pregnancies. Physiol Genomics 2023; 55:357-367. [PMID: 37458464 PMCID: PMC10642922 DOI: 10.1152/physiolgenomics.00013.2023] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 06/12/2023] [Accepted: 07/06/2023] [Indexed: 08/12/2023] Open
Abstract
High-altitude (>2,500 m) residence increases the risk of pregnancy vascular disorders such as fetal growth restriction and preeclampsia, each characterized by impaired placental function. Genetic attributes of highland ancestry confer relative protection against vascular disorders of pregnancy at high altitudes. Although ion channels have been implicated in placental function regulation, neither their expression in high-altitude placentas nor their relationship to high-altitude preeclampsia has been determined. Here, we measured the expression of 26 ion-channel genes in placentas from preeclampsia cases and normotensive controls in La Paz, Bolivia (3,850 m). In addition, we correlated gene transcription to maternal and infant ancestry proportions. Gene expression was assessed by PCR, genetic ancestry evaluated by ADMIXTURE, and ion channel proteins localized by immunofluorescence. In preeclamptic placentas, 11 genes were downregulated (ABCC9, ATP2A2, CACNA1C, KCNE1, KCNJ8, KCNK3, KCNMA1, KCNQ1, KCNQ4, PKD2, and TRPV6) and two were upregulated (KCNQ3 and SCNN1G). KCNE1 expression was positively correlated with high-altitude Amerindian ancestry and negatively correlated with non-high altitude. SCNN1G was negatively correlated with African ancestry, despite minimal African admixture. Most ion channels were localized in syncytiotrophoblasts (Cav1.2, TRPP2, TRPV6, and Kv7.1), whereas expression of Kv7.4 was primarily in microvillous membranes, Kir6.1 in chorionic plate and fetal vessels, and MinK in stromal cells. Our findings suggest a role for differential placental ion channel expression in the development of preeclampsia. Functional studies are needed to determine processes affected by these ion channels in the placenta and whether therapies directed at modulating their activity could influence the onset or severity of preeclampsia.
Collapse
Affiliation(s)
- Colleen G Julian
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Julie A Houck
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Sahand Fallahi
- Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Litzi Lazo-Vega
- Department of Obstetrics and Gynecology, Hospital Materno-Infantil, La Paz, Bolivia
| | - Christopher J Matarazzo
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Breea Diamond
- Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | | | - Bernardo J Krause
- Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua, Chile
| | - Lorna G Moore
- Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Jonathan A Shortt
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Lilian Toledo-Jaldin
- Department of Obstetrics and Gynecology, Hospital Materno-Infantil, La Paz, Bolivia
| | - Ramón A Lorca
- Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| |
Collapse
|
|
12
|
Titaux-Delgado G, Lopez-Giraldo AE, Carrillo E, Cofas-Vargas LF, Carranza LE, López-Vera E, García-Hernández E, Del Rio-Portilla F. Beta-KTx14.3, a scorpion toxin, blocks the human potassium channel KCNQ1. BIOCHIMICA ET BIOPHYSICA ACTA. PROTEINS AND PROTEOMICS 2023; 1871:140906. [PMID: 36918120 DOI: 10.1016/j.bbapap.2023.140906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 02/25/2023] [Accepted: 03/06/2023] [Indexed: 03/14/2023]
Abstract
Potassium channels play a key role in regulating many physiological processes, thus, alterations in their proper functioning can lead to the development of several diseases. Hence, the search for compounds capable of regulating the activity of these channels constitutes an intense field of investigation. Potassium scorpion toxins are grouped into six subfamilies (α, β, γ, κ, δ, and λ). However, experimental structures and functional analyses of the long chain β-KTx subfamily are lacking. In this study, we recombinantly produced the toxins TcoKIK and beta-KTx14.3 present in the venom of Tityus costatus and Lychas mucronatus scorpions, respectively. The 3D structures of these β-KTx toxins were determined by nuclear magnetic resonance. In both toxins, the N-terminal region is unstructured, while the C-terminal possesses the classic CSα/β motif. TcoKIK did not show any clear activity against frog Shaker and human KCNQ1 potassium channels; however, beta-KTx14.3 was able to block the KCNQ1 channel. The toxin-channel interaction mode was investigated using molecular dynamics simulations. The results showed that this toxin could form a stable network of polar-to-polar and hydrophobic interactions with KCNQ1, involving key conserved residues in both molecular partners. The discovery and characterization of a toxin capable of inhibiting KCNQ1 pave the way for the future development of novel drugs for the treatment of human diseases caused by the malfunction of this potassium channel. STATEMENT OF SIGNIFICANCE: Scorpion toxins have been shown to rarely block human KCNQ1 channels, which participate in the regulation of cardiac processes. In this study, we obtained recombinant beta-KTx14.3 and TcoKIK toxins and determined their 3D structures by nuclear magnetic resonance. Electrophysiological studies and molecular dynamics models were employed to examine the interactions between these two toxins and the human KCNQ1, which is the major driver channel of cardiac repolarization; beta-KTx14.3 was found to block effectively this channel. Our findings provide insights for the development of novel toxin-based drugs for the treatment of cardiac channelopathies involving KCNQ1-like channels.
Collapse
Affiliation(s)
- Gustavo Titaux-Delgado
- Departamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, CU, Ciudad de México 04510, Mexico
| | - Andrea Estefanía Lopez-Giraldo
- Departamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, CU, Ciudad de México 04510, Mexico
| | - Elisa Carrillo
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center, Houston, TX 77030, USA
| | - Luis Fernando Cofas-Vargas
- Departamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, CU, Ciudad de México 04510, Mexico
| | - Luis Enrique Carranza
- Departamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, CU, Ciudad de México 04510, Mexico
| | - Estuardo López-Vera
- Laboratorio de Toxinología Marina, Unidad Académica de Ecología y Biodiversidad Acuática, Instituto de Ciencias del Mar y Limnología, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México 04510, Mexico
| | - Enrique García-Hernández
- Departamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, CU, Ciudad de México 04510, Mexico.
| | - Federico Del Rio-Portilla
- Departamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, CU, Ciudad de México 04510, Mexico.
| |
Collapse
|
|
13
|
Haddadi A, Farhadi P, Fatemi R, Mohamadynejad P, Moghanibashi M. Differential expression of KCNQ1 and ATP4A genes according to the sex and age in the stomach. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2023; 42:1019-1027. [PMID: 37367232 DOI: 10.1080/15257770.2023.2228371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 06/12/2023] [Accepted: 06/18/2023] [Indexed: 06/28/2023]
Abstract
We compared the expression of six genes in stomach tissue samples between healthy men and women in different age groups to study sexually dimorphic gene expression. Real-Time RT-PCR was used to compare gene expression between men and women. Our results showed that the expression of KCNQ1 (p = 0.01) was significantly higher in non-menopausal women compared to post-menopausal women. In addition, the expression level of the ATP4A gene in men under 35 years was significantly higher than in men above 50 (p = 0.026). Sexually and age dimorphic gene expression in some genes throughout life may affect gastric function.
Collapse
Affiliation(s)
- Azadeh Haddadi
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Pegah Farhadi
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Raziyeh Fatemi
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Parisa Mohamadynejad
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Mehdi Moghanibashi
- Department of Genetics, Faculty of Medicine, Kazerun Branch, Islamic Azad University, Kazerun, Iran
| |
Collapse
|
|
14
|
Satish H, Machireddy RR. Computational Study on Effect of KCNQ1 P535T Mutation in a Cardiac Ventricular Tissue. J Membr Biol 2023; 256:287-297. [PMID: 37166559 DOI: 10.1007/s00232-023-00287-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 04/20/2023] [Indexed: 05/12/2023]
Abstract
Heart diseases such as arrhythmia are the main causes of sudden death. Arrhythmias are typically caused by mutations in specific genes, damage in the cardiac tissue, or due to some chemical exposure. Arrhythmias caused due to mutation is called inherited arrhythmia. Induced arrhythmias are caused due to tissue damage or chemical exposure. Mutations in genes that encode ion channels of the cardiac cells usually result in (dysfunction) improper functioning of the channel. Improper functioning of the ion channel may lead to major changes in the action potential (AP) of the cardiac cells. This further leads to distorted electrical activity of the heart. Distorted electrical activity will affect the ECG that results in arrhythmia. KCNQ1 P535T mutation is one such gene mutation that encodes the potassium ion channel (KV7.1) of the cardiac ventricular tissue. Its clinical significance is not known. This study aims to perform a simulation study on P535T mutation in the KCNQ1 gene that encodes the potassium ion channel KV7.1 in the ventricular tissue grid. The effect of P535T mutation on transmural tissue grids for three genotypes (wild type, heterozygous, and homozygous) of cells are studied and the generated pseudo-ECGs are compared. Results show the delayed repolarization in the cells of ventricular tissue grid. Slower propagation of action potential in the transmural tissue grid is observed in the mutated (heterozygous and homozygous) genotypes. Longer QT interval is also observed in the pseudo-ECG of heterozygous and homozygous genotype tissue grids. From the pseudo-ECGs, it is observed that KCNQ1 P535T mutation leads to Long QT Syndrome (LQTS) which may result in life-threatening arrhythmias, such as Torsade de Pointes (TdP), Jervell and Lange-Nielsen syndrome (JLNS), and Romano-Ward syndrome (RWS).
Collapse
Affiliation(s)
- Helan Satish
- Department of Applied Mechanics and Biomedical Engineering, Indian Institute of Technology Madras, Chennai, India.
| | - Ramasubba Reddy Machireddy
- Department of Applied Mechanics and Biomedical Engineering, Indian Institute of Technology Madras, Chennai, India
| |
Collapse
|
|
15
|
Abrahamyan A, Eldstrom J, Sahakyan H, Karagulyan N, Mkrtchyan L, Karapetyan T, Sargsyan E, Kneussel M, Nazaryan K, Schwarz JR, Fedida D, Vardanyan V. Mechanism of external K+ sensitivity of KCNQ1 channels. J Gen Physiol 2023; 155:213880. [PMID: 36809486 PMCID: PMC9960071 DOI: 10.1085/jgp.202213205] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 12/20/2022] [Accepted: 01/31/2023] [Indexed: 02/23/2023] Open
Abstract
KCNQ1 voltage-gated K+ channels are involved in a wide variety of fundamental physiological processes and exhibit the unique feature of being markedly inhibited by external K+. Despite the potential role of this regulatory mechanism in distinct physiological and pathological processes, its exact underpinnings are not well understood. In this study, using extensive mutagenesis, molecular dynamics simulations, and single-channel recordings, we delineate the molecular mechanism of KCNQ1 modulation by external K+. First, we demonstrate the involvement of the selectivity filter in the external K+ sensitivity of the channel. Then, we show that external K+ binds to the vacant outermost ion coordination site of the selectivity filter inducing a diminution in the unitary conductance of the channel. The larger reduction in the unitary conductance compared to whole-cell currents suggests an additional modulatory effect of external K+ on the channel. Further, we show that the external K+ sensitivity of the heteromeric KCNQ1/KCNE complexes depends on the type of associated KCNE subunits.
Collapse
Affiliation(s)
- Astghik Abrahamyan
- Molecular Neuroscience Group, Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia , Yerevan, Armenia
| | - Jodene Eldstrom
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia , Vancouver, BC, Canada
| | - Harutyun Sahakyan
- Laboratory of Computational Modeling of Biological Processes, Institute of Molecular Biology of National Academy of Sciences of the Republic of Armenia , Yerevan, Armenia
| | - Nare Karagulyan
- Molecular Neuroscience Group, Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia , Yerevan, Armenia
| | - Liana Mkrtchyan
- Molecular Neuroscience Group, Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia , Yerevan, Armenia
| | - Tatev Karapetyan
- Molecular Neuroscience Group, Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia , Yerevan, Armenia
| | - Ernest Sargsyan
- Molecular Neuroscience Group, Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia , Yerevan, Armenia
| | - Matthias Kneussel
- Institute for Molecular Neurogenetics, Center for Molecular Neurobiology Hamburg , Hamburg, Germany
| | - Karen Nazaryan
- Laboratory of Computational Modeling of Biological Processes, Institute of Molecular Biology of National Academy of Sciences of the Republic of Armenia , Yerevan, Armenia
| | - Jürgen R Schwarz
- Institute for Molecular Neurogenetics, Center for Molecular Neurobiology Hamburg , Hamburg, Germany
| | - David Fedida
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia , Vancouver, BC, Canada
| | - Vitya Vardanyan
- Molecular Neuroscience Group, Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia , Yerevan, Armenia
| |
Collapse
|
|
16
|
Barro-Soria R. Sensing its own permeant ion: KCNQ1 channel inhibition by external K. J Gen Physiol 2023; 155:e202313337. [PMID: 36961346 PMCID: PMC10072219 DOI: 10.1085/jgp.202313337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2023] Open
Abstract
External potassium inhibits KCNQ1 channel through a mechanism involving increased occupancy of the filter S0 site by K+o.
Collapse
Affiliation(s)
- Rene Barro-Soria
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA
| |
Collapse
|
|
17
|
Fan W, Sun X, Yang C, Wan J, Luo H, Liao B. Pacemaker activity and ion channels in the sinoatrial node cells: MicroRNAs and arrhythmia. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 177:151-167. [PMID: 36450332 DOI: 10.1016/j.pbiomolbio.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 11/13/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022]
Abstract
The primary pacemaking activity of the heart is determined by a spontaneous action potential (AP) within sinoatrial node (SAN) cells. This unique AP generation relies on two mechanisms: membrane clocks and calcium clocks. Nonhomologous arrhythmias are caused by several functional and structural changes in the myocardium. MicroRNAs (miRNAs) are essential regulators of gene expression in cardiomyocytes. These miRNAs play a vital role in regulating the stability of cardiac conduction and in the remodeling process that leads to arrhythmias. Although it remains unclear how miRNAs regulate the expression and function of ion channels in the heart, these regulatory mechanisms may support the development of emerging therapies. This study discusses the spread and generation of AP in the SAN as well as the regulation of miRNAs and individual ion channels. Arrhythmogenicity studies on ion channels will provide a research basis for miRNA modulation as a new therapeutic target.
Collapse
Affiliation(s)
- Wei Fan
- Department of Cardiovascular Surgery, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China
| | - Xuemei Sun
- Department of Pharmacy, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China
| | - Chao Yang
- Department of Cardiovascular Surgery, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China
| | - Juyi Wan
- Department of Cardiovascular Surgery, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China.
| | - Hongli Luo
- Department of Pharmacy, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China.
| | - Bin Liao
- Department of Cardiovascular Surgery, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China.
| |
Collapse
|
|
18
|
Dixit G, Stowe RB, Bates A, Jaycox CK, Escobar JR, Harding BD, Drew DL, New CP, Sahu ID, Edelmann RE, Dabney-Smith C, Sanders CR, Lorigan GA. Purification and membrane interactions of human KCNQ1 100-370 potassium ion channel. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2022; 1864:184010. [PMID: 35870481 PMCID: PMC11524546 DOI: 10.1016/j.bbamem.2022.184010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 07/12/2022] [Accepted: 07/14/2022] [Indexed: 06/15/2023]
Abstract
KCNQ1 (Kv7.1 or KvLQT1) is a voltage-gated potassium ion channel that is involved in the ventricular repolarization following an action potential in the heart. It forms a complex with KCNE1 in the heart and is the pore forming subunit of slow delayed rectifier potassium current (Iks). Mutations in KCNQ1, leading to a dysfunctional channel or loss of activity have been implicated in a cardiac disorder, long QT syndrome. In this study, we report the overexpression, purification, biochemical characterization of human KCNQ1100-370, and lipid bilayer dynamics upon interaction with KCNQ1100-370. The recombinant human KCNQ1 was expressed in Escherichia coli and purified into n-dodecylphosphocholine (DPC) micelles. The purified KCNQ1100-370 was biochemically characterized by SDS-PAGE electrophoresis, western blot and nano-LC-MS/MS to confirm the identity of the protein. Circular dichroism (CD) spectroscopy was utilized to confirm the secondary structure of purified protein in vesicles. Furthermore, 31P and 2H solid-state NMR spectroscopy in DPPC/POPC/POPG vesicles (MLVs) indicated a direct interaction between KCNQ100-370 and the phospholipid head groups. Finally, a visual inspection of KCNQ1100-370 incorporated into MLVs was confirmed by transmission electron microscopy (TEM). The findings of this study provide avenues for future structural studies of the human KCNQ1 ion channel to have an in depth understanding of its structure-function relationship.
Collapse
Affiliation(s)
- Gunjan Dixit
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA; Cell, Molecular and Structural Biology Program, Department of Chemistry & Biochemistry, Miami University, Oxford, OH 45056, USA
| | - Rebecca B Stowe
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA
| | - Alison Bates
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA
| | - Colleen K Jaycox
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA
| | - Jorge R Escobar
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA; Cell, Molecular and Structural Biology Program, Department of Chemistry & Biochemistry, Miami University, Oxford, OH 45056, USA
| | - Benjamin D Harding
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA
| | - Daniel L Drew
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA
| | - Christopher P New
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA; Cell, Molecular and Structural Biology Program, Department of Chemistry & Biochemistry, Miami University, Oxford, OH 45056, USA
| | - Indra D Sahu
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA
| | - Richard E Edelmann
- Center for Advanced Microscopy and Imaging, Miami University, Oxford, OH 45056, USA
| | - Carole Dabney-Smith
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA; Cell, Molecular and Structural Biology Program, Department of Chemistry & Biochemistry, Miami University, Oxford, OH 45056, USA
| | - Charles R Sanders
- Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA
| | - Gary A Lorigan
- Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH 45056, USA; Cell, Molecular and Structural Biology Program, Department of Chemistry & Biochemistry, Miami University, Oxford, OH 45056, USA.
| |
Collapse
|
|
19
|
Pan J, Purev C, Zhao H, Zhang Z, Wang F, Wendoule N, Qi G, Liu Y, Zhou H. Discovery of exercise-related genes and pathway analysis based on comparative genomes of Mongolian originated Abaga and Wushen horse. Open Life Sci 2022; 17:1269-1281. [PMID: 36249530 PMCID: PMC9518662 DOI: 10.1515/biol-2022-0487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/21/2022] [Accepted: 07/28/2022] [Indexed: 11/17/2022] Open
Abstract
The Mongolian horses have excellent endurance and stress resistance to adapt to the cold and harsh plateau conditions. Intraspecific genetic diversity is mainly embodied in various genetic advantages of different branches of the Mongolian horse. Since people pay progressive attention to the athletic performance of horse, we expect to guide the exercise-oriented breeding of horses through genomics research. We obtained the clean data of 630,535,376,400 bp through the entire genome second-generation sequencing for the whole blood of four Abaga horses and ten Wushen horses. Based on the data analysis of single nucleotide polymorphism, we severally detected that 479 and 943 positively selected genes, particularly exercise related, were mainly enriched on equine chromosome 4 in Abaga horses and Wushen horses, which implied that chromosome 4 may be associated with the evolution of the Mongolian horse and athletic performance. Four hundred and forty genes of positive selection were enriched in 12 exercise-related pathways and narrowed in 21 exercise-related genes in Abaga horse, which were distinguished from Wushen horse. So, we speculated that the Abaga horse may have oriented genes for the motorial mechanism and 21 exercise-related genes also provided a molecular genetic basis for exercise-directed breeding of the Mongolian horse.
Collapse
Affiliation(s)
- Jing Pan
- Faculty of Life Sciences, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia Autonomous Region, People’s Republic of China
- Department of Reproductive Medicine, Inner Mongolia Maternal and Child Health Care Hospitaly, Hohhot, Inner Mongolia Autonomous Region, People’s Republic of China
| | - Chimge Purev
- Mongolia-China Joint Laboratory of Applied Molecular Biology, “Administration of the Science Park” CSTI, Ulaanbaatar, Mongolia
| | - Hongwei Zhao
- Beijing 8omics Gene Technology Co. Ltd, Beijing, People’s Republic of China
| | - Zhipeng Zhang
- Faculty of Life Sciences, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia Autonomous Region, People’s Republic of China
| | - Feng Wang
- Faculty of Life Sciences, Nankai University, Tianjin, People’s Republic of China
| | - Nashun Wendoule
- Animal Husbandry Workstation of Ewenki Autonomous County, Hulun Buir, Inner Mongolia Autonomous Region, People’s Republic of China
| | - Guichun Qi
- Bayanta Village of Animal Husbandry and Veterinary Station of Ewenki Autonomous County, Hulun Buir, Inner Mongolia Autonomous Region, People’s Republic of China
| | - Yongbin Liu
- Sheep Collaboration and Innovation Center, Inner Mongolia Universityy, Hohhot, Inner Mongolia Autonomous Region, People’s Republic of China
| | - Huanmin Zhou
- Faculty of Life Sciences, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia Autonomous Region, People’s Republic of China
- Sheep Collaboration and Innovation Center, Inner Mongolia Universityy, Hohhot, Inner Mongolia Autonomous Region, People’s Republic of China
| |
Collapse
|
|
20
|
Winbo A, Diamant U, Persson J, Jensen SM, Rydberg A. To Modify or Not to Modify: Allele‐Specific Effects of 3'UTR‐
KCNQ1
Single Nucleotide Polymorphisms on Clinical Phenotype in a Long QT 1 Founder Population Segregating a Dominant‐Negative Mutation. J Am Heart Assoc 2022; 11:e025981. [DOI: 10.1161/jaha.122.025981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background
There are conflicting reports with regard to the allele‐specific gene suppression effects of single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of the
KCNQ1
gene in long QT syndrome type 1 (LQT1) populations. Here we assess the allele‐specific effects of 3 previously published 3'UTR‐
KCNQ1
's SNPs in a LQT1 founder population segregating a dominant‐negative mutation.
Methods and Results
Bidirectional sequencing of the
KCNQ1
'
s
3'UTR was performed in the p.Y111C founder population (n=232, 147 genotype positive), with a minor allele frequency of 0.1 for SNP1 (rs2519184) and 0.6 for linked SNP2 (rs8234) and SNP3 (rs107980). Allelic phase was assessed in trios aided by haplotype data, revealing a high prevalence of derived SNP2/3
in cis
with p.Y111C (89%). Allele‐specific association analyses, corrected using a relatedness matrix, were performed between 3'UTR‐
KCNQ1
SNP genotypes and clinical phenotypes. SNP1
in trans
was associated with a significantly higher proportion of symptomatic phenotype compared with no derived SNP1 allele
in trans
(58% versus 32%, corrected
P
=0.027). SNP2/3
in cis
was associated with a significantly lower proportion of symptomatic phenotype compared with no derived SNP2/3 allele
in cis
(32% versus 69%, corrected
P
=0.010).
Conclusions
Allele‐specific modifying effects on symptomatic phenotype of 3'UTR‐
KCNQ1
SNPs rs2519184, rs8234, and rs107980 were seen in a LQT1 founder population segregating a dominant‐negative mutation. The high prevalence of suppressive 3'UTR‐
KCNQ1
SNPs segregating with the founder mutation could contribute to the previously documented low incidence of cardiac events in heterozygous carriers of the p.Y111C
KCNQ1
mutation.
Collapse
Affiliation(s)
- Annika Winbo
- Department of Clinical Sciences, Pediatrics Umeå University Umeå Sweden
- Department of Physiology University of Auckland Auckland New Zealand
| | - Ulla‐Britt Diamant
- Department of Public Health and Clinical Medicine Heart Centre, Umeå University Umeå Sweden
| | - Johan Persson
- Department of Clinical Sciences, Pediatrics Umeå University Umeå Sweden
| | - Steen M. Jensen
- Department of Public Health and Clinical Medicine Heart Centre, Umeå University Umeå Sweden
| | - Annika Rydberg
- Department of Clinical Sciences, Pediatrics Umeå University Umeå Sweden
| |
Collapse
|
|
21
|
Liu LX, Gu RR, Jin Y, Chen XQ, Li XW, Zheng YM, Gao ZB, Guo YW. Diversity-oriented synthesis of marine polybrominated diphenyl ethers as potential KCNQ potassium channel activators. Bioorg Chem 2022; 126:105909. [DOI: 10.1016/j.bioorg.2022.105909] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/03/2022] [Accepted: 05/22/2022] [Indexed: 01/10/2023]
|
|
22
|
Ma GC, Chen TH, Wu WJ, Lee DJ, Lin WH, Chen M. Proposal for Practical Approach in Prenatal Diagnosis of Beckwith–Wiedemann Syndrome and Review of the Literature. Diagnostics (Basel) 2022; 12:diagnostics12071709. [PMID: 35885613 PMCID: PMC9315620 DOI: 10.3390/diagnostics12071709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 07/07/2022] [Accepted: 07/12/2022] [Indexed: 01/08/2023] Open
Abstract
Background: Beckwith–Wiedemann syndrome (BWS) is a phenotypically and genetically heterogeneous disorder associated with epigenetic/genetic aberrations on chromosome 11p15.4p15.5. There is no consensus criterion for prenatal diagnosis of BWS. Methods: Three BWS patients with their clinical histories, prenatal ultrasonographic features, and results of molecular diagnosis were presented. Likewise, by incorporating the findings of our cases and literature review, the phenotypic spectrum and genotype–phenotype correlations of fetal BWS were summarized, and a practical approach in prenatal diagnosis of BWS was proposed. Results: A total of 166 BWS cases with prenatal features were included for analysis. Common fetal features include abdominal wall defects (42.8%), polyhydramnios (33.1%), and macrosomia (32.5%). Molecular pathologies include methylation changes in imprinting control region 1 and 2 (ICR1 and ICR2), paternal uniparental disomy of chromosome 11p15.5, copy number change involving 11p15, etc. Some genotype–phenotype correlations were observed. However, the broad phenotypic spectrum but limited features manifested by affected fetuses rendering ultrasonographic diagnosis not easy. Conclusions: Molecular tests are used for prenatal diagnosis of BWS suspected by ultrasonography. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is recommended as the first-line molecular tool because it simultaneously detects ICR1/ICR2 methylation statuses and copy numbers that solve the majority of clinical cases in the prenatal scenario.
Collapse
Affiliation(s)
- Gwo-Chin Ma
- Department of Genomic Medicine and Center for Medical Genetics, Changhua Christian Hospital, Changhua 50046, Taiwan; (G.-C.M.); (W.-J.W.)
- Research Department, Changhua Christian Hospital, Changhua 50006, Taiwan;
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung 40601, Taiwan
| | - Tze-Ho Chen
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua 50006, Taiwan;
| | - Wan-Ju Wu
- Department of Genomic Medicine and Center for Medical Genetics, Changhua Christian Hospital, Changhua 50046, Taiwan; (G.-C.M.); (W.-J.W.)
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua 50006, Taiwan;
| | - Dong-Jay Lee
- Research Department, Changhua Christian Hospital, Changhua 50006, Taiwan;
| | - Wen-Hsiang Lin
- Welgene Biotechnology Company, Nangang Business Park, Taipei 11560, Taiwan;
| | - Ming Chen
- Department of Genomic Medicine and Center for Medical Genetics, Changhua Christian Hospital, Changhua 50046, Taiwan; (G.-C.M.); (W.-J.W.)
- Research Department, Changhua Christian Hospital, Changhua 50006, Taiwan;
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua 50006, Taiwan;
- Department of Medical Genetics, National Taiwan University Hospital, Taipei 10041, Taiwan
- Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei 10041, Taiwan
- Department of Medical Science, National Tsing Hua University, Hsinchu 30013, Taiwan
- Department of Biomedical Science, Da-Yeh University, Changhua 51591, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan
- Correspondence: or ; Tel.: +886-4722-5121 (ext. 2323)
| |
Collapse
|
|
23
|
Edmond MA, Hinojo-Perez A, Wu X, Perez Rodriguez ME, Barro-Soria R. Distinctive mechanisms of epilepsy-causing mutants discovered by measuring S4 movement in KCNQ2 channels. eLife 2022; 11:77030. [PMID: 35642783 PMCID: PMC9197397 DOI: 10.7554/elife.77030] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/31/2022] [Indexed: 01/10/2023] Open
Abstract
Neuronal KCNQ channels mediate the M-current, a key regulator of membrane excitability in the central and peripheral nervous systems. Mutations in KCNQ2 channels cause severe neurodevelopmental disorders, including epileptic encephalopathies. However, the impact that different mutations have on channel function remains poorly defined, largely because of our limited understanding of the voltage-sensing mechanisms that trigger channel gating. Here, we define the parameters of voltage sensor movements in wt-KCNQ2 and channels bearing epilepsy-associated mutations using cysteine accessibility and voltage clamp fluorometry (VCF). Cysteine modification reveals that a stretch of eight to nine amino acids in the S4 becomes exposed upon voltage sensing domain activation of KCNQ2 channels. VCF shows that the voltage dependence and the time course of S4 movement and channel opening/closing closely correlate. VCF reveals different mechanisms by which different epilepsy-associated mutations affect KCNQ2 channel voltage-dependent gating. This study provides insight into KCNQ2 channel function, which will aid in uncovering the mechanisms underlying channelopathies.
Collapse
Affiliation(s)
- Michaela A Edmond
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, United States
| | - Andy Hinojo-Perez
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, United States
| | - Xiaoan Wu
- Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United States
| | - Marta E Perez Rodriguez
- Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United States
| | - Rene Barro-Soria
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, United States
| |
Collapse
|
|
24
|
Singh SP, William M, Malavia M, Chu XP. Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders. MEMBRANES 2022; 12:membranes12050499. [PMID: 35629827 PMCID: PMC9143857 DOI: 10.3390/membranes12050499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/26/2022] [Accepted: 05/03/2022] [Indexed: 02/01/2023]
Abstract
The broad distribution of voltage-gated potassium channels (VGKCs) in the human body makes them a critical component for the study of physiological and pathological function. Within the KCNQ family of VGKCs, these aqueous conduits serve an array of critical roles in homeostasis, especially in neural tissue. Moreover, the greater emphasis on genomic identification in the past century has led to a growth in literature on the role of the ion channels in pathological disease as well. Despite this, there is a need to consolidate the updated findings regarding both the pharmacotherapeutic and pathological roles of KCNQ channels, especially regarding neural plasticity and motor disorders which have the largest body of literature on this channel. Specifically, KCNQ channels serve a remarkable role in modulating the synaptic efficiency required to create appropriate plasticity in the brain. This role can serve as a foundation for clinical approaches to chronic pain. Additionally, KCNQ channels in motor disorders have been utilized as a direction for contemporary pharmacotherapeutic developments due to the muscarinic properties of this channel. The aim of this study is to provide a contemporary review of the behavior of these channels in neural plasticity and motor disorders. Upon review, the behavior of these channels is largely dependent on the physiological role that KCNQ modulatory factors (i.e., pharmacotherapeutic options) serve in pathological diseases.
Collapse
|
|
25
|
Haverinen J, Hassinen M, Vornanen M. Effect of Channel Assembly (KCNQ1 or KCNQ1 + KCNE1) on the Response of Zebrafish IKs Current to IKs Inhibitors and Activators. J Cardiovasc Pharmacol 2022; 79:670-677. [PMID: 35377576 DOI: 10.1097/fjc.0000000000001230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/15/2022] [Indexed: 11/26/2022]
Abstract
ABSTRACT In cardiac myocytes, the slow component of the delayed rectifier K+ current (IKs) ensures repolarization of action potential during beta-adrenergic activation or when other repolarizing K+ currents fail. As a key factor of cardiac repolarization, IKs should be present in model species used for cardiovascular drug screening, preferably with pharmacological characteristics similar to those of the human IKs. To this end, we investigated the effects of inhibitors and activators of the IKs on KCNQ1 and KCNQ1 + KCNE1 channels of the zebrafish, an important model species, in Chinese hamster ovary cells. Inhibitors of IKs, chromanol 293B and HMR-1556, inhibited zebrafish IKs channels with approximately similar potency as that of mammalian IKs. Chromanol 293B concentration for half-maximal inhibition (IC50) of zebrafish IKs was at 13.1 ± 5.8 and 13.4 ± 2.8 µM for KCNQ1 and KCNQ1+KCNE1 channels, respectively. HMR-1556 was a more potent inhibitor of zebrafish IKs channels with IC50 = 0.1 ± 0.1 µM and 1.5 ± 0.8 µM for KCNQ1 and KCNQ1 + KCNE1 channels, respectively. R-L3 and mefenamic acid, generally identified as IKs activators, both inhibited zebrafish IKs. R-L3 almost completely inhibited the current generated by KCNQ1 and KCNQ1 + KCNE1 channels with similar potency (IC50 1.1 ± 0.4 and 1.0 ± 0.4 µM, respectively). Mefenamic acid partially blocked zebrafish KCNQ1 (IC50 = 9.5 ± 4.8 µM) and completely blocked KCNQ1 + KCNE1 channels (IC50 = 3.3 ± 1.8 µM). Although zebrafish IKs channels respond to IKs inhibitors in the same way as mammalian IKs channels, their response to activators is atypical, probably because of the differences in the binding domain of KCNE1 to KCNQ1. Therefore, care must be taken when translating the results from zebrafish to humans.
Collapse
Affiliation(s)
- Jaakko Haverinen
- Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland
| | | | | |
Collapse
|
|
26
|
Associations between KCNQ1 and ITIH4 gene polymorphisms and infant weight gain in early life. Pediatr Res 2022; 91:1290-1295. [PMID: 34247200 DOI: 10.1038/s41390-021-01601-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 04/17/2021] [Accepted: 05/20/2021] [Indexed: 11/08/2022]
Abstract
BACKGROUND An earlier meta-analysis of genome-wide association studies in Asian populations detected five novel body mass index-associated single-nucleotide polymorphisms (SNPs), including potassium voltage-gated channel subfamily Q member 1 (KCNQ1) (rs2237892), ALDH2/MYL2 (rs671, rs12229654), ITIH4 (rs2535633), and NT5C2 (rs11191580). Whether these SNPs take effect in early life, for example, affect infant rapid weight gain (RWG), is unclear. METHODS We obtained genomic DNA from 460 term infants with normal birth weight. RWG was defined as the change of weight-for-age standardized Z-score, calculated according to the Children Growth Standard released by the World Health Organization, from birth to 3 months of age >0.67. Using genetic models, associations between the candidate SNPs and infant RWG were examined, along with the interaction between the SNPs and the potential risk factors. RESULTS RWG was presented in 225 of 460 infants. SNP rs2535633 and rs2237892 were associated with the risk of RWG. Both additive and multiplicative interaction effects were found between infant delivery mode and rs2237892. The negative association between the rs2237892 T allele and infant RWG was only observed in vaginally delivered infants. CONCLUSIONS Obesity-related loci rs2535633 and rs2237892 are associated with infant RWG in the first 3 months of infancy. The relationship between rs2237892 and infant RGW might be moderated by cesarean delivery. IMPACT Genetic predisposition is an essential aspect to understand infant weight gain. Obesity-related SNPs, rs2535633 and rs2237892, are associated with RWG in very early years of life. The negative association between rs2237892 T allele and RWG is only observed in infants delivered vaginally instead of cesarean section.
Collapse
|
|
27
|
A benzodiazepine activator locks K v7.1 channels open by electro-mechanical uncoupling. Commun Biol 2022; 5:301. [PMID: 35365746 PMCID: PMC8976019 DOI: 10.1038/s42003-022-03229-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 02/22/2022] [Indexed: 01/18/2023] Open
Abstract
Loss-of-function mutations in Kv7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with arrhythmia and subsequent sudden cardiac death. The discovery of agonistic IKs modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine derivative (R)-L3 potently activates Kv7.1 channels and shortens action potential duration, thus may represent a starting point for drug development. However, the molecular mechanisms underlying modulation by (R)-L3 are still unknown. By combining alanine scanning mutagenesis, non-canonical amino acid incorporation, voltage-clamp electrophysiology and fluorometry, and in silico protein modelling, we show that (R)-L3 not only stimulates currents by allosteric modulation of the pore domain but also alters the kinetics independently from the pore domain effects. We identify novel (R)-L3-interacting key residues in the lower S4-segment of Kv7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments.
Collapse
|
|
28
|
Genomics and Epigenomics of Gestational Diabetes Mellitus: Understanding the Molecular Pathways of the Disease Pathogenesis. Int J Mol Sci 2022; 23:ijms23073514. [PMID: 35408874 PMCID: PMC8998752 DOI: 10.3390/ijms23073514] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/01/2022] [Accepted: 03/04/2022] [Indexed: 11/16/2022] Open
Abstract
One of the most common complications during pregnancy is gestational diabetes mellitus (GDM), hyperglycemia that occurs for the first time during pregnancy. The condition is multifactorial, caused by an interaction between genetic, epigenetic, and environmental factors. However, the underlying mechanisms responsible for its pathogenesis remain elusive. Moreover, in contrast to several common metabolic disorders, molecular research in GDM is lagging. It is important to recognize that GDM is still commonly diagnosed during the second trimester of pregnancy using the oral glucose tolerance test (OGGT), at a time when both a fetal and maternal pathophysiology is already present, demonstrating the increased blood glucose levels associated with exacerbated insulin resistance. Therefore, early detection of metabolic changes and associated epigenetic and genetic factors that can lead to an improved prediction of adverse pregnancy outcomes and future cardio-metabolic pathologies in GDM women and their children is imperative. Several genomic and epigenetic approaches have been used to identify the genes, genetic variants, metabolic pathways, and epigenetic modifications involved in GDM to determine its etiology. In this article, we explore these factors as well as how their functional effects may contribute to immediate and future pathologies in women with GDM and their offspring from birth to adulthood. We also discuss how these approaches contribute to the changes in different molecular pathways that contribute to the GDM pathogenesis, with a special focus on the development of insulin resistance.
Collapse
|
|
29
|
Almansoori A, Bhamidimarri PM, Bendardaf R, Hamoudi R. In silico Analysis of Publicly Available Transcriptomics Data Identifies Putative Prognostic and Therapeutic Molecular Targets for Papillary Thyroid Carcinoma. Int J Gen Med 2022; 15:3097-3120. [PMID: 35330879 PMCID: PMC8939872 DOI: 10.2147/ijgm.s345336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 02/25/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Thyroid cancer is the most common endocrine malignancy. However, the molecular mechanism involved in its pathogenesis is not well characterized. PURPOSE The objective of this study is to identify key cellular pathways and differentially expressed genes along the thyroid cancer pathogenesis sequence as well as to identify potential prognostic and therapeutic targets. METHODS Publicly available transcriptomics data comprising a total of 95 samples consisting of 41 normal, 28 non-aggressive and 26 metastatic papillary thyroid carcinoma (PTC) cases were used. Transcriptomics data were normalized and filtered identifying 9394 differentially expressed genes. The genes identified were subjected to pathway analysis using absGSEA identifying PTC related pathways. Three of the genes identified were validated on 508 thyroid cancer biopsies using RNAseq and TNMplot. RESULTS Pathway analysis revealed a total of 2193 differential pathways among non-aggressive samples and 1969 among metastatic samples compared to normal tissue. Pathways for non-aggressive PTC include calcium and potassium ion transport, hormone signaling, protein tyrosine phosphatase activity and protein tyrosine kinase activity. Metastatic pathways include growth, apoptosis, activation of MAPK and regulation of serine threonine kinase activity. Genes for non-aggressive are KCNQ1, CACNA1D, KCNN4, BCL2, and PTK2B and metastatic PTC are EGFR, PTK2B, KCNN4 and BCL2. Three of the genes identified were validated using clinical biopsies showing significant overexpression in aggressive compared to non-aggressive PTC; EGFR (p < 0.05), KCNN4 (p < 0.001) and PTK2B (p < 0.001). DrugBank database search identified several FDA approved drug targets including anti-EGFR Vandetanib used to treat thyroid cancer in addition to others that may prove useful in treating PTC. CONCLUSION Transcriptomics analysis identified putative prognostic targets including EGFR, PTK2B, BCL2, KCNQ1, KCNN4 and CACNA1D. EGFR, PTK2B and KCN44 were validated using thyroid cancer clinical biopsies. The drug search identified FDA approved drugs including Vandetanib in addition to others that may prove useful in treating the disease.
Collapse
Affiliation(s)
- Asma Almansoori
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | | | - Riyad Bendardaf
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Department of Oncology, University Hospital Sharjah, Sharjah, United Arab Emirates
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London, UK
| |
Collapse
|
|
30
|
Lubberding AF, Juhl CR, Skovhøj EZ, Kanters JK, Mandrup‐Poulsen T, Torekov SS. Celebrities in the heart, strangers in the pancreatic beta cell: Voltage-gated potassium channels K v 7.1 and K v 11.1 bridge long QT syndrome with hyperinsulinaemia as well as type 2 diabetes. Acta Physiol (Oxf) 2022; 234:e13781. [PMID: 34990074 PMCID: PMC9286829 DOI: 10.1111/apha.13781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 12/20/2021] [Accepted: 01/02/2022] [Indexed: 12/13/2022]
Abstract
Voltage‐gated potassium (Kv) channels play an important role in the repolarization of a variety of excitable tissues, including in the cardiomyocyte and the pancreatic beta cell. Recently, individuals carrying loss‐of‐function (LoF) mutations in KCNQ1, encoding Kv7.1, and KCNH2 (hERG), encoding Kv11.1, were found to exhibit post‐prandial hyperinsulinaemia and episodes of hypoglycaemia. These LoF mutations also cause the cardiac disorder long QT syndrome (LQTS), which can be aggravated by hypoglycaemia. Interestingly, patients with LQTS also have a higher burden of diabetes compared to the background population, an apparent paradox in relation to the hyperinsulinaemic phenotype, and KCNQ1 has been identified as a type 2 diabetes risk gene. This review article summarizes the involvement of delayed rectifier K+ channels in pancreatic beta cell function, with emphasis on Kv7.1 and Kv11.1, using the cardiomyocyte for context. The functional and clinical consequences of LoF mutations and polymorphisms in these channels on blood glucose homeostasis are explored using evidence from pre‐clinical, clinical and genome‐wide association studies, thereby evaluating the link between LQTS, hyperinsulinaemia and type 2 diabetes.
Collapse
Affiliation(s)
- Anniek F. Lubberding
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Christian R. Juhl
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Emil Z. Skovhøj
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Jørgen K. Kanters
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Thomas Mandrup‐Poulsen
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Signe S. Torekov
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| |
Collapse
|
|
31
|
Olgar Y, Durak A, Bitirim CV, Tuncay E, Turan B. Insulin acts as an atypical KCNQ1/KCNE1-current activator and reverses long QT in insulin-resistant aged rats by accelerating the ventricular action potential repolarization through affecting the β 3 -adrenergic receptor signaling pathway. J Cell Physiol 2021; 237:1353-1371. [PMID: 34632595 DOI: 10.1002/jcp.30597] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 09/22/2021] [Accepted: 09/24/2021] [Indexed: 12/13/2022]
Abstract
Insufficient-heart function is associated with myocardial insulin resistance in the elderly, particularly associated with long-QT, in a dependency on dysfunctional KCNQ1/KCNE1-channels. So, we aimed to examine the contribution of alterations in KCNQ1/KCNE1-current (IKs ) to the aging-related remodeling of the heart as well as the role of insulin treatment on IKs in the aged rats. Prolonged late-phase action potential (AP) repolarization of ventricular cardiomyocytes from insulin-resistant 24-month-old rats was significantly reversed by in vitro treatment of insulin or PKG inhibitor (in vivo, as well) via recovery in depressed IKs . Although the protein level of either KCNQ1 or KCNE1 in cardiomyocytes was not affected with aging, PKG level was significantly increased in those cells. The inhibited IKs in β3 -ARs-stimulated cells could be reversed with a PKG inhibitor, indicating the correlation between PKG-activation and β3 -ARs activation. Furthermore, in vivo treatment of aged rats, characterized by β3 -ARs activation, with either insulin or a PKG inhibitor for 2 weeks provided significant recoveries in IKs , prolonged late phases of APs, prolonged QT-intervals, and low heart rates without no effect on insulin resistance. In vivo insulin treatment provided also significant recovery in increased PKG and decreased PIP2 level, without the insulin effect on the KCNQ1 level in β3 -ARs overexpressed cells. The inhibition of IKs in aged-rat cardiomyocytes seems to be associated with activated β3 -ARs dependent remodeling in the interaction between KCNQ1 and KCNE1. Significant recoveries in ventricular-repolarization of insulin-treated aged cardiomyocytes via recovery in IKs strongly emphasize two important issues: (1) IKs can be a novel target in aging-associated remodeling in the heart and insulin may be a cardioprotective agent in the maintenance of normal heart function during the aging process. (2) This study is one of the first to demonstrate insulin's benefits on long-QT in insulin-resistant aged rats by accelerating the ventricular AP repolarization through reversing the depressed IKs via affecting the β3 -ARs signaling pathway and particularly affecting activated PKG.
Collapse
Affiliation(s)
- Yusuf Olgar
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Aysegul Durak
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | | | - Erkan Tuncay
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Belma Turan
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey.,Department of Biophysics, Faculty of Medicine, Lokman Hekim University, Ankara, Turkey
| |
Collapse
|
|
32
|
Kacher YG, Karlova MG, Glukhov GS, Zhang H, Zaklyazminskaya EV, Loussouarn G, Sokolova OS. The Integrative Approach to Study of the Structure and Functions of Cardiac Voltage-Dependent Ion Channels. CRYSTALLOGR REP+ 2021. [DOI: 10.1134/s1063774521050072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
|
|
33
|
Winbo A, Ramanan S, Eugster E, Rydberg A, Jovinge S, Skinner JR, Montgomery JM. Functional hyperactivity in long QT syndrome type 1 pluripotent stem cell-derived sympathetic neurons. Am J Physiol Heart Circ Physiol 2021; 321:H217-H227. [PMID: 34142889 DOI: 10.1152/ajpheart.01002.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Sympathetic activation is an established trigger of life-threatening cardiac events in long QT syndrome type 1 (LQT1). KCNQ1 loss-of-function variants, which underlie LQT1, have been associated with both cardiac arrhythmia and neuronal hyperactivity pathologies. However, the LQT1 sympathetic neuronal phenotype is unknown. Here, we aimed to study human induced pluripotent stem cell (hiPSC)-derived sympathetic neurons (SNs) to evaluate neuronal functional phenotype in LQT1. We generated hiPSC-SNs from two patients with LQT1 with a history of sympathetically triggered arrhythmia and KCNQ1 loss-of-function genotypes (c.781_782delinsTC and p.S349W/p.R518X). Characterization of hiPSC-SNs was performed using immunohistochemistry, enzyme-linked immunosorbent assay, and whole cell patch clamp electrophysiology, and functional LQT1 hiPSC-SN phenotypes compared with healthy control (WT) hiPSC-SNs. hiPSC-SNs stained positive for tyrosine hydroxylase, peripherin, KCNQ1, and secreted norepinephrine. hiPSC-SNs at 60 ± 2.2 days in vitro had healthy resting membrane potentials (-60 ± 1.3 mV), and fired rapid action potentials with mature kinetics in response to stimulation. Significant hyperactivity in LQT1 hiPSC-SNs was evident via increased norepinephrine release, increased spontaneous action potential frequency, increased total inward current density, and reduced afterhyperpolarization, compared with age-matched WT hiPSC-SNs. A significantly higher action potential frequency upon current injection and larger synaptic current amplitudes in compound heterozygous p.S349W/p.R518X hiPSC-SNs compared with heterozygous c.781_782delinsTC hiPSC-SNs was also observed, suggesting a potential genotype-phenotype correlation. Together, our data reveal increased neurotransmission and excitability in heterozygous and compound heterozygous patient-derived LQT1 sympathetic neurons, suggesting that the cellular arrhythmogenic potential in LQT1 is not restricted to cardiomyocytes.NEW & NOTEWORTHY Here, we present the first study of patient-derived LQT1 sympathetic neurons that are norepinephrine secreting, and electrophysiologically functional, in vitro. Our data reveal a novel LQT1 sympathetic neuronal phenotype of increased neurotransmission and excitability. The identified sympathetic neuronal hyperactivity phenotype is of particular relevance as it could contribute to the mechanisms underlying sympathetically triggered arrhythmia in LQT1.
Collapse
Affiliation(s)
- Annika Winbo
- Department of Physiology, University of Auckland, Auckland, New Zealand.,Manaaki Mānawa Centre for Heart Research, University of Auckland, Auckland, New Zealand.,Department of Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand.,The Cardiac Inherited Disease Group (CIDG), Auckland, New Zealand.,Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden
| | - Suganeya Ramanan
- Department of Physiology, University of Auckland, Auckland, New Zealand.,Manaaki Mānawa Centre for Heart Research, University of Auckland, Auckland, New Zealand
| | - Emily Eugster
- DeVos Cardiovascular Research Program Spectrum Health/Van Andel Research Institute, Grand Rapids, Michigan
| | - Annika Rydberg
- Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden
| | - Stefan Jovinge
- DeVos Cardiovascular Research Program Spectrum Health/Van Andel Research Institute, Grand Rapids, Michigan.,Cardiovascular Institute, Stanford University of Medicine, Stanford, California
| | - Jonathan R Skinner
- Manaaki Mānawa Centre for Heart Research, University of Auckland, Auckland, New Zealand.,Department of Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand.,The Cardiac Inherited Disease Group (CIDG), Auckland, New Zealand
| | - Johanna M Montgomery
- Department of Physiology, University of Auckland, Auckland, New Zealand.,Manaaki Mānawa Centre for Heart Research, University of Auckland, Auckland, New Zealand
| |
Collapse
|
|
34
|
Lubberding AF, Zhang J, Lundh M, Nielsen TS, Søndergaard MS, Villadsen M, Skovhøj EZ, Boer GA, Hansen JB, Thomsen MB, Treebak JT, Holst JJ, Kanters JK, Mandrup-Poulsen T, Jespersen T, Emanuelli B, Torekov SS. Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V. Sci Rep 2021; 11:12253. [PMID: 34112814 PMCID: PMC8192901 DOI: 10.1038/s41598-021-90452-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 05/05/2021] [Indexed: 11/24/2022] Open
Abstract
Loss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K+ channel Kv7.1, lead to long QT syndrome 1 (LQT1). LQT1 patients also present with post-prandial hyperinsulinemia and hypoglycaemia. In contrast, KCNQ1 polymorphisms are associated with diabetes, and LQTS patients have a higher prevalence of diabetes. We developed a mouse model with a LoF Kcnq1 mutation using CRISPR-Cas9 and hypothesized that this mouse model would display QT prolongation, increased glucose-stimulated insulin secretion and allow for interrogation of Kv7.1 function in islets. Mice were characterized by electrocardiography and oral glucose tolerance tests. Ex vivo, islet glucose-induced insulin release was measured, and beta-cell area quantified by immunohistochemistry. Homozygous mice had QT prolongation. Ex vivo, glucose-stimulated insulin release was increased in islets from homozygous mice at 12–14 weeks, while beta-cell area was reduced. Non-fasting blood glucose levels were decreased at this age. In follow-up studies 8–10 weeks later, beta-cell area was similar in all groups, while glucose-stimulated insulin secretion was now reduced in islets from hetero- and homozygous mice. Non-fasting blood glucose levels had normalized. These data suggest that Kv7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.
Collapse
Affiliation(s)
- Anniek F Lubberding
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Jinyi Zhang
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Morten Lundh
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Svava Nielsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mathilde S Søndergaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Maria Villadsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Emil Z Skovhøj
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Geke A Boer
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jakob B Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Morten B Thomsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Jonas T Treebak
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jørgen K Kanters
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Thomas Mandrup-Poulsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Thomas Jespersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Brice Emanuelli
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Signe S Torekov
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark. .,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
35
|
Bazard P, Frisina RD, Acosta AA, Dasgupta S, Bauer MA, Zhu X, Ding B. Roles of Key Ion Channels and Transport Proteins in Age-Related Hearing Loss. Int J Mol Sci 2021; 22:6158. [PMID: 34200434 PMCID: PMC8201059 DOI: 10.3390/ijms22116158] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/30/2021] [Accepted: 05/31/2021] [Indexed: 12/25/2022] Open
Abstract
The auditory system is a fascinating sensory organ that overall, converts sound signals to electrical signals of the nervous system. Initially, sound energy is converted to mechanical energy via amplification processes in the middle ear, followed by transduction of mechanical movements of the oval window into electrochemical signals in the cochlear hair cells, and finally, neural signals travel to the central auditory system, via the auditory division of the 8th cranial nerve. The majority of people above 60 years have some form of age-related hearing loss, also known as presbycusis. However, the biological mechanisms of presbycusis are complex and not yet fully delineated. In the present article, we highlight ion channels and transport proteins, which are integral for the proper functioning of the auditory system, facilitating the diffusion of various ions across auditory structures for signal transduction and processing. Like most other physiological systems, hearing abilities decline with age, hence, it is imperative to fully understand inner ear aging changes, so ion channel functions should be further investigated in the aging cochlea. In this review article, we discuss key various ion channels in the auditory system and how their functions change with age. Understanding the roles of ion channels in auditory processing could enhance the development of potential biotherapies for age-related hearing loss.
Collapse
Affiliation(s)
- Parveen Bazard
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL 33620, USA; (P.B.); (A.A.A.); (S.D.); (M.A.B.); (X.Z.); (B.D.)
- Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Robert D. Frisina
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL 33620, USA; (P.B.); (A.A.A.); (S.D.); (M.A.B.); (X.Z.); (B.D.)
- Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
- Department Communication Sciences and Disorders, College of Behavioral & Communication Sciences, Tampa, FL 33620, USA
| | - Alejandro A. Acosta
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL 33620, USA; (P.B.); (A.A.A.); (S.D.); (M.A.B.); (X.Z.); (B.D.)
- Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Sneha Dasgupta
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL 33620, USA; (P.B.); (A.A.A.); (S.D.); (M.A.B.); (X.Z.); (B.D.)
- Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Mark A. Bauer
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL 33620, USA; (P.B.); (A.A.A.); (S.D.); (M.A.B.); (X.Z.); (B.D.)
- Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Xiaoxia Zhu
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL 33620, USA; (P.B.); (A.A.A.); (S.D.); (M.A.B.); (X.Z.); (B.D.)
- Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Bo Ding
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL 33620, USA; (P.B.); (A.A.A.); (S.D.); (M.A.B.); (X.Z.); (B.D.)
- Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| |
Collapse
|
|
36
|
Ozturk N, Uslu S, Ozdemir S. Diabetes-induced changes in cardiac voltage-gated ion channels. World J Diabetes 2021; 12:1-18. [PMID: 33520105 PMCID: PMC7807254 DOI: 10.4239/wjd.v12.i1.1] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 11/05/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus affects the heart through various mechanisms such as microvascular defects, metabolic abnormalities, autonomic dysfunction and incompatible immune response. Furthermore, it can also cause functional and structural changes in the myocardium by a disease known as diabetic cardiomyopathy (DCM) in the absence of coronary artery disease. As DCM progresses it causes electrical remodeling of the heart, left ventricular dysfunction and heart failure. Electrophysiological changes in the diabetic heart contribute significantly to the incidence of arrhythmias and sudden cardiac death in diabetes mellitus patients. In recent studies, significant changes in repolarizing K+ currents, Na+ currents and L-type Ca2+ currents along with impaired Ca2+ homeostasis and defective contractile function have been identified in the diabetic heart. In addition, insulin levels and other trophic factors change significantly to maintain the ionic channel expression in diabetic patients. There are many diagnostic tools and management options for DCM, but it is difficult to detect its development and to effectively prevent its progress. In this review, diabetes-associated alterations in voltage-sensitive cardiac ion channels are comprehensively assessed to understand their potential role in the pathophysiology and pathogenesis of DCM.
Collapse
Affiliation(s)
- Nihal Ozturk
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| | - Serkan Uslu
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| | - Semir Ozdemir
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| |
Collapse
|
|
37
|
Mehboob R, Kurdi M, Ahmad M, Gilani SA, Khalid S, Nasief H, Mirdad A, Malibary H, Hakamy S, Hassan A, Alaifan M, Bamaga A, Shahzad SA. Comprehensive Analysis of Genes Associated With Sudden Infant Death Syndrome. Front Pediatr 2021; 9:742225. [PMID: 34722422 PMCID: PMC8555024 DOI: 10.3389/fped.2021.742225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 09/13/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Sudden infant death syndrome (SIDS) is a tragic incident which remains a mystery even after post-mortem investigation and thorough researches. Methods: This comprehensive review is based on the genes reported in the molecular autopsy studies conducted on SIDS so far. A total of 20 original studies and 7 case reports were identified and included in this analysis. The genes identified in children or adults were not included. Most of the genes reported in these studies belonged to cardiac channel and cardiomyopathy. Cardiac channel genes in SIDS were scrutinized for further analysis. Results: After screening and removing the duplicates, 42 unique genes were extracted. When the location of these genes was assessed, it was observed that most of these belonged to Chromosomes 11, 1 and 3 in sequential manner. The pathway analysis shows that these genes are involved in the regulation of heart rate, action potential, cardiac muscle cell contraction and heart contraction. The protein-protein interaction network was also very big and highly interactive. SCN5A, CAV3, ALG10B, AKAP9 and many more were mainly found in these cases and were regulated by many transcription factors such as MYOG C2C1 and CBX3 HCT11. Micro RNA, "hsa-miR-133a-3p" was found to be prevalent in the targeted genes. Conclusions: Molecular and computational approaches are a step forward toward exploration of these sad demises. It is so far a new arena but seems promising to dig out the genetic cause of SIDS in the years to come.
Collapse
Affiliation(s)
- Riffat Mehboob
- Research Unit, Faculty of Allied Health Sciences, The University of Lahore, Lahore, Pakistan.,Lahore Medical Research Center, LLP, Lahore, Pakistan
| | - Maher Kurdi
- Department of Pathology, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mursleen Ahmad
- Department of Medicine, Sahiwal Medical College, Sahiwal, Pakistan
| | - Syed Amir Gilani
- Research Unit, Faculty of Allied Health Sciences, The University of Lahore, Lahore, Pakistan
| | - Sidra Khalid
- Lahore Medical Research Center, LLP, Lahore, Pakistan
| | - Hisham Nasief
- Department of Obstetric and Gynecology, Faculty of Medicine, King Abdulaziz University and Hospital, Jeddah, Saudi Arabia
| | - Abeer Mirdad
- Pediatric Department, East Jeddah Hospital, Jeddah, Saudi Arabia
| | - Husam Malibary
- Department of Internal Medicine, Faculty of Medicine, King Abdul Aziz University, Jeddah, Saudi Arabia
| | - Sahar Hakamy
- Center of Excellence in Genomic Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Amber Hassan
- Research Unit, Faculty of Allied Health Sciences, The University of Lahore, Lahore, Pakistan
| | - Meshari Alaifan
- Department of Paediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ahmed Bamaga
- Paediatric Department, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.,Neurology and Pediatric Department, Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Syed Adnan Shahzad
- Faculty of Medicine and University Hospital of Cologne, Institute of Virology, University of Cologne, Cologne, Germany
| |
Collapse
|
|
38
|
Epigenetic mechanisms involved in intrauterine growth restriction and aberrant kidney development and function. J Dev Orig Health Dis 2020; 12:952-962. [PMID: 33349286 DOI: 10.1017/s2040174420001257] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Intrauterine growth restriction (IUGR) due to uteroplacental insufficiency results in a placenta that is unable to provide adequate nutrients and oxygen to the fetus. These growth-restricted babies have an increased risk of hypertension and chronic kidney disease later in life. In rats, both male and female growth-restricted offspring have nephron deficits but only males develop kidney dysfunction and high blood pressure. In addition, there is transgenerational transmission of nephron deficits and hypertension risk. Therefore, epigenetic mechanisms may explain the sex-specific programming and multigenerational transmission of IUGR-related phenotypes. Expression of DNA methyltransferases (Dnmt1and Dnmt3a) and imprinted genes (Peg3, Snrpn, Kcnq1, and Cdkn1c) were investigated in kidney tissues of sham and IUGR rats in F1 (embryonic day 20 (E20) and postnatal day 1 (PN1)) and F2 (6 and 12 months of age, paternal and maternal lines) generations (n = 6-13/group). In comparison to sham offspring, F1 IUGR rats had a 19% decrease in Dnmt3a expression at E20 (P < 0.05), with decreased Cdkn1c (19%, P < 0.05) and increased Kcnq1 (1.6-fold, P < 0.01) at PN1. There was a sex-specific difference in Cdkn1c and Snrpn expression at E20, with 29% and 34% higher expression in IUGR males compared to females, respectively (P < 0.05). Peg3 sex-specific expression was lost in the F2 IUGR offspring, only in the maternal line. These findings suggest that epigenetic mechanisms may be altered in renal embryonic and/or fetal development in growth-restricted offspring, which could alter kidney function, predisposing these offspring to kidney disease later in life.
Collapse
|
|
39
|
Cosme D, Estevinho MM, Rieder F, Magro F. Potassium channels in intestinal epithelial cells and their pharmacological modulation: a systematic review. Am J Physiol Cell Physiol 2020; 320:C520-C546. [PMID: 33326312 DOI: 10.1152/ajpcell.00393.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Several potassium channels (KCs) have been described throughout the gastrointestinal tract. Notwithstanding, their contribution to both physiologic and pathophysiologic conditions, as inflammatory bowel disease (IBD), remains underexplored. Therefore, we aim to systematically review, for the first time, the evidence on the characteristics and modulation of KCs in intestinal epithelial cells (IECs). PubMed, Scopus, and Web of Science were searched to identify studies focusing on KCs and their modulation in IECs. The included studies were assessed using a reporting inclusiveness checklist. From the 745 identified records, 73 met the inclusion criteria; their reporting inclusiveness was moderate-high. Some studies described the physiological role of KCs, while others explored their importance in pathological settings. Globally, in IBD animal models, apical KCa1.1 channels, responsible for luminal secretion, were upregulated. In human colonocytes, basolateral KCa3.1 channels were downregulated. The pharmacological inhibition of K2P and Kv influenced intestinal barrier function, promoting inflammation. Evidence suggests a strong association between KCs expression and secretory mechanisms in human and animal IECs. Further research is warranted to explore the usefulness of KC pharmacological modulation as a therapeutic target.
Collapse
Affiliation(s)
- Dina Cosme
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.,MedInUP, Center for Drug Discovery and Innovative Medicines, Porto, Portugal
| | - Maria Manuela Estevinho
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Gastroenterology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
| | - Florian Rieder
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases, and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Fernando Magro
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.,MedInUP, Center for Drug Discovery and Innovative Medicines, Porto, Portugal.,Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal
| |
Collapse
|
|
40
|
Wu X, Larsson HP. Insights into Cardiac IKs (KCNQ1/KCNE1) Channels Regulation. Int J Mol Sci 2020; 21:ijms21249440. [PMID: 33322401 PMCID: PMC7763278 DOI: 10.3390/ijms21249440] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/05/2020] [Accepted: 12/09/2020] [Indexed: 12/19/2022] Open
Abstract
The delayed rectifier potassium IKs channel is an important regulator of the duration of the ventricular action potential. Hundreds of mutations in the genes (KCNQ1 and KCNE1) encoding the IKs channel cause long QT syndrome (LQTS). LQTS is a heart disorder that can lead to severe cardiac arrhythmias and sudden cardiac death. A better understanding of the IKs channel (here called the KCNQ1/KCNE1 channel) properties and activities is of great importance to find the causes of LQTS and thus potentially treat LQTS. The KCNQ1/KCNE1 channel belongs to the superfamily of voltage-gated potassium channels. The KCNQ1/KCNE1 channel consists of both the pore-forming subunit KCNQ1 and the modulatory subunit KCNE1. KCNE1 regulates the function of the KCNQ1 channel in several ways. This review aims to describe the current structural and functional knowledge about the cardiac KCNQ1/KCNE1 channel. In addition, we focus on the modulation of the KCNQ1/KCNE1 channel and its potential as a target therapeutic of LQTS.
Collapse
|
|
41
|
Rapetti-Mauss R, Berenguier C, Allegrini B, Soriani O. Interplay Between Ion Channels and the Wnt/β-Catenin Signaling Pathway in Cancers. Front Pharmacol 2020; 11:525020. [PMID: 33117152 PMCID: PMC7552962 DOI: 10.3389/fphar.2020.525020] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 08/31/2020] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence point out the important roles of ion channels in the physiopathology of cancers, so that these proteins are now considered as potential new therapeutic targets and biomarkers in this disease. Indeed, ion channels have been largely described to participate in many hallmarks of cancers such as migration, invasion, proliferation, angiogenesis, and resistance to apoptosis. At the molecular level, the development of cancers is characterised by alterations in transduction pathways that control cell behaviors. However, the interactions between ion channels and cancer-related signaling pathways are poorly understood so far. Nevertheless, a limited number of reports have recently addressed this important issue, especially regarding the interaction between ion channels and one of the main driving forces for cancer development: the Wnt/β-catenin signaling pathway. In this review, we propose to explore and discuss the current knowledge regarding the interplay between ion channels and the Wnt/β-catenin signaling pathway in cancers.
Collapse
|
|
42
|
Potier-Cartereau M, Raoul W, Weber G, Mahéo K, Rapetti-Mauss R, Gueguinou M, Buscaglia P, Goupille C, Le Goux N, Abdoul-Azize S, Lecomte T, Fromont G, Chantome A, Mignen O, Soriani O, Vandier C. Potassium and Calcium Channel Complexes as Novel Targets for Cancer Research. Rev Physiol Biochem Pharmacol 2020; 183:157-176. [PMID: 32767122 DOI: 10.1007/112_2020_24] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The intracellular Ca2+ concentration is mainly controlled by Ca2+ channels. These channels form complexes with K+ channels, which function to amplify Ca2+ flux. In cancer cells, voltage-gated/voltage-dependent Ca2+ channels and non-voltage-gated/voltage-independent Ca2+ channels have been reported to interact with K+ channels such as Ca2+-activated K+ channels and voltage-gated K+ channels. These channels are activated by an increase in cytosolic Ca2+ concentration or by membrane depolarization, which induces membrane hyperpolarization, increasing the driving force for Ca2+ flux. These complexes, composed of K+ and Ca2+ channels, are regulated by several molecules including lipids (ether lipids and cholesterol), proteins (e.g. STIM), receptors (e.g. S1R/SIGMAR1), and peptides (e.g. LL-37) and can be targeted by monoclonal antibodies, making them novel targets for cancer research.
Collapse
Affiliation(s)
| | - William Raoul
- N2C UMR 1069, University of Tours, INSERM, Tours, France
| | - Gunther Weber
- N2C UMR 1069, University of Tours, INSERM, Tours, France
| | - Karine Mahéo
- N2C UMR 1069, University of Tours, INSERM, Tours, France
| | | | | | - Paul Buscaglia
- LBAI UMR 1227, University of Brest, INSERM, Brest, France
| | - Caroline Goupille
- N2C UMR 1069, University of Tours, INSERM, CHRU de Tours, Tours, France
| | - Nelig Le Goux
- LBAI UMR 1227, University of Brest, INSERM, Brest, France
| | | | - Thierry Lecomte
- EA 7501 GICC, University of Tours, CHRU de Tours, Department of Hepato-Gastroenterology and Digestive Oncology, Tours, France
| | - Gaëlle Fromont
- N2C UMR 1069, University of Tours, INSERM, CHRU de Tours, Department of Pathology, Tours, France
| | | | - Olivier Mignen
- LBAI UMR 1227, University of Brest, INSERM, Brest, France
| | - Olivier Soriani
- iBV, INSERM, CNRS, University of the Côte d'Azur, Nice, France
| | | |
Collapse
|
|
43
|
Sahu ID, Dixit G, Reynolds WD, Kaplevatsky R, Harding BD, Jaycox CK, McCarrick RM, Lorigan GA. Characterization of the Human KCNQ1 Voltage Sensing Domain (VSD) in Lipodisq Nanoparticles for Electron Paramagnetic Resonance (EPR) Spectroscopic Studies of Membrane Proteins. J Phys Chem B 2020; 124:2331-2342. [PMID: 32130007 DOI: 10.1021/acs.jpcb.9b11506] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Membrane proteins are responsible for conducting essential biological functions that are necessary for the survival of living organisms. In spite of their physiological importance, limited structural information is currently available as a result of challenges in applying biophysical techniques for studying these protein systems. Electron paramagnetic resonance (EPR) spectroscopy is a very powerful technique to study the structural and dynamic properties of membrane proteins. However, the application of EPR spectroscopy to membrane proteins in a native membrane-bound state is extremely challenging due to the complexity observed in inhomogeneity sample preparation and the dynamic motion of the spin label. Detergent micelles are very popular membrane mimetics for membrane proteins due to their smaller size and homogeneity, providing high-resolution structure analysis by solution NMR spectroscopy. However, it is important to test whether the protein structure in a micelle environment is the same as that of its membrane-bound state. Lipodisq nanoparticles or styrene-maleic acid copolymer-lipid nanoparticles (SMALPs) have been introduced as a potentially good membrane-mimetic system for structural studies of membrane proteins. Recently, we reported on the EPR characterization of the KCNE1 membrane protein having a single transmembrane incorporated into lipodisq nanoparticles. In this work, lipodisq nanoparticles were used as a membrane mimic system for probing the structural and dynamic properties of the more complicated membrane protein system human KCNQ1 voltage sensing domain (Q1-VSD) having four transmembrane helices using site-directed spin-labeling EPR spectroscopy. Characterization of spin-labeled Q1-VSD incorporated into lipodisq nanoparticles was carried out using CW-EPR spectral line shape analysis and pulsed EPR double-electron electron resonance (DEER) measurements. The CW-EPR spectra indicate an increase in spectral line broadening with the addition of the styrene-maleic acid (SMA) polymer which approaches close to the rigid limit providing a homogeneous stabilization of the protein-lipid complex. Similarly, EPR DEER measurements indicated a superior quality of distance measurement with an increase in the phase memory time (Tm) values upon incorporation of the sample into lipodisq nanoparticles when compared to proteoliposomes. These results are consistent with the solution NMR structural studies on the Q1-VSD. This study will be beneficial for researchers working on investigating the structural and dynamic properties of more complicated membrane protein systems using lipodisq nanoparticles.
Collapse
Affiliation(s)
- Indra D Sahu
- Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States.,Natural Science Division, Campbellsville University, Campbellsville, Kentucky 42718, United States
| | - Gunjan Dixit
- Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
| | - Warren D Reynolds
- Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
| | - Ryan Kaplevatsky
- Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
| | - Benjamin D Harding
- Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
| | - Colleen K Jaycox
- Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
| | - Robert M McCarrick
- Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
| | - Gary A Lorigan
- Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
| |
Collapse
|
|
44
|
Brueggemann LI, Cribbs LL, Byron KL. Structural Determinants of Kv7.5 Potassium Channels That Confer Changes in Phosphatidylinositol 4,5-Bisphosphate (PIP 2) Affinity and Signaling Sensitivities in Smooth Muscle Cells. Mol Pharmacol 2020; 97:145-158. [PMID: 31871302 DOI: 10.1124/mol.119.117192] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 12/16/2019] [Indexed: 11/22/2022] Open
Abstract
Smooth muscle cells express Kv7.4 and Kv7.5 voltage-dependent potassium channels, which have each been implicated as regulators of smooth muscle contractility, though they display different sensitivities to signaling via cAMP/protein kinase A (PKA) and protein kinase C (PKC). We expressed chimeric channels composed of different components of the Kv7.4 and Kv7.5 α-subunits in vascular smooth muscle cells to determine which components are essential for enhancement or inhibition of channel activity. Forskolin, an activator of the cAMP/PKA pathway, increased wild-type Kv7.5 but not wild-type Kv7.4 current amplitude. Replacing the amino terminus of Kv7.4 with the amino terminus of Kv7.5 conferred partial responsiveness to forskolin. In contrast, swapping carboxy-terminal phosphatidylinositol 4,5-bisphosphate (PIP2) binding domains, or the entire C terminus, was without effect on the forskolin response, but the latter conferred responsiveness to arginine-vasopressin (an inhibitory PKC-dependent response). Serine-to-alanine mutation at position 53 of the Kv7.5 amino terminus abrogated its ability to confer forskolin sensitivity to Kv7.4. Forskolin treatment reduced the sensitivity of Kv7.5 channels to Ciona intestinalis voltage-sensing phosphatase (Ci-VSP)-induced PIP2 depletion, whereas activation of PKC with phorbol-12-myristate-13-acetate potentiated the Ci-VSP-induced decline in Kv7.5 current amplitude. Our findings suggest that PKA-dependent phosphorylation of serine 53 on the amino terminus of Kv7.5 increases its affinity for PIP2, whereas PKC-dependent phosphorylation of the Kv7.5 carboxy terminus is associated with a reduction in PIP2 affinity; these changes in PIP2 affinity have corresponding effects on channel activity. Resting affinities for PIP2 differ for Kv7.4 and Kv7.5 based on differential responsiveness to Ci-VSP activation and different rates of current rundown in ruptured patch recordings. SIGNIFICANCE STATEMENT: Kv7.4 and Kv7.5 channels are known signal transduction intermediates and drug targets for regulation of smooth muscle tone. The present studies identify distinct functional domains that confer differential sensitivities of Kv7.4 and Kv7.5 to stimulatory and inhibitory signaling and reveal structural features of the channel subunits that determine their biophysical properties. These findings may improve our understanding of the roles of these channels in smooth muscle physiology and disease, particularly in conditions where Kv7.4 and Kv7.5 are differentially expressed.
Collapse
Affiliation(s)
- Lyubov I Brueggemann
- Loyola University Chicago, Stritch School of Medicine, Departments of Molecular Pharmacology & Neuroscience (L.I.B., K.L.B.) and Cell and Molecular Physiology (L.L.C.), Maywood, Illinois
| | - Leanne L Cribbs
- Loyola University Chicago, Stritch School of Medicine, Departments of Molecular Pharmacology & Neuroscience (L.I.B., K.L.B.) and Cell and Molecular Physiology (L.L.C.), Maywood, Illinois
| | - Kenneth L Byron
- Loyola University Chicago, Stritch School of Medicine, Departments of Molecular Pharmacology & Neuroscience (L.I.B., K.L.B.) and Cell and Molecular Physiology (L.L.C.), Maywood, Illinois
| |
Collapse
|
|
45
|
Chang WT, Liu PY, Lee K, Feng YH, Wu SN. Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes. Int J Mol Sci 2020; 21:1672. [PMID: 32121388 PMCID: PMC7084345 DOI: 10.3390/ijms21051672] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 02/25/2020] [Accepted: 02/27/2020] [Indexed: 12/31/2022] Open
Abstract
Lapatinib (LAP) and sorafenib (SOR) are multitargeted tyrosine kinase inhibitors (TKIs) with antineoplastic properties. In clinical observations, LAP and SOR may contribute to QTc prolongation, but the detailed mechanism for this has been largely unexplored. In this study, we investigated whether LAP and SOR affect the activities of membrane ion channels. Using a small animal model and primary cardiomyocytes, we studied the impact of LAP and SOR on Na+ and K+ currents. We found that LAP-induced QTc prolongation in mice was reversed by isoproterenol. LAP or SOR suppressed the amplitude of the slowly activating delayed-rectifier K+ current (IK(S)) in H9c2 cells in a time- and concentration-dependent fashion. The LAP-mediated inhibition of IK(S) was reversed by adding isoproterenol or meclofenamic acid, but not by adding diazoxide. The steady-state activation curve of IK(S) during exposure to LAP or SOR was shifted toward a less negative potential, with no change in the gating charge required to activate the current. LAP shortened the recovery from IK(S) deactivation. As rapid repetitive stimuli, the IK(S) amplitude decreased; however; the LAP-induced inhibition of IK(S) remained effective. LAP or SOR alone also suppressed inwardly rectifying K+ and voltage-gated Na+ current in neonatal rat ventricular myocytes. The inhibition of ionic currents during exposure to TKIs could be an important mechanism underlying changes in QTc intervals.
Collapse
Affiliation(s)
- Wei-Ting Chang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (W.-T.C.); (P.-Y.L.)
- Division of Cardiovascular Medicine, Chi-Mei Medical Center, Tainan 71004, Taiwan
- Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 71004, Taiwan
| | - Ping-Yen Liu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (W.-T.C.); (P.-Y.L.)
- Division of Cardiology, Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan 70401, Taiwan
| | - Kaisen Lee
- Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan;
| | - Yin-Hsun Feng
- Division of Oncology, Chi-Mei Medical Center, Tainan 71004, Taiwan;
| | - Sheng-Nan Wu
- Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan;
- Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 70101, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| |
Collapse
|
|
46
|
The effects of the DNA Demethylating reagent, 5-azacytidine on SMCHD1 genomic localization. BMC Genet 2020; 21:3. [PMID: 31941450 PMCID: PMC6964063 DOI: 10.1186/s12863-020-0809-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/06/2020] [Indexed: 12/03/2022] Open
Abstract
Background DNA methylation is an epigenetic modification that mainly repress expression of genes essential during embryogenesis and development. There are key ATPase-dependent enzymes that read or write DNA methylation to remodel chromatin and regulate gene expression. Structural maintenance of chromosome hinge domain containing 1 (SMCHD1) is an architectural protein that regulates expression of numerous genes, some of which are imprinted, that are sensitive to DNA methylation. In addition, SMCHD1 germline mutations lead to developmental diseases; facioscapulohumoral muscular dystrophy (FSHD), bosma arhinia and micropthalmia (BAMS). Current evidence suggests that SMCHD1 functions through maintenance or de novo DNA methylation required for chromatin compaction. However, it is unclear if DNA methylation is also essential for genomic recruitment of SMCHD1 and its role as an architectural protein. We previously isolated SMCHD1 using a methylated DNA region from mouse pituitary growth hormone (Gh1) promoter, suggesting that methylation is required for SMCHD1 DNA binding. The goal of this study was to further understand DNA methylation directed role of SMCHD1 in regulating gene expression. Therefore, we profiled SMCHD1 genome wide occupancy in human neuroblastoma SH-SY5Y cells and evaluated if DNA methylation is required for SMCHD1 genomic binding by treating cells with the DNA demethylating reagent, 5-azacytidine (5-azaC). Results Our data suggest that the majority of SMCHD1 binding occurs in intron and intergenic regions. Gene ontology analysis of genes associated with SMCHD1 genomic occupancy that is sensitive to 5-azaC treatment suggests SMCHD1 involvement in central nervous system development. The potassium voltage-gated channel subfamily Q member1 (KCNQ1) gene that associates with central nervous system is a known SMCHD1 target. We showed SMCHD1 binding to an intronic region of KCNQ1 that is lost following 5-azaC treatment suggesting DNA methylation facilitated binding of SMCHD1. Indeed, deletion of SMCHD1 by CRISPR- Cas9 increases KCNQ1 gene expression confirming its role in regulating KCNQ1 gene expression. Conclusion These findings provide novel insights on DNA methylation directed function of SMCHD1 in regulating expression of genes associated with central nervous system development that impact future drug development strategies.
Collapse
|
|
47
|
Lin Y, Zhao T, He S, Huang J, Liu Q, Yang Z, Qin J, Yu N, Lu H, Lin X. Compound and heterozygous mutations of KCNQ1 in long QT syndrome with familial history of unexplained sudden death: Identified by analysis of whole exome sequencing and predisposing genes. Ann Noninvasive Electrocardiol 2020; 25:e12694. [PMID: 31565860 PMCID: PMC7358849 DOI: 10.1111/anec.12694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 08/05/2019] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Long QT syndrome (LQTS) increases the risk of life-threatening arrhythmia in young individuals with structurally normal hearts. Sixteen genes such as the KCNQ1, KCNH2, and SCN5A have been reported for association with LQTS. CASE PRESENTATION We identified the compound heterozygous mutations in the KCNQ1 gene at c. G527A (p.W176X) and c.G1765A (p.G589S) predicted as "damaging." The in-silico analysis showed that when compared to the characteristics of mRNA and protein of wild-type KCNQ1, the mRNA of c.G527A mutation was significantly different in the centroid secondary structure. The subunit coded by W176X would lose the transmembrane domains S3-S6 and helices A-D. The protein secondary structure of G589S was slightly shortened in helix structure; the protein physics-chemical parameters of W176X and G589S significantly and slightly changed, respectively. CONCLUSIONS The compound heterozygous mutations of W176X and G589S coexisting in KCNQ1 gene of homologous chromosomes, resulting in more severe phenotype, are the likely pathogenic and genetic risks of LQTS and USD in this Chinese family.
Collapse
Affiliation(s)
- Yubi Lin
- Department of Cardiology and Cardiovascular InterventionInterventional Medical CenterThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular ImagingThe Fifth Affiliated Hospital, Sun Yat-sen UniversityZhuhaiChina
- Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Cardiovascular Institute, Guangdong Geriatrics InstituteGuangzhouChina
| | - Ting Zhao
- Department of Cardiology and Cardiovascular InterventionInterventional Medical CenterThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina
| | - Siqi He
- The Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina
| | - Jiana Huang
- The Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina
| | | | - Zhe Yang
- Department of Cardiology and Cardiovascular InterventionInterventional Medical CenterThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina
| | - Jiading Qin
- Department of Cardiology and Cardiovascular InterventionInterventional Medical CenterThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina
| | - Nan Yu
- Department of Clinical LaboratoryZhujiang Hospital of Southern Medical UniversityGuangzhouChina
| | - Hongyun Lu
- Department of EndocrinologyThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina
| | - Xiufang Lin
- Department of Cardiology and Cardiovascular InterventionInterventional Medical CenterThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina
| |
Collapse
|
|
48
|
Wang X, Wu J, Wu Y, Wang M, Wang Z, Wu T, Chen D, Tang X, Qin X, Wu Y, Hu Y. Pleiotropic Effects of a KCNQ1 Variant on Lipid Profiles and Type 2 Diabetes: A Family-Based Study in China. J Diabetes Res 2020; 2020:8278574. [PMID: 32016123 PMCID: PMC6982365 DOI: 10.1155/2020/8278574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/03/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE The genetic variant rs2237895, located in the Potassium Voltage-Gated Channel Subfamily Q Member 1 (KCNQ1) gene, has been replicated to be associated with type 2 diabetes mellitus (T2DM) susceptibility, but the relationship with lipids is conflicting. Furthermore, the common genetic predisposition to T2DM and lipids was not fully detected. METHODS In total, 5839 individuals (2220 were T2DM patients) across 2885 families were included. The effect of rs2237895 on T2DM and lipids was estimated using linear regression and logistic regression models after adjustment for multiple covariates. Mediation analysis was then used to test whether KCNQ1 participated in T2DM pathogenesis via lipid-mediated pathways. RESULTS Per allele-C of rs2237895 was associated with 17% (11-23%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%. CONCLUSION KCNQ1 had pleiotropic effects on lipids and T2DM, and the unexpected genetic effect on association of HDL-C with T2DM was observed, indicating the different pathways to lipids and T2DM. Further research studies are needed to verify potential biological mechanisms.
Collapse
Affiliation(s)
- Xiaowen Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
| | - Junhui Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
| | - Yao Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
| | - Mengying Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
| | - Zijing Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
| | - Tao Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
| | - Dafang Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
| | - Xun Tang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
| | - Xueying Qin
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
| | - Yiqun Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
| | - Yonghua Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
- Medical Informatics Center, Peking University Health Science Center, Beijing 100191, China
| |
Collapse
|
|
49
|
Sun J, MacKinnon R. Structural Basis of Human KCNQ1 Modulation and Gating. Cell 2019; 180:340-347.e9. [PMID: 31883792 DOI: 10.1016/j.cell.2019.12.003] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 10/25/2019] [Accepted: 12/04/2019] [Indexed: 01/04/2023]
Abstract
KCNQ1, also known as Kv7.1, is a voltage-dependent K+ channel that regulates gastric acid secretion, salt and glucose homeostasis, and heart rhythm. Its functional properties are regulated in a tissue-specific manner through co-assembly with beta subunits KCNE1-5. In non-excitable cells, KCNQ1 forms a complex with KCNE3, which suppresses channel closure at negative membrane voltages that otherwise would close it. Pore opening is regulated by the signaling lipid PIP2. Using cryoelectron microscopy (cryo-EM), we show that KCNE3 tucks its single-membrane-spanning helix against KCNQ1, at a location that appears to lock the voltage sensor in its depolarized conformation. Without PIP2, the pore remains closed. Upon addition, PIP2 occupies a site on KCNQ1 within the inner membrane leaflet, which triggers a large conformational change that leads to dilation of the pore's gate. It is likely that this mechanism of PIP2 activation is conserved among Kv7 channels.
Collapse
Affiliation(s)
- Ji Sun
- Laboratory of Molecular Neurobiology and Biophysics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Roderick MacKinnon
- Laboratory of Molecular Neurobiology and Biophysics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
| |
Collapse
|
|
50
|
The membrane protein KCNQ1 potassium ion channel: Functional diversity and current structural insights. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2019; 1862:183148. [PMID: 31825788 DOI: 10.1016/j.bbamem.2019.183148] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 11/15/2019] [Accepted: 12/04/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Ion channels play crucial roles in cellular biology, physiology, and communication including sensory perception. Voltage-gated potassium (Kv) channels execute their function by sensor activation, pore-coupling, and pore opening leading to K+ conductance. SCOPE OF REVIEW This review focuses on a voltage-gated K+ ion channel KCNQ1 (Kv 7.1). Firstly, discussing its positioning in the human ion chanome, and the role of KCNQ1 in the multitude of cellular processes. Next, we discuss the overall channel architecture and current structural insights on KCNQ1. Finally, the gating mechanism involving members of the KCNE family and its interaction with non-KCNE partners. MAJOR CONCLUSIONS KCNQ1 executes its important physiological functions via interacting with KCNE1 and non-KCNE1 proteins/molecules: calmodulin, PIP2, PKA. Although, KCNQ1 has been studied in great detail, several aspects of the channel structure and function still remain unexplored. This review emphasizes the structural and biophysical studies of KCNQ1, its interaction with KCNE1 and non-KCNE1 proteins and focuses on several seminal findings showing the role of VSD and the pore domain in the channel activation and gating properties. GENERAL SIGNIFICANCE KCNQ1 mutations can result in channel defects and lead to several diseases including atrial fibrillation and long QT syndrome. Therefore, a thorough structure-function understanding of this channel complex is essential to understand its role in both normal and disease biology. Moreover, unraveling the molecular mechanisms underlying the regulation of this channel complex will help to find therapeutic strategies for several diseases.
Collapse
|