• Atrial fibrillation
• Atrial remodeling
• Drug repurposing
• Empagliflozin
• HIF-1α
• Oxidative stress and inflammation

• Atrial Fibrillation/diagnostic imaging
• Atrial Fibrillation/drug therapy
• Atrial Fibrillation/physiopathology
• Atrial Fibrillation/prevention & control
• NF-kappa B/metabolism
• Atrial Remodeling/drug effects
• Benzhydryl Compounds/pharmacology
• Benzhydryl Compounds/therapeutic use
• Heart/diagnostic imaging
• Heart/drug effects
• Heart/physiopathology
• Animals
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Male
• Rats, Wistar
• Electrocardiography
• Oxidative Stress/drug effects
• Inflammation/complications
• Inflammation/pathology
• Apoptosis/drug effects
• Signal Transduction
• Fibrosis/complications
• Fibrosis/pathology

• Acid-sensing ion channel
• Current
• Dorsal root ganglion neuron
• Insulin
• Nociceptive behavior

• Animals
• Acid Sensing Ion Channels/metabolism
• Insulin/metabolism
• Sensory Receptor Cells/metabolism
• Sensory Receptor Cells/drug effects
• Ganglia, Spinal/metabolism
• Ganglia, Spinal/drug effects
• Ganglia, Spinal/cytology
• Rats
• Receptor, Insulin/metabolism
• Male
• Signal Transduction/drug effects
• Action Potentials/drug effects
• Rats, Sprague-Dawley
• Hyperalgesia/metabolism
• Cells, Cultured

• No. 81671101 National Natural Science Foundation of China

• transient receptor potential channels
• ion channels in the nervous system
• permeation and transport

• Humans
• TRPA1 Cation Channel/genetics
• TRPA1 Cation Channel/metabolism
• Codon, Nonsense
• Transient Receptor Potential Channels/genetics
• Transient Receptor Potential Channels/metabolism
• Calcium/metabolism

• R35 GM142825 NIGMS NIH HHS
• T32 GM008284 NIGMS NIH HHS
• T32 GM008283 NIGMS NIH HHS
• U.S. Department of Health & Human Services | National Institutes of Health (NIH)

• Cholesterol
• Exocytosis
• Fatty acids
• Lipid post-translational modification
• Neurotransmission
• Phosphoinositide
• Phospholipases
• Phospholipids
• Secretory vesicle
• Sphingolipids

• Humans
• Biological Transport
• Brain
• Exocytosis
• Memory
• Phosphatidylinositols
• Phospholipases

• Diabetic Cardiomyopathy
• Epigenetics
• Flavonoids

• Calcium
• Diabetes
• Ion channel
• Smooth muscle
• Vasculature

• Humans
• Hyperglycemia/metabolism
• Calcium Channels, L-Type/metabolism
• Muscle, Smooth, Vascular/metabolism
• Diabetes Mellitus/metabolism
• Myocytes, Smooth Muscle/metabolism
• A Kinase Anchor Proteins/metabolism

• Cav1.2
• gestational diabetes
• hypertension
• myogenic tone
• preeclampsia
• reactive oxygen species

• R01 HL149608 NHLBI NIH HHS
• HD083132 NIH HHS
• HL149608 NIH HHS

• Flavonoids
• T2DM
• insulin resistance
• microRNAs
• phytochemicals

• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Polyphenols/pharmacology
• Polyphenols/therapeutic use
• Epigenesis, Genetic
• Diabetes Complications/drug therapy
• Diabetes Complications/genetics
• Gene Expression Regulation
• Diabetes Mellitus/drug therapy
• Diabetes Mellitus/genetics

Background: Cordyceps is a precious Chinese herbal medicine with rich bio-active ingredients and is used for regulating arrhythmia alongside routine treatments. However, the efficacy and potential mechanisms of Cordyceps on patients with arrhythmia remain unclear.

Methods: Randomized controlled trials of bradycardia treatment with Cordyceps were retrieved from diverse databases and available data. Dichotomous variables were expressed as a risk ratio (RR) with a 95% confidence interval (CI). Continuous variables were expressed as a standardized mean difference (SMD) with a 95% CI. Network pharmacology was used to identify potential targets of Cordyceps for arrhythmia. Metascape was used for gene ontology (GO) and genome (KEGG) pathway enrichment analysis.

Results: Nineteen trials included 1,805 patients with arrhythmia, of whom 918 were treated with Ningxinbao capsule plus routine drugs, and, as a control, 887 were treated with only routine drugs. Six trials reported on bradycardia and the other 13 on tachycardia. Treatment with Cordyceps significantly improved the total efficacy rate in both bradycardia (RR = 1.24; 95% CI, 1.15 to 1.35; P_z <0.00001) and tachycardia (RR = 1.27; 95% CI, 1.17 to 1.39; P_z <0.00001). Cordyceps also had beneficial secondary outcomes. No serious adverse events occurred in patients treated with Cordyceps. The results of KEGG pathway enrichment analysis were mainly connected to adrenergic signaling in cardiomyocytes and the PI3K-Akt signaling pathway. IL6, TNF, TP53, CASP3, CTNNB1, EGF, and NOS3 might be key targets for Cordyceps in the treatment of arrhythmia.

Conclusion: This study confirmed that Cordyceps has a certain positive effect on the treatment of arrhythmia and that its main mechanism may be through the regulation of adrenergic signaling in cardiomyocytes and the PI3K-Akt signaling pathway.

• Natural Science Foundation of Shandong Province
• Postdoctoral Research Foundation of China
• Natural Science Foundation of Guangdong Province

• Calcium signaling
• ER stress
• Energy metabolism
• Exercise tolerance
• Mass spectrometry
• Mitochondria
• Proteomics
• Proteostasis
• STIM1
• Skeletal muscle

• Animals
• Calcium/metabolism
• Energy Metabolism
• Exercise Tolerance
• Mice
• Muscle, Skeletal/metabolism
• Proteostasis
• Stromal Interaction Molecule 1/genetics
• Stromal Interaction Molecule 1/metabolism

• P30 DK124723 NIDDK NIH HHS
• R01 DK109911 NIDDK NIH HHS
• T32 HL007101 NHLBI NIH HHS

• CRAC channel
• calcium signaling
• ion channels
• light-sensitive Ca2+ permeable channels
• opsins
• optogenetics

• Animals
• Calcium/metabolism
• Calcium Signaling
• Disease
• Humans
• Ion Channels/metabolism
• Optics and Photonics
• Optogenetics

• P 30567 Austrian Science Fund FWF
• P 32851 Austrian Science Fund FWF
• R01 GM129325 NIGMS NIH HHS
• W 1250 Austrian Science Fund FWF

• Dravet syndrome
• Electrophysiology
• Epilepsy
• Phosphorylation
• Sodium channels

• PI3K/AKT signaling
• ischemic heart disease
• microRNA-126
• myocardial ischemia reperfusion injury
• naringenin

• Alzheimer’s disease
• biomarkers
• insulin resistance
• memory
• metabolism

• Deubiquitinase
• Flow cytometry
• Ion channel trafficking
• Nanobody
• Ubiquitin

• Cell Membrane/metabolism
• Ion Channels/genetics
• Ion Channels/metabolism
• Ubiquitin-Protein Ligases/genetics
• Ubiquitin-Protein Ligases/metabolism
• Ubiquitination

• R01 HL142111 NHLBI NIH HHS
• R01 HL121253 NHLBI NIH HHS
• F31 DK118866 NIDDK NIH HHS

• calcium channel
• internalization
• trafficking

• Action potential
• Cardiac ion channels
• Diabetes
• L-type Ca2+ channels
• Potassium channels
• Sodium channels

Brugada syndrome (BrS) is an inherited arrhythmogenic disease that may lead to sudden cardiac death in young adults with structurally normal hearts. No pharmacological therapy is available for BrS patients. This situation highlights the urgent need to overcome current difficulties by developing novel groundbreaking curative strategies. BrS has been associated with mutations in 18 different genes of which loss-of-function (LoF) CACNA1C mutations constitute the second most common cause. Here we tested the hypothesis that BrS associated with mutations in the CACNA1C gene encoding the L-type calcium channel (LTCC) pore-forming unit (Ca_vα1.2) is functionally reverted by administration of a mimetic peptide (MP), which through binding to the LTCC chaperone beta subunit (Ca_vβ2) restores the physiological life cycle of aberrant LTCCs. Two novel Ca_vα1.2 mutations associated with BrS were identified in young individuals. Transient transfection in heterologous and cardiac cells showed LoF phenotypes with reduced Ca²⁺ current (I_Ca). In HEK293 cells overexpressing the two novel Ca_vα1.2 mutations, Western blot analysis and cell surface biotinylation assays revealed reduced Ca_vα1.2 protein levels at the plasma membrane for both mutants. Nano-BRET, Nano-Luciferase assays, and confocal microscopy analyses showed (i) reduced affinity of Ca_vα1.2 for its Ca_vβ2 chaperone, (ii) shortened Ca_vα1.2 half-life in the membrane, and (iii) impaired subcellular localization. Treatment of Ca_vα1.2 mutant-transfected cells with a cell permeant MP restored channel trafficking and physiologic channel half-life, thereby resulting in I_Ca similar to wild type. These results represent the first step towards the development of a gene-specific treatment for BrS due to defective trafficking of mutant LTCC.

• L-type calcium channel
• arrhythmia
• brugada syndrome
• cardiac disease
• channel trafficking
• corrective therapy
• mimetic peptide

• Arrhythmia
• Atrial fibrillation
• Candesartan
• Cardiac
• Genetic variants
• Ibrutinib
• LY294002
• Molecular therapy
• PI3K(p110α)
• Remodelling
• Risk factors
• phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and phosphatidylinositol 4,5-bisphosphate (PIP2)

• Animals
• Dictyostelium/genetics
• Humans
• Signal Transduction

• Diabetes
• Myogenic tone
• Vasculopathies

• Animals
• Calcium Channels/metabolism
• Cyclic AMP-Dependent Protein Kinases/metabolism
• Diabetes Mellitus/metabolism
• Diabetes Mellitus/pathology
• Endothelial Cells/metabolism
• Glucose/metabolism
• Humans
• Hyperglycemia/metabolism
• Hyperglycemia/pathology
• Ion Channels/metabolism
• Muscle, Smooth, Vascular/metabolism

• UC Davis Academic Federation Innovative Development Award University of California Davis
• R01HL121059 NHLBI NIH HHS
• CN-19-147 UC MEXUS-CONACYT
• R01HL098200 National Heart, Lung, and Blood Institute (US)
• R01 HL149127 NHLBI NIH HHS
• R01 HL121059 NHLBI NIH HHS
• R01 HL098200 NHLBI NIH HHS
• R01HL149127 NHLBI NIH HHS
• R01HL121059 NHLBI NIH HHS
• R01HL149127 NHLBI NIH HHS
• National Heart, Lung, and Blood Institute

• acid-sensing ion channel 1a
• factors
• membrane trafficking
• molecular mechanisms
• protein expression

• Animals
• Antihypertensive Agents/pharmacology
• Aorta, Thoracic/drug effects
• Aorta, Thoracic/enzymology
• Aorta, Thoracic/physiopathology
• Blood Pressure/drug effects
• Calcium Signaling/drug effects
• Cell Line
• Disease Models, Animal
• Drugs, Chinese Herbal/pharmacology
• Hypertension/drug therapy
• Hypertension/enzymology
• Hypertension/physiopathology
• Male
• Muscle, Smooth, Vascular/drug effects
• Muscle, Smooth, Vascular/enzymology
• Muscle, Smooth, Vascular/physiopathology
• Myocytes, Smooth Muscle/drug effects
• Myocytes, Smooth Muscle/enzymology
• Proto-Oncogene Proteins c-akt/metabolism
• Rats, Inbred SHR
• Rats, Inbred WKY
• Vasodilation/drug effects
• Vasodilator Agents/pharmacology

• schizophrenia
• neuroscience

Heart rate control by the funny current (I_f) involves both fast, cAMP-dependent, and slow, membrane expression–based mechanisms to adapt to different needs.

• Arsenic
• Calcium influx
• Diabetes
• Mechanism
• Pancreatic islets

Acute myocardial ischaemia/reperfusion (MI/R) injury causes severe arrhythmias with a high rate of lethality. Extensive research focus on endoplasmic reticulum (ER) stress and its dysfunction which leads to cardiac injury in MI/R Our study evaluated the effects of sulodexide (SDX) on MI/R by establishing MI/R mice models and in vitro oxidative stress models in H9C2 cells. We found that SDX decreases cardiac injury during ischaemia reperfusion and decreased myocardial apoptosis and infarct area, which was paralleled by increased superoxide dismutase and reduced malondialdehyde in mice plasm, increased Bcl‐2 expression, decreased BAX expression in a mouse model of MI/R. In vitro, SDX exerted a protective effect by the suppression of the ER stress which induced by tert‐butyl hydroperoxide (TBHP) treatment. Both of the in vivo and in vitro effects were involved in the phosphatidylinositol 3‐kinase (PI3K)/Akt signalling pathway. Inhibition of PI3K/Akt pathway by specific inhibitor, LY294002, partially reduced the protective effect of SDX. In short, our results suggested that the cardioprotective role of SDX was related to the suppression of ER stress in mice MI/R models and TBHP‐induced H9C2 cell injury which was through the PI3K/Akt signalling pathway.

• PI3K/Akt
• endoplasmic reticulum stress
• myocardial ischaemia / reperfusion
• sulodexide

After axonal insult and injury, Dual leucine-zipper kinase (DLK) conveys retrograde pro-degenerative signals to neuronal cell bodies via its downstream target c-Jun N-terminal kinase (JNK). We recently reported that such signals critically require modification of DLK by the fatty acid palmitate, via a process called palmitoylation. Compounds that inhibit DLK palmitoylation could thus reduce neurodegeneration, but identifying such inhibitors requires a suitable assay. Here we report that DLK subcellular localization in non-neuronal cells is highly palmitoylation-dependent and can thus serve as a proxy readout to identify inhibitors of DLK palmitoylation by High Content Screening (HCS). We optimized an HCS assay based on this readout, which showed highly robust performance in a 96-well format. Using this assay we screened a library of 1200 FDA-approved compounds and found that ketoconazole, the compound that most dramatically affected DLK localization in our primary screen, dose-dependently inhibited DLK palmitoylation in follow-up biochemical assays. Moreover, ketoconazole significantly blunted phosphorylation of c-Jun in primary sensory neurons subjected to trophic deprivation, a well known model of DLK-dependent pro-degenerative signaling. Our HCS platform is thus capable of identifying novel inhibitors of DLK palmitoylation and signalling that may have considerable therapeutic potential.

Insulin resistance plays a key role in the pathogenesis of type 2 diabetes and is also related to other health problems like obesity, hypertension, and metabolic syndrome. Imbalance between insulin vascular actions via the phosphatidylinositol 3-Kinase (PI3K) and the mitogen activated protein kinase (MAPK) signaling pathways during insulin resistant states results in impaired endothelial PI3K/eNOS- and augmented MAPK/endothelin 1 pathways leading to endothelial dysfunction and abnormal vasoconstriction. The role of PI3K, MAPK, and protein kinase C (PKC) in Ca²⁺ handling of resistance arteries involved in blood pressure regulation is poorly understood. Therefore, we assessed here whether PI3K, MAPK, and PKC play a role in the Ca²⁺ signaling pathways linked to adrenergic vasoconstriction in resistance arteries. Simultaneous measurements of intracellular calcium concentration ([Ca²⁺]_i) in vascular smooth muscle (VSM) and tension were performed in endothelium-denuded branches of mesenteric arteries from Wistar rats mounted in a microvascular myographs. Responses to CaCl₂ were assessed in arteries activated with phenylephrine (PE) and kept in Ca²⁺-free solution, in the absence and presence of the selective antagonist of L-type Ca²⁺ channels nifedipine, cyclopiazonic acid (CPA) to block sarcoplasmic reticulum (SR) intracellular Ca²⁺ release or specific inhibitors of PI3K, ERK-MAPK, or PKC. Activation of α₁-adrenoceptors with PE stimulated both intracellular Ca²⁺ mobilization and Ca²⁺ entry along with contraction in resistance arteries. Both [Ca²⁺]_i and contractile responses were inhibited by nifedipine while CPA abolished intracellular Ca²⁺ mobilization and modestly reduced Ca²⁺ entry suggesting that α₁-adrenergic vasoconstriction is largely dependent Ca²⁺ influx through L-type Ca²⁺ channel and to a lesser extent through store-operated Ca²⁺ channels. Inhibition of ERK-MAPK did not alter intracellular Ca²⁺ mobilization but largely reduced L-type Ca²⁺ entry elicited by PE without altering vasoconstriction. The PI3K blocker LY-294002 moderately reduced intracellular Ca²⁺ release, Ca²⁺ entry and contraction induced by the α₁-adrenoceptor agonist, while PKC inhibition decreased PE-elicited Ca²⁺ entry and to a lesser extent contraction without affecting intracellular Ca²⁺ mobilization. Under conditions of ryanodine receptor (RyR) blockade to inhibit Ca²⁺-induced Ca²⁺-release (CICR), inhibitors of PI3K, ERK-MAPK, or PKC significantly reduced [Ca²⁺]_i increases but not contraction elicited by high K⁺ depolarization suggesting an activation of L-type Ca²⁺ entry in VSM independent of RyR. In summary, our results demonstrate that PI3K, ERK-MAPK, and PKC regulate Ca²⁺ handling coupled to the α₁-adrenoceptor in VSM of resistance arteries and related to both contractile and non-contractile functions. These kinases represent potential pharmacological targets in pathologies associated to vascular dysfunction and abnormal Ca²⁺ handling such as obesity, hypertension and diabetes mellitus, in which these signaling pathways are profoundly impaired.

• ERK-MAPK
• L-type Ca2+ channel
• PI3K
• PKC
• RyR
• intracellular Ca2+ mobilization
• resistance arteries
• α1-adrenergic vasoconstriction

• GSK1016790A
• TRPV4
• calcium
• endothelial cells
• membrane trafficking

Calcium regulation plays a central role in cardiac function. Several variants in the calcium channel Ca_v1.2 have been implicated in arrhythmic syndromes. We screened patients with Brugada syndrome, short QT syndrome, early repolarisation syndrome, and idiopathic ventricular fibrillation to determine the frequency and pathogenicity of Ca_v1.2 variants. Ca_v1.2 related genes, CACNA1C, CACNB2 and CACNA2D1, were screened in 65 probands. Missense variants were introduced in the Ca_v1.2 alpha subunit plasmid by mutagenesis to assess their pathogenicity using patch clamp approaches. Six missense variants were identified in CACNA1C in five individuals. Five of them, A1648T, A1689T, G1795R, R1973Q, C1992F, showed no major alterations of the channel function. The sixth C-terminal variant, Ca_vα_1c-T1787M, present mostly in the African population, was identified in two patients with resuscitated cardiac arrest. The first patient originated from Cameroon and the second was an inhabitant of La Reunion Island with idiopathic ventricular fibrillation originating from Purkinje tissues. Patch-clamp analysis revealed that Ca_vα_1c-T1787M reduces the calcium and barium currents by increasing the auto-inhibition mediated by the C-terminal part and increases the voltage-dependent inhibition. We identified a loss-of-function variant, Ca_vα_1c-T1787M, present in 0.8% of the African population, as a new risk factor for ventricular arrhythmia.

Recent studies, have shown that insulin increases extrasynaptic GABA_A receptor-mediated currents in the hippocampus, causing alterations of neuronal excitability. The prefrontal cortex (PFC) is another brain area which is involved in cognition functions and expresses insulin receptors. Here, we used electrophysiological, molecular, and immunocytochemical techniques to examine the effect of insulin on the extrasynaptic GABA_A receptor-mediated tonic currents in brain slices. We found that insulin (20–500 nM) increases GABA_A-mediated tonic currents. Our results suggest that insulin promotes the trafficking of extrasynaptic GABA_A receptors from the cytoplasm to the cell membrane. Western blot analysis and immunocytochemistry showed that PFC extrasynaptic GABA_A receptors contain α-5 and δ subunits. Insulin effect on tonic currents decreased the firing rate and neuronal excitability in layer 5–6 PFC cells. These effects of insulin were dependent on the activation of the PI3K enzyme, a key mediator of the insulin response within the brain. Taken together, these results suggest that insulin modulation of the GABA_A-mediated tonic currents can modify the activity of neural circuits within the PFC. These actions could help to explain the alterations of cognitive processes associated with changes in insulin signaling.

• ambient GABA
• brain slices
• extrasynaptic GABAA receptors
• neuronal excitability
• receptor trafficking

• L-type Ca(2+) channel
• MAP kinases
• Obesity
• PI3K
• PKC
• Resistance arteries
• SR

• Association
• Attention-deficit/hyperactivity disorder
• Genetic susceptibility
• Gene–environment interaction
• PIK3CG gene

The incidence of QT prolongation and torsades de pointes is on the rise due to the use of cardiovascular and non-cardiovascular drugs. Robust efforts have been made and are still ongoing to understand the underlying mechanisms that can enhance or prevent the development of drug-induced proarrhythmia. A caveat in the use of antiarrhythmic drugs is the ability to obtain safe action potential prolongation therapeutic effects, through IKr blockade. This remains as yet completely unachievable, as blockers of the potassium channel have not provided complete safe measures. Because of this, efforts at understanding the mechanisms of proarrhythmia have continued. PI3K/Akt signalling pathway appears to possess some potential advantage in this regard because cardiomyocytes intracellular dialysis with phosphatidylinositol (3,4,5)-trisphosphate (PIP3) normalises ion channel alterations and eliminates proarrhythmic features. However, there is a conundrum. Increased activities of PIP3 signalling can enhance cell proliferation and survival, and reduced activities of PIP3 signalling can lead to proarrhythmia. PI3K inhibitors used in cancer treatment have been found to cause proarrhythmia, and represent a potential avenue for the research and evaluation of potential effectiveness of a battery of antiarrhythmic and cancer drugs that are either currently in use or in development. Despite this knowledge, limited information is available on PI3K/Akt signalling and arrhythmogenesis. This highlights the need to search for new ways to improve testing of antiarrhythmic drugs and increase our understanding in PI3K/Akt signalling and arrhythmogenesis.

• arrhythmias
• cardiac remodelling
• ventricular fibrillation

• Aldehyde Reductase/genetics
• Aldehyde Reductase/metabolism
• Animals
• Calcium/metabolism
• Cell Line
• Cell Survival
• Cytokines/immunology
• Diabetes Mellitus, Experimental/immunology
• Diabetes Mellitus, Experimental/metabolism
• Enzyme-Linked Immunosorbent Assay
• Gene Knockdown Techniques
• Humans
• Hyperglycemia/immunology
• Hyperglycemia/metabolism
• Immunity, Innate/immunology
• Immunoblotting
• Inflammasomes/immunology
• Interleukin-1beta/immunology
• Male
• Mice
• Monocytes/immunology
• Monocytes/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/immunology
• Oxidative Stress/immunology
• RNA, Small Interfering
• Reactive Oxygen Species/metabolism
• Reverse Transcriptase Polymerase Chain Reaction

• R01 DK104786 NIDDK NIH HHS

• AKT/NR pathway
• CaMKIV/CREB pathway
• cognitive decline
• insulin resistance
• minimal hepatic encephalopathy
• rosiglitazone

• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Type 4/metabolism
• Cells, Cultured
• Cyclic AMP Response Element-Binding Protein/metabolism
• Disease Models, Animal
• Hepatic Encephalopathy/enzymology
• Hepatic Encephalopathy/metabolism
• Hepatic Encephalopathy/pathology
• Hippocampus/cytology
• Hippocampus/drug effects
• Hypoglycemic Agents/pharmacology
• Insulin Resistance
• Maze Learning
• Phosphorylation
• Protein Binding
• Proto-Oncogene Proteins c-akt/metabolism
• Rats
• Rats, Sprague-Dawley
• Receptor, Insulin/metabolism
• Receptors, N-Methyl-D-Aspartate/metabolism
• Rosiglitazone
• Thiazolidinediones/pharmacology

In regulatory toxicology, the dose-response relationship is a key element towards fulfilling safety assessments and satisfying regulatory authorities. Conventionally, the larger the dose, the greater the response, following the dogma “the dose makes the poison”. Many endocrine disrupting chemicals, including bisphenol-A (BPA), induce non-monotonic dose response (NMDR) relationships, which are unconventional and have tremendous implications in risk assessment. Although several molecular mechanisms have been proposed to explain NMDR relationships, they are largely undemonstrated. Using mouse pancreatic β-cells from wild-type and oestrogen receptor ERβ−/− mice, we found that exposure to increasing doses of BPA affected Ca²⁺ entry in an NMDR manner. Low doses decreased plasma membrane Ca²⁺ currents after downregulation of Cav2.3 ion channel expression, in a process involving ERβ. High doses decreased Ca²⁺ currents through an ERβ-mediated mechanism and simultaneously increased Ca²⁺ currents via oestrogen receptor ERα. The outcome of both molecular mechanisms explains the NMDR relationship between BPA and Ca²⁺ entry in β-cells.

• calcium
• hypertrophy
• myocytes, cardiac
• myocytes, smooth muscle
• signal transduction

• airway
• cystic fibrosis transmembrane conductance regulator
• dexamethasone
• glucocorticoids
• neural precursor cell expressed, developmentally downregulated 4-like
• phosphoinositide 3-kinase
• protein kinase B
• serum and glucocorticoid dependent kinase 1

• Alveolar Epithelial Cells/drug effects
• Alveolar Epithelial Cells/metabolism
• Alveolar Epithelial Cells/pathology
• Animals
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
• Dexamethasone/administration & dosage
• Humans
• Immediate-Early Proteins/genetics
• Immediate-Early Proteins/metabolism
• Nedd4 Ubiquitin Protein Ligases/genetics
• Nedd4 Ubiquitin Protein Ligases/metabolism
• Phosphatidylinositol 3-Kinases/genetics
• Phosphatidylinositol 3-Kinases/metabolism
• Primary Cell Culture
• Protein Serine-Threonine Kinases/genetics
• Protein Serine-Threonine Kinases/metabolism
• Proto-Oncogene Proteins c-akt/genetics
• Rats
• Signal Transduction/drug effects

• Anticancerous
• Biomolecular interaction
• Isoquinoline
• System biology

• Cross-Sectional Studies
• Female
• Hearing Loss/complications
• Hearing Loss/genetics
• Hearing Loss, Central/complications
• Humans
• Male
• Membrane Proteins/genetics
• Mutation, Missense
• Oman
• Pedigree

• Fear conditioning
• Mice
• Propranolol
• Transcranial direct current stimulation (tDCS)

• Animals
• Fear/drug effects
• Fear/physiology
• Learning/drug effects
• Learning/physiology
• Male
• Memory/drug effects
• Memory/physiology
• Memory Disorders/physiopathology
• Mice
• Neuropsychological Tests
• Prefrontal Cortex/drug effects
• Prefrontal Cortex/physiology
• Propranolol/pharmacology
• Transcranial Direct Current Stimulation/methods

• calcium channel
• heterologous expression
• protein kinase A
• regulation

• Alzheimer disease
• Autophagy
• Bipolar disorder
• Dictyostelium discoideum
• Epilepsy
• INO1
• Inositol