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Li Y, Xiao Z, Mori W, Sun J, Yamasaki T, Rong J, Fujinaga M, Chen J, Kumata K, Zhao C, Zhang Y, Collier TL, Hu K, Xie L, Zhou X, Zhang W, Song Z, Gao Y, Sun Z, Zhang K, Patel JS, Ran C, Chaudhary A, Sheffler DJ, Cosford NDP, Zhang L, Zhai C, Haider A, Yuan H, Zhang MR, Liang SH. Radiosynthesis and preclinical evaluation of a carbon-11 labeled PET ligand for imaging metabotropic glutamate receptor 7. AMERICAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 2024; 14:306-315. [PMID: 39583907 PMCID: PMC11578812 DOI: 10.62347/puai9230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 08/29/2024] [Indexed: 11/26/2024]
Abstract
Metabotropic glutamate receptor 7 (mGlu7) is a G protein-coupled receptor that is preferentially found in the active zone of neurotransmitter release in the central nervous system (CNS). mGlu7 plays a vital role in memory, learning, and neuronal development, rendering it a potential target for treating epilepsy, depression, and anxiety. The development of noninvasive imaging ligands targeting mGlu7 could help elucidate the functional significance of mGlu7 and accelerate drug discovery for neurological and psychiatric disorders. In this report, a novel carbon-11 labeled positron emission tomography (PET) tracer designated [11C]18 (codenamed MG7-2109) was synthesized via 11C-methylation in 23% decay-corrected radiochemical yield (RCY). In vitro serum stability, serum protein binding, in vitro autoradiography and ex vivo biodistribution studies of [11C]18 were conducted. Preliminary PET imaging results revealed a homogeneous distribution of [11C]18 and rapid clearance in rodent brains. This study provides valuable insights into the development of mGlu7-targeted PET tracer based on an isoxazolo(5,4-c)pyridine scaffold.
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Affiliation(s)
- Yinlong Li
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical SchoolBoston, MA 02114, USA
| | - Zhiwei Xiao
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical SchoolBoston, MA 02114, USA
| | - Wakana Mori
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and TechnologyChiba 263-8555, Japan
| | - Jiyun Sun
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical SchoolBoston, MA 02114, USA
| | - Tomoteru Yamasaki
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and TechnologyChiba 263-8555, Japan
| | - Jian Rong
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical SchoolBoston, MA 02114, USA
| | - Masayuki Fujinaga
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and TechnologyChiba 263-8555, Japan
| | - Jiahui Chen
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical SchoolBoston, MA 02114, USA
| | - Katsushi Kumata
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and TechnologyChiba 263-8555, Japan
| | - Chunyu Zhao
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical SchoolBoston, MA 02114, USA
| | - Yiding Zhang
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and TechnologyChiba 263-8555, Japan
| | - Thomas L Collier
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical SchoolBoston, MA 02114, USA
| | - Kuan Hu
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and TechnologyChiba 263-8555, Japan
| | - Lin Xie
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and TechnologyChiba 263-8555, Japan
| | - Xin Zhou
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
| | - Wei Zhang
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
| | - Zhendong Song
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
| | - Yabiao Gao
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
| | - Zhenkun Sun
- Department of Pharmacology and Chemical Biology, Emory University School of MedicineAtlanta, GA 30322, USA
| | - Kuo Zhang
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
| | - Jimmy S Patel
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
- Department of Radiation Oncology, Winship Cancer Institute of Emory UniversityAtlanta, GA 30322, USA
| | - Chongzhao Ran
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical SchoolBoston, MA 02114, USA
| | - Ahmad Chaudhary
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
| | - Douglas J Sheffler
- Cancer Molecular Therapeutics Program and Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Prebys Medical Discovery InstituteLa Jolla, CA 92037, USA
| | - Nicholas DP Cosford
- Cancer Molecular Therapeutics Program and Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Prebys Medical Discovery InstituteLa Jolla, CA 92037, USA
| | - Linqi Zhang
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
| | - Chuangyan Zhai
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
| | - Ahmed Haider
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical SchoolBoston, MA 02114, USA
| | - Hongjie Yuan
- Department of Pharmacology and Chemical Biology, Emory University School of MedicineAtlanta, GA 30322, USA
| | - Ming-Rong Zhang
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and TechnologyChiba 263-8555, Japan
| | - Steven H Liang
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA 30322, USA
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical SchoolBoston, MA 02114, USA
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Al-Beltagi M, Saeed NK, Bediwy AS, Bediwy EA, Elbeltagi R. Decoding the genetic landscape of autism: A comprehensive review. World J Clin Pediatr 2024; 13:98468. [PMID: 39350903 PMCID: PMC11438927 DOI: 10.5409/wjcp.v13.i3.98468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 08/30/2024] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by heterogeneous symptoms and genetic underpinnings. Recent advancements in genetic and epigenetic research have provided insights into the intricate mechanisms contributing to ASD, influencing both diagnosis and therapeutic strategies. AIM To explore the genetic architecture of ASD, elucidate mechanistic insights into genetic mutations, and examine gene-environment interactions. METHODS A comprehensive systematic review was conducted, integrating findings from studies on genetic variations, epigenetic mechanisms (such as DNA methylation and histone modifications), and emerging technologies [including Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 and single-cell RNA sequencing]. Relevant articles were identified through systematic searches of databases such as PubMed and Google Scholar. RESULTS Genetic studies have identified numerous risk genes and mutations associated with ASD, yet many cases remain unexplained by known factors, suggesting undiscovered genetic components. Mechanistic insights into how these genetic mutations impact neural development and brain connectivity are still evolving. Epigenetic modifications, particularly DNA methylation and non-coding RNAs, also play significant roles in ASD pathogenesis. Emerging technologies like CRISPR-Cas9 and advanced bioinformatics are advancing our understanding by enabling precise genetic editing and analysis of complex genomic data. CONCLUSION Continued research into the genetic and epigenetic underpinnings of ASD is crucial for developing personalized and effective treatments. Collaborative efforts integrating multidisciplinary expertise and international collaborations are essential to address the complexity of ASD and translate genetic discoveries into clinical practice. Addressing unresolved questions and ethical considerations surrounding genetic research will pave the way for improved diagnostic tools and targeted therapies, ultimately enhancing outcomes for individuals affected by ASD.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatric, Faculty of Medicine, Tanta University, Alghrabia, Tanta 31511, Egypt
- Department of Pediatric, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Department of Pathology, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 12, Bahrain
- Medical Microbiology Section, Department of Pathology, Irish Royal College of Surgeon, Muharraq, Busaiteen 15503, Bahrain
| | - Adel Salah Bediwy
- Department of Pulmonology, Faculty of Medicine, Tanta University, Alghrabia, Tanta 31527, Egypt
- Department of Pulmonology, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
| | - Eman A Bediwy
- Internal Medicine, Faculty of Medicine, Tanta University, Algharbia, Tanta 31527, Egypt
| | - Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland-Bahrain, Muharraq, Busiateen 15503, Bahrain
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Zaki-Dizaji M, Abazari MF, Razzaghi H, Shkolnikov I, Christie BR. GRM7 deficiency, from excitotoxicity and neuroinflammation to neurodegeneration: Systematic review of GRM7 deficient patients. Brain Behav Immun Health 2024; 39:100808. [PMID: 38983774 PMCID: PMC11231722 DOI: 10.1016/j.bbih.2024.100808] [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: 12/20/2023] [Revised: 06/03/2024] [Accepted: 06/10/2024] [Indexed: 07/11/2024] Open
Abstract
The metabotropic glutamate receptor 7 (mGluR7) is a presynaptic G-protein-coupled glutamate receptor that modulates neurotransmitter release and synaptic plasticity at presynaptic terminals. It is encoded by GRM7, and recently variants have been identified in patients with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental delay (DD), intellectual disability (ID), and brain malformations. To gain updated insights into the function of GRM7 and the phenotypic spectrum of genetic variations within this gene, we conducted a systematic review of relevant literature utilizing PubMed, Web of Science, and Scopus databases. Among the 14 articles meeting the inclusion criteria, a total of 42 patients (from 28 families) harboring confirmed mutations in the GRM7 gene have been documented. Specifically, there were 17 patients with heterozygous mutations, 20 patients with homozygous mutations, and 5 patients with compound heterozygous mutations. Common clinical features included intellectual behavioral disability, seizure/epilepsy, microcephaly, developmental delay, peripheral hypertonia and hypomyelination. Genotype-phenotype correlation was not clear and each variant had unique characteristics including gene dosage, mutant protein surface expression, and degradation pathway that result with a spectrum of phenotype manifestations through ASD or ADHD to severe DD/ID with brain malformations. Neuroinflammation may play a role in the development and/or progression of GRM7-related neurodegeneration along with excitotoxicity. The clinical and functional data presented here demonstrate that both autosomal dominant and recessive inheritance of GRM7 mutation can cause disease spectrum phenotypes through ASD or ADHD to severe DD/ID and seizure with brain malformations.
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Affiliation(s)
- Majid Zaki-Dizaji
- Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mohammad Foad Abazari
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
- Island Medical Program, University of British Columbia, Victoria, British Columbia, Canada
| | - Hossein Razzaghi
- Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Irene Shkolnikov
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Brian R Christie
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
- Island Medical Program, University of British Columbia, Victoria, British Columbia, Canada
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Cristiano N, Cabayé A, Brabet I, Glatthar R, Tora A, Goudet C, Bertrand HO, Goupil-Lamy A, Flor PJ, Pin JP, McCort-Tranchepain I, Acher FC. Novel Inhibitory Site Revealed by XAP044 Mode of Action on the Metabotropic Glutamate 7 Receptor Venus Flytrap Domain. J Med Chem 2024; 67:11662-11687. [PMID: 38691510 DOI: 10.1021/acs.jmedchem.3c01924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
Metabotropic glutamate (mGlu) receptors play a key role in modulating most synapses in the brain. The mGlu7 receptors inhibit presynaptic neurotransmitter release and offer therapeutic possibilities for post-traumatic stress disorders or epilepsy. Screening campaigns provided mGlu7-specific allosteric modulators as the inhibitor XAP044 (Gee et al. J. Biol. Chem. 2014). In contrast to other mGlu receptor allosteric modulators, XAP044 does not bind in the transmembrane domain but to the extracellular domain of the mGlu7 receptor and not at the orthosteric site. Here, we identified the mode of action of XAP044, combining synthesis of derivatives, modeling and docking experiments, and mutagenesis. We propose a unique mode of action of these inhibitors, preventing the closure of the Venus flytrap agonist binding domain. While acting as a noncompetitive antagonist of L-AP4, XAP044 and derivatives act as apparent competitive antagonists of LSP4-2022. These data revealed more potent XAP044 analogues and new possibilities to target mGluRs.
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Affiliation(s)
- Nunzia Cristiano
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Cité, CNRS UMR 8601, 75006 Paris, France
| | - Alexandre Cabayé
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Cité, CNRS UMR 8601, 75006 Paris, France
- BIOVIA Dassault Systèmes, F-78140 Vélizy-Villacoublay Cedex, France
| | - Isabelle Brabet
- Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, 34094 Montpellier, France
| | - Ralf Glatthar
- Novartis Biomedical Research, CH-4002 Basel, Switzerland
| | - Amelie Tora
- Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, 34094 Montpellier, France
| | - Cyril Goudet
- Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, 34094 Montpellier, France
| | | | - Anne Goupil-Lamy
- BIOVIA Dassault Systèmes, F-78140 Vélizy-Villacoublay Cedex, France
| | - Peter J Flor
- Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany
| | - Jean-Philippe Pin
- Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, 34094 Montpellier, France
| | - Isabelle McCort-Tranchepain
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Cité, CNRS UMR 8601, 75006 Paris, France
| | - Francine C Acher
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Cité, CNRS UMR 8601, 75006 Paris, France
- Saints-Pères Paris Institute for the Neurosciences, Université Paris Cité, CNRS UMR 8003, 75006 Paris, France
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Kumar V, Lee KY, Acharya A, Babik MS, Christian-Hinman CA, Rhodes JS, Tsai NP. mGluR7 allosteric modulator AMN082 corrects protein synthesis and pathological phenotypes in FXS. EMBO Mol Med 2024; 16:506-522. [PMID: 38374465 PMCID: PMC10940663 DOI: 10.1038/s44321-024-00038-w] [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: 08/05/2023] [Revised: 01/31/2024] [Accepted: 02/06/2024] [Indexed: 02/21/2024] Open
Abstract
Fragile X syndrome (FXS) is the leading cause of inherited autism and intellectual disabilities. Aberrant protein synthesis due to the loss of fragile X messenger ribonucleoprotein (FMRP) is the major defect in FXS, leading to a plethora of cellular and behavioral abnormalities. However, no treatments are available to date. In this study, we found that activation of metabotropic glutamate receptor 7 (mGluR7) using a positive allosteric modulator named AMN082 represses protein synthesis through ERK1/2 and eIF4E signaling in an FMRP-independent manner. We further demonstrated that treatment of AMN082 leads to a reduction in neuronal excitability, which in turn ameliorates audiogenic seizure susceptibility in Fmr1 KO mice, the FXS mouse model. When evaluating the animals' behavior, we showed that treatment of AMN082 reduces repetitive behavior and improves learning and memory in Fmr1 KO mice. This study uncovers novel functions of mGluR7 and AMN082 and suggests the activation of mGluR7 as a potential therapeutic approach for treating FXS.
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Affiliation(s)
- Vipendra Kumar
- Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Kwan Young Lee
- Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Anirudh Acharya
- Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Matthew S Babik
- Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Catherine A Christian-Hinman
- Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Justin S Rhodes
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, IL, 61820, USA
| | - Nien-Pei Tsai
- Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
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Januel L, Chatron N, Rivier-Ringenbach C, Cabet S, Labalme A, Sahin Y, Darvish H, Kruer M, Bakhtiari S, Sanlaville D, de Sainte Agathe JM, Lesca G. GRM7-related disorder: five additional patients from three independent families and review of the literature. Eur J Med Genet 2024; 67:104893. [PMID: 38070825 DOI: 10.1016/j.ejmg.2023.104893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 10/22/2023] [Accepted: 12/03/2023] [Indexed: 12/19/2023]
Abstract
Developmental and epileptic encephalopathies (DEEs) refer to a group of severe epileptic syndromes characterized by seizures as well as a developmental delay which can be a consequence of the underlying etiology and/or the epileptic encephalopathy. The genes responsible for DEEs are numerous and their number is increasing since the availability of Next-Generation Sequencing. Pathogenic variants in GRM7, encoding the metabotropic glutamate receptor 7, were recently shown as a cause of a severe DEE with autosomal recessive inheritance. To date, only ten patients have been reported in the literature, generally with severe phenotypes including early-onset epilepsy, microcephaly, brain anomalies, and spasticity. We report here 5 patients from 3 independent families with biallelic variants in the GRM7 gene. We review the literature and provide further elements for the understanding of the genotype-phenotype correlation of this rare syndrome.
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Affiliation(s)
- Louis Januel
- Hospices Civils de Lyon, Groupe Hospitalier Est, Service de Génétique, Bron, France.
| | - Nicolas Chatron
- Hospices Civils de Lyon, Groupe Hospitalier Est, Service de Génétique, Bron, France; Institut NeuroMyoGene PNMG, CNRS UMR5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France
| | | | - Sara Cabet
- Hospices Civils de Lyon, Groupe Hospitalier Est, Service de Radiologie, Bron, France
| | - Audrey Labalme
- Hospices Civils de Lyon, Groupe Hospitalier Est, Service de Génétique, Bron, France
| | | | - Hossein Darvish
- Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA
| | - Michael Kruer
- Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA
| | - Somayeh Bakhtiari
- Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA
| | - Damien Sanlaville
- Hospices Civils de Lyon, Groupe Hospitalier Est, Service de Génétique, Bron, France; Institut NeuroMyoGene PNMG, CNRS UMR5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France
| | | | - Gaetan Lesca
- Hospices Civils de Lyon, Groupe Hospitalier Est, Service de Génétique, Bron, France; Institut NeuroMyoGene PNMG, CNRS UMR5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France
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Lei X, Hofmann CS, Rodriguez AL, Niswender CM. Differential Activity of Orthosteric Agonists and Allosteric Modulators at Metabotropic Glutamate Receptor 7. Mol Pharmacol 2023; 104:17-27. [PMID: 37105671 PMCID: PMC10289241 DOI: 10.1124/molpharm.123.000678] [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] [Received: 01/24/2023] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 04/29/2023] Open
Abstract
Metabotropic glutamate receptor 7 (mGlu7) is a G protein coupled receptor that has demonstrated promise as a therapeutic target across a number of neurologic and psychiatric diseases. Compounds that modulate the activity of mGlu7, such as positive and negative allosteric modulators, may represent new therapeutic strategies to modulate receptor activity. The endogenous neurotransmitter associated with the mGlu receptor family, glutamate, exhibits low efficacy and potency in activating mGlu7, and surrogate agonists, such as the compound L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4), are often used for receptor activation and compound profiling. To understand the implications of the use of such agonists in the development of positive allosteric modulators (PAMs), we performed a systematic evaluation of receptor activation using a system in which mutations can be made in either protomer of the mGlu7 dimer; we employed mutations that prevent interaction with the orthosteric site as well as the G-protein coupling site of the receptor. We then measured increases in calcium levels downstream of a promiscuous G protein to assess the effects of mutations in one of the two protomers in the presence of two different agonists and three positive allosteric modulators. Our results reveal that distinct PAMs, for example N-[3-Chloro-4-[(5-chloro-2-pyridinyl)oxy]phenyl]-2-pyridinecarboxamide (VU0422288) and 3-(2,3-Difluoro-4-methoxyphenyl)-2,5-dimethyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (VU6005649), do exhibit different maximal levels of potentiation with L-AP4 versus glutamate, but there appear to be common stable receptor conformations that are shared among all of the compounds examined here. SIGNIFICANCE STATEMENT: This manuscript describes the systematic evaluation of the mGlu7 agonists glutamate and L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) in the presence and absence of three distinct potentiators examining possible mechanistic differences. These findings demonstrate that mGlu7 potentiators display subtle variances in response to glutamate versus L-AP4.
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Affiliation(s)
- Xia Lei
- Department of Pharmacology (X.L., C.S.H., A.L.R., C.M.N.), Warren Center for Neuroscience Drug Discovery (X.L., A.L.R., C.M.N.), Vanderbilt Institute of Chemical Biology (C.M.N.), and Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennesee (C.M.N.); and Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee (C.M.N.)
| | - Christopher S Hofmann
- Department of Pharmacology (X.L., C.S.H., A.L.R., C.M.N.), Warren Center for Neuroscience Drug Discovery (X.L., A.L.R., C.M.N.), Vanderbilt Institute of Chemical Biology (C.M.N.), and Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennesee (C.M.N.); and Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee (C.M.N.)
| | - Alice L Rodriguez
- Department of Pharmacology (X.L., C.S.H., A.L.R., C.M.N.), Warren Center for Neuroscience Drug Discovery (X.L., A.L.R., C.M.N.), Vanderbilt Institute of Chemical Biology (C.M.N.), and Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennesee (C.M.N.); and Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee (C.M.N.)
| | - Colleen M Niswender
- Department of Pharmacology (X.L., C.S.H., A.L.R., C.M.N.), Warren Center for Neuroscience Drug Discovery (X.L., A.L.R., C.M.N.), Vanderbilt Institute of Chemical Biology (C.M.N.), and Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennesee (C.M.N.); and Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee (C.M.N.)
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8
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Design and Synthesis of New Quinazolin-4-one Derivatives with Negative mGlu 7 Receptor Modulation Activity and Antipsychotic-Like Properties. Int J Mol Sci 2023; 24:ijms24031981. [PMID: 36768302 PMCID: PMC9916658 DOI: 10.3390/ijms24031981] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 01/21/2023] Open
Abstract
Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3H)-one (A9-7, ALX-171, mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment.
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9
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Kalbfleisch JJ, Rodriguez AL, Lei X, Weiss K, Blobaum AL, Boutaud O, Niswender CM, Lindsley CW. Persistent challenges in the development of an mGlu 7 PAM in vivo tool compound: The discovery of VU6046980. Bioorg Med Chem Lett 2023; 80:129106. [PMID: 36528230 PMCID: PMC10201562 DOI: 10.1016/j.bmcl.2022.129106] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/06/2022] [Accepted: 12/11/2022] [Indexed: 12/16/2022]
Abstract
Herein, we report on the further chemical optimization of the first reported mGlu7 positive allosteric modulator (PAM), VU6027459. Replacement of the quinoline core by a cinnoline scaffold increased mGlu7 PAM potency by ∼ 10-fold, and concomitant introduction of a chiral tricyclic motif led to potent mGlu7 PAMs with enantioselective mGlu receptor selectivity profiles. Of these, VU6046980 emerged as a putative in vivo tool compound with excellent CNS penetration (Kp = 4.1; Kp,uu = 0.7) and efficacy in preclinical models. However, either off-target activity at the sigma-1 receptor or activity at a target not elucidated by large ancillary pharmacology panels led to sedation not driven by activation of mGlu7 (validated in Grm7 knockout mice). Thus, despite a significant advance, a viable mGlu7 PAM in vivo tool remains elusive.
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Affiliation(s)
- Jacob J Kalbfleisch
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
| | - Alice L Rodriguez
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Xia Lei
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Kelly Weiss
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Annie L Blobaum
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Olivier Boutaud
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Colleen M Niswender
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
| | - Craig W Lindsley
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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10
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Feng Y, Zhang C, Wei Z, Li G, Gan Y, Liu C, Deng Y. Gene variations of glutamate metabolism pathway and epilepsy. ACTA EPILEPTOLOGICA 2022. [DOI: 10.1186/s42494-022-00103-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Epilepsy is a paroxysmal disorder of the brain, caused by an imbalance of neuronal excitation and inhibition. Glutamate is the most important excitatory neurotransmitter in the brain and plays an important role in epileptogenesis. Mutations in genes at any step/component of the glutamate metabolic pathway may lead to the development of epilepsy or epileptic encephalopathy.
Methods
Clinical history of 3 epilepsy patients with genetic variations of the glutamate metabolism pathway was collected. Electroencephalogram recording and magnetic resonance imaging were performed in each patient. We also reviewed recent literature for a variety of the genetic variations involved in epilepsy.
Results
Case 1 was a SLC1A2 mutation-carrier diagnosed with developmental and epileptic encephalopathy (DEE) 41, whose seizures decreased after start of the ketogenic diet. Case 2 carried a GRIN2A gene mutation and was seizure-free for three years after taking levetiracetam and vitamin B6. Case 3 was a GRIN2B mutation-carrier diagnosed with DEE 27, who seizures diminished after taking oxcarbazepine.
Conclusions
Preclinical and clinical evidence supports the therapeutic potential of glutamatergic signaling-targeting treatments for epilepsy. More studies are needed to discover novel DEE-related genetic mutations in the glutamate metabolic pathway.
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11
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Wang X, Cheng S, Chen X, Zhang W, Xie Y, Liu W, You Y, Yi C, Zhu B, Gu M, Xu B, Lu Y, Wang J, Hu W. A metabotropic glutamate receptor affects the growth and development of Schistosoma japonicum. Front Microbiol 2022; 13:1045490. [PMID: 36532433 PMCID: PMC9750798 DOI: 10.3389/fmicb.2022.1045490] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/08/2022] [Indexed: 12/07/2023] Open
Abstract
Schistosomiasis is a zoonotic parasitic disease caused by schistosome infection that severely threatens human health. Therapy relies mainly on single drug treatment with praziquantel. Therefore, there is an urgent need to develop alternative medicines. The glutamate neurotransmitter in helminths is involved in many physiological functions by interacting with various cell-surface receptors. However, the roles and detailed regulatory mechanisms of the metabotropic glutamate receptor (mGluR) in the growth and development of Schistosoma japonicum remain poorly understood. In this study, we identified two putative mGluRs in S. japonicum and named them SjGRM7 (Sjc_001309, similar to GRM7) and SjGRM (Sjc_001163, similar to mGluR). Further validation using a calcium mobilization assay showed that SjGRM7 and SjGRM are glutamate-specific. The results of in situ hybridization showed that SjGRM is mainly located in the nerves of both males and gonads of females, and SjGRM7 is principally found in the nerves and gonads of males and females. In a RNA interference experiment, the results showed that SjGRM7 knockdown by double-stranded RNA (dsRNA) in S. japonicum caused edema, chassis detachment, and separation of paired worms in vitro. Furthermore, dsRNA interference of SjGRM7 could significantly affect the development and egg production of male and female worms in vivo and alleviate the host liver granulomas and fibrosis. Finally, we examined the molecular mechanisms underlying the regulatory function of mGluR using RNA sequencing. The data suggest that SjGRM7 propagates its signals through the G protein-coupled receptor signaling pathway to promote nervous system development in S. japonicum. In conclusion, SjGRM7 is a potential target for anti-schistosomiasis. This study enables future research on the mechanisms of action of Schistosomiasis japonica drugs.
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Affiliation(s)
- Xiaoling Wang
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai, China
| | - Shaoyun Cheng
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Xiangyu Chen
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Wei Zhang
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Yuxiang Xie
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Wanling Liu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yanmin You
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Cun Yi
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Bingkuan Zhu
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Mengjie Gu
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Bin Xu
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai, China
| | - Yan Lu
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Jipeng Wang
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Wei Hu
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai, China
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- College of Life Sciences, Inner Mongolia University, Hohhot, China
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12
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Lin X, Fisher NM, Dogra S, Senter RK, Reed CW, Kalbfleisch JJ, Lindsley CW, Asher WB, Xiang Z, Niswender CM, Javitch JA. Differential activity of mGlu 7 allosteric modulators provides evidence for mGlu 7/8 heterodimers at hippocampal Schaffer collateral-CA1 synapses. J Biol Chem 2022; 298:102458. [PMID: 36063995 PMCID: PMC9531177 DOI: 10.1016/j.jbc.2022.102458] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 11/25/2022] Open
Abstract
Glutamate acts at eight metabotropic glutamate (mGlu) receptor subtypes expressed in a partially overlapping fashion in distinct brain circuits. Recent evidence indicates that specific mGlu receptor protomers can heterodimerize and that these heterodimers can exhibit different pharmacology when compared to their homodimeric counterparts. Group III mGlu agonist-induced suppression of evoked excitatory potentials and induction of long-term potentiation at Schaffer collateral-CA1 (SC-CA1) synapses in the rodent hippocampus can be blocked by the selective mGlu7 negative allosteric modulator (NAM), ADX71743. Curiously, a different mGlu7 NAM, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one, failed to block these responses in brain slices despite its robust activity at mGlu7 homodimers in vitro. We hypothesized that this might result from heterodimerization of mGlu7 with another mGlu receptor protomer and focused on mGlu8 as a candidate given the reported effects of mGlu8-targeted compounds in the hippocampus. Here, we used complemented donor acceptor-resonance energy transfer to study mGlu7/8 heterodimer activation in vitro and observed that ADX71743 blocked responses of both mGlu7/7 homodimers and mGlu7/8 heterodimers, whereas 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one only antagonized responses of mGlu7/7 homodimers. Taken together with our electrophysiology observations, these results suggest that a receptor with pharmacology consistent with an mGlu7/8 heterodimer modulates the activity of SC-CA1 synapses. Building on this hypothesis, we identified two additional structurally related mGlu7 NAMs that also differ in their activity at mGlu7/8 heterodimers, in a manner consistent with their ability to inhibit synaptic transmission and plasticity at SC-CA1. Thus, we propose that mGlu7/8 heterodimers are a key molecular target for modulating the activity of hippocampal SC-CA1 synapses.
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Affiliation(s)
- Xin Lin
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA
| | - Nicole M Fisher
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA
| | - Shalini Dogra
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA
| | - Rebecca K Senter
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA
| | - Carson W Reed
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA
| | - Jacob J Kalbfleisch
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA
| | - Craig W Lindsley
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee, USA; Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA
| | - Wesley B Asher
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA
| | - Zixiu Xiang
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA
| | - Colleen M Niswender
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee, USA; Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
| | - Jonathan A Javitch
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA; Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
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13
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Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice. Cells 2022; 11:cells11111817. [PMID: 35681512 PMCID: PMC9180111 DOI: 10.3390/cells11111817] [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: 04/22/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 12/01/2022] Open
Abstract
Chronic psychosocial stress participates prominently in the etiology of various psychiatric conditions and comorbid somatic pathologies; however, suitable pharmacotherapy of these disorders is still of high medical need. During the last few decades, research on mGlu receptors advanced remarkably and much attention was given to the mGlu7 subtype. Here, genetic mGlu7 ablation, short-term pharmacological mGlu7 blockade, as well as siRNA-mediated knockdown of mGlu7 were shown to result in an acute anti-stress, antidepressant- and anxiolytic-like phenotype in mice. Moreover, we recently revealed a prominent stress-protective effect of genetic mGlu7 ablation also with respect to chronic psychosocial stress. In addition, we are able to demonstrate in the present study that the chronic pharmacological blockade of mGlu7 interferes with various chronic stress-induced alterations. For this, we used the chronic subordinate colony housing (CSC), a mouse model of chronic male subordination, in combination with chronic treatment with the mGlu7-selective orthosteric-like antagonist XAP044 (7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one). Interestingly, XAP044 dose-dependently ameliorates hypothalamic–pituitary–adrenal axis dysfunctions, thymus atrophy, as well as the CSC-induced increase in innate anxiety. Taken together, our findings provide further evidence for the role of mGlu7 in chronic psychosocial stress-induced alterations and suggests the pharmacological blockade of mGlu7 as a promising therapeutic approach for the treatment of chronic stress-related pathologies in men.
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14
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Klotz L, Enz R. MGluR7 is a presynaptic metabotropic glutamate receptor at ribbon synapses of inner hair cells. FASEB J 2021; 35:e21855. [PMID: 34644430 DOI: 10.1096/fj.202100672r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/15/2021] [Accepted: 07/29/2021] [Indexed: 01/17/2023]
Abstract
Glutamate is the most pivotal excitatory neurotransmitter in the central nervous system. Metabotropic glutamate receptors (mGluRs) dimerize and can couple to inhibitory intracellular signal cascades, thereby protecting glutamatergic neurons from excessive excitation and cell death. MGluR7 is correlated with age-related hearing deficits and noise-induced hearing loss; however its exact localization in the cochlea is unknown. Here, we analyzed the expression and localization of mGluR7a and mGluR7b in mouse cochlear wholemounts in detail, using confocal microscopy and 3D reconstructions. We observed a presynaptic localization of mGluR7a at inner hair cells (IHCs), close to the synaptic ribbon. To detect mGluR7b, newly generated antibodies were characterized and showed co-localization with mGluR7a at IHC ribbon synapses. Compared to the number of synaptic ribbons, the numbers of mGluR7a and mGluR7b puncta were reduced at higher frequencies (48 to 64 kHz) and in older animals (6 and 12 months). Previously, we reported a presynaptic localization of mGluR4 and mGluR8b at this synapse type. This enables the possibility for the formation of homo- and/or heterodimeric receptors composed of mGluR4, mGluR7a, mGluR7b and mGluR8b at IHC ribbon synapses. These receptor complexes might represent new molecular targets suited for pharmacological concepts to protect the cochlea against noxious stimuli and excitotoxicity.
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Affiliation(s)
- Lisa Klotz
- Institute for Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Ralf Enz
- Institute for Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
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15
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Jdila MB, Mignon-Ravix C, Ncir SB, Kammoun F, Fakhfakh F, Villard L, Triki C. A large consanguineous family with a homozygous Metabotropic Glutamate Receptor 7 (mGlu7) variant and developmental epileptic encephalopathy: Effect on protein structure and ligand affinity. Orphanet J Rare Dis 2021; 16:317. [PMID: 34273994 PMCID: PMC8286605 DOI: 10.1186/s13023-021-01951-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 07/11/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Developmental and epileptic encephalopathies (DEE) are chronic neurological conditions where epileptic activity contributes to the progressive disruption of brain function, frequently leading to impaired motor, cognitive and sensory development. PATIENTS AND METHODS The present study reports a clinical investigation and a molecular analysis by Next Generation Sequencing (NGS) of a large consanguineous family comprising several cases of developmental and epileptic encephalopathy. Bioinformatic prediction and molecular docking analysis were also carried out. RESULTS The majority of patients in our studied family had severe developmental impairments, early-onset seizures, brain malformations such as cortical atrophy and microcephaly, developmental delays and intellectual disabilities. The molecular investigations revealed a novel homozygous variant c.1411G>A (p.Gly471Arg) in the GRM7 gene which was segregating with the disease in the family. Bioinformatic tools predicted its pathogenicity and docking analysis revealed its potential effects on mGlu7 protein binding to its ligand. CONCLUSION Our results contribute to a better understanding of the impact of GRM7 variants for the newly described associated phenotype.
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Affiliation(s)
- Marwa Ben Jdila
- Research Laboratory 'NeuroPédiatrie' (LR19ES15), Sfax Medical School, Sfax University, Sfax, Tunisia. .,Laboratory of Molecular and Functional Genetics, Faculty of Science of Sfax, Sfax University, Sfax, Tunisia.
| | | | - Sihem Ben Ncir
- Research Laboratory 'NeuroPédiatrie' (LR19ES15), Sfax Medical School, Sfax University, Sfax, Tunisia.,Child Neurology Department, Hedi Chaker Universitary Hospital of Sfax, Sfax, Tunisia
| | - Fatma Kammoun
- Research Laboratory 'NeuroPédiatrie' (LR19ES15), Sfax Medical School, Sfax University, Sfax, Tunisia.,Child Neurology Department, Hedi Chaker Universitary Hospital of Sfax, Sfax, Tunisia
| | - Faiza Fakhfakh
- Laboratory of Molecular and Functional Genetics, Faculty of Science of Sfax, Sfax University, Sfax, Tunisia
| | - Laurent Villard
- Inserm, MMG, Aix Marseille Univ, Marseille, France.,Département de Génétique Médicale, Hôpital d'Enfants de la Timone, Assistance Publique Hôpitaux de Marseille, 13385, Marseille, France
| | - Chahnez Triki
- Research Laboratory 'NeuroPédiatrie' (LR19ES15), Sfax Medical School, Sfax University, Sfax, Tunisia.,Child Neurology Department, Hedi Chaker Universitary Hospital of Sfax, Sfax, Tunisia
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16
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Wang X, Gao C, Zhang Y, Hu S, Qiao Y, Zhao Z, Gou L, Song J, Wang Q. Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice. Front Cell Neurosci 2021; 15:689611. [PMID: 34335187 PMCID: PMC8319395 DOI: 10.3389/fncel.2021.689611] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/24/2021] [Indexed: 11/13/2022] Open
Abstract
Autism spectrum disorder (ASD) is associated with a range of abnormalities pertaining to socialization, communication, repetitive behaviors, and restricted interests. Owing to its complexity, the etiology of ASD remains incompletely understood. The presynaptic G protein-coupled glutamate receptor metabotropic glutamate receptor 7 (mGluR7) is known to be essential for synaptic transmission and is also tightly linked with ASD incidence. Herein, we report that prefrontal cortex (PFC) mGluR7 protein levels were decreased in C57BL/6J mice exposed to valproic acid (VPA) and BTBR T+ Itpr3tf/J mice. The overexpression of mGluR7 in the PFC of these mice using a lentiviral vector was sufficient to reduce the severity of ASD-like behavioral patterns such that animals exhibited decreases in abnormal social interactions and communication, anxiety-like, and stereotyped/repetitive behaviors. Intriguingly, patch-clamp recordings revealed that the overexpression of mGluR7 suppressed neuronal excitability by inhibiting action potential discharge frequencies, together with enhanced action potential threshold and increased rheobase. These data offer a scientific basis for the additional study of mGluR7 as a promising therapeutic target in ASD and related neurodevelopmental disorders.
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Affiliation(s)
- Xiaona Wang
- Department of Nuclear Medicine, Affiliated Hospital of Guangdong Medical College, Zhanjiang, China
| | - Chao Gao
- Department of Rehabilitation, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Yaodong Zhang
- Department of Nuclear Medicine, Affiliated Hospital of Guangdong Medical College, Zhanjiang, China
| | - Shunan Hu
- Department of Nuclear Medicine, Affiliated Hospital of Guangdong Medical College, Zhanjiang, China
| | - Yidan Qiao
- Department of Pathology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Zhengqin Zhao
- Department of Nuclear Medicine, Affiliated Hospital of Guangdong Medical College, Zhanjiang, China
| | - Lingshan Gou
- Center for Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital, Xuzhou, China
| | - Jijun Song
- Henan Infectious Disease Hospital, The Sixth People's Hospital of Zhengzhou, Zhengzhou, China
| | - Qi Wang
- Department of Histology and Embryology, Guizhou Medical University, Guizhou, China
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17
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El-Ansary A, Zayed N, Al-Ayadhi L, Qasem H, Anwar M, Meguid NA, Bhat RS, Doşa MD, Chirumbolo S, Bjørklund G. GABA synaptopathy promotes the elevation of caspases 3 and 9 as pro-apoptotic markers in Egyptian patients with autism spectrum disorder. Acta Neurol Belg 2021; 121:489-501. [PMID: 31673995 DOI: 10.1007/s13760-019-01226-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 10/10/2019] [Indexed: 12/14/2022]
Abstract
Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder characterized by reduced social communication as well as repetitive behaviors. Many studies have proved that defective synapses in ASD influence how neurons in the brain connect and communicate with each other. Synaptopathies arise from alterations that affecting the integrity and/or functionality of synapses and can contribute to synaptic pathologies. This study investigated the GABA levels in plasma being an inhibitory neurotransmitter, caspase 3 and 9 as pro-apoptotic proteins in 20 ASD children and 20 neurotypical controls using the ELISA technique. Analysis of receiver-operating characteristic (ROC) of the data that was obtained to evaluate the diagnostic value of the aforementioned evaluated biomarkers. Pearson's correlations and multiple regressions between the measured variables were also done. While GABA level was reduced in ASD patients, levels of caspases 3 and 9 were significantly higher when compared to neurotypical control participants. ROC and predictiveness curves showed that caspases 3, caspases 9, and GABA might be utilized as predictive markers in autism diagnosis. The present study indicates that the presence of GABAergic dysfunction promotes apoptosis in Egyptian ASD children. The obtained GABA synaptopathies and their connection with apoptosis can both relate to neuronal excitation, and imbalance of the inhibition system, which can be used as reliable predictive biomarkers for ASD.
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18
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Matsunaga H, Aruga J. Trans-Synaptic Regulation of Metabotropic Glutamate Receptors by Elfn Proteins in Health and Disease. Front Neural Circuits 2021; 15:634875. [PMID: 33790745 PMCID: PMC8005653 DOI: 10.3389/fncir.2021.634875] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 02/08/2021] [Indexed: 12/20/2022] Open
Abstract
Trans-regulation of G protein-coupled receptors (GPCRs) by leucine-rich repeat (LRR) transmembrane proteins has emerged as a novel type of synaptic molecular interaction in the last decade. Several studies on LRR–GPCR interactions have revealed their critical role in synapse formation and in establishing synaptic properties. Among them, LRR–GPCR interactions between extracellular LRR fibronectin domain-containing family proteins (Elfn1 and Elfn2) and metabotropic glutamate receptors (mGluRs) are particularly interesting as they can affect a broad range of synapses through the modulation of signaling by glutamate, the principal excitatory transmitter in the mammalian central nervous system (CNS). Elfn–mGluR interactions have been investigated in hippocampal, cortical, and retinal synapses. Postsynaptic Elfn1 in the hippocampus and cerebral cortex mediates the tonic regulation of excitatory input onto somatostatin-positive interneurons (INs) through recruitment of presynaptic mGluR7. In the retina, presynaptic Elfn1 binds to mGluR6 and is necessary for synapse formation between rod photoreceptor cells and rod-bipolar cells. The repertoire of binding partners for Elfn1 and Elfn2 includes all group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8), and both Elfn1 and Elfn2 can alter mGluR-mediated signaling through trans-interaction. Importantly, both preclinical and clinical studies have provided support for the involvement of the Elfn1–mGluR7 interaction in attention-deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and epilepsy. In fact, Elfn1–mGluR7-associated disorders may reflect the altered function of somatostatin-positive interneuron inhibitory neural circuits, the mesolimbic and nigrostriatal dopaminergic pathway, and habenular circuits, highlighting the need for further investigation into this interaction.
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Affiliation(s)
- Hayato Matsunaga
- Department of Medical Pharmacology, Nagasaki University Institute of Biomedical Sciences, Nagasaki, Japan
| | - Jun Aruga
- Department of Medical Pharmacology, Nagasaki University Institute of Biomedical Sciences, Nagasaki, Japan
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19
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Pathogenic GRM7 Mutations Associated with Neurodevelopmental Disorders Impair Axon Outgrowth and Presynaptic Terminal Development. J Neurosci 2021; 41:2344-2359. [PMID: 33500274 DOI: 10.1523/jneurosci.2108-20.2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 01/11/2021] [Accepted: 01/16/2021] [Indexed: 12/18/2022] Open
Abstract
Metabotropic glutamate receptor 7 (mGlu7) is an inhibitory heterotrimeric G-protein-coupled receptor that modulates neurotransmitter release and synaptic plasticity at presynaptic terminals in the mammalian central nervous system. Recent studies have shown that rare mutations in glutamate receptors and synaptic scaffold proteins are associated with neurodevelopmental disorders (NDDs). However, the role of presynaptic mGlu7 in the pathogenesis of NDDs remains largely unknown. Recent whole-exome sequencing (WES) studies in families with NDDs have revealed that several missense mutations (c.1865G>A:p.R622Q; c.461T>C:p.I154T; c.1972C>T:p.R658W and c.2024C>A:p.T675K) or a nonsense mutation (c.1757G>A:p.W586X) in the GRM7 gene may be linked to NDDs. In the present study, we investigated the mechanistic links between GRM7 point mutations and NDD pathology. We find that the pathogenic GRM7 I154T and R658W/T675K mutations lead to the degradation of the mGlu7 protein. In particular, the GRM7 R658W/T675K mutation results in a lack of surface mGlu7 expression in heterologous cells and cultured neurons isolated from male and female rat embryos. We demonstrate that the expression of mGlu7 variants or exposure to mGlu7 antagonists impairs axon outgrowth through the mitogen-activated protein kinase (MAPK)-cAMP-protein kinase A (PKA) signaling pathway during early neuronal development, which subsequently leads to a decrease in the number of presynaptic terminals in mature neurons. Treatment with an mGlu7 agonist restores the pathologic phenotypes caused by mGlu7 I154T but not by mGlu7 R658W/T675K because of its lack of neuronal surface expression. These findings provide evidence that stable neuronal surface expression of mGlu7 is essential for neural development and that mGlu7 is a promising therapeutic target for NDDs.SIGNIFICANCE STATEMENT Neurodevelopmental disorders (NDDs) affect brain development and function by multiple etiologies. Metabotropic glutamate receptor 7 (mGlu7) is a receptor that controls excitatory neurotransmission and synaptic plasticity. Since accumulating evidence indicates that the GRM7 gene locus is associated with NDD risk, we analyzed the functional effects of human GRM7 variants identified in patients with NDDs. We demonstrate that stable neuronal surface expression of mGlu7 is essential for axon outgrowth and presynaptic terminal development in neurons. We found that mitogen-activated protein kinase (MAPK)-cAMP-protein kinase A (PKA) signaling and subsequent cytoskeletal dynamics are defective because of the degradation of mGlu7 variants. Finally, we show that the defects caused by mGlu7 I154T can be reversed by agonists, providing the rationale for proposing mGlu7 as a potential therapeutic target for NDDs.
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20
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Gregory KJ, Goudet C. International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors. Pharmacol Rev 2021; 73:521-569. [PMID: 33361406 DOI: 10.1124/pr.119.019133] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Metabotropic glutamate (mGlu) receptors respond to glutamate, the major excitatory neurotransmitter in the mammalian brain, mediating a modulatory role that is critical for higher-order brain functions such as learning and memory. Since the first mGlu receptor was cloned in 1992, eight subtypes have been identified along with many isoforms and splice variants. The mGlu receptors are transmembrane-spanning proteins belonging to the class C G protein-coupled receptor family and represent attractive targets for a multitude of central nervous system disorders. Concerted drug discovery efforts over the past three decades have yielded a wealth of pharmacological tools including subtype-selective agents that competitively block or mimic the actions of glutamate or act allosterically via distinct sites to enhance or inhibit receptor activity. Herein, we review the physiologic and pathophysiological roles for individual mGlu receptor subtypes including the pleiotropic nature of intracellular signal transduction arising from each. We provide a comprehensive analysis of the in vitro and in vivo pharmacological properties of prototypical and commercially available orthosteric agonists and antagonists as well as allosteric modulators, including ligands that have entered clinical trials. Finally, we highlight emerging areas of research that hold promise to facilitate rational design of highly selective mGlu receptor-targeting therapeutics in the future. SIGNIFICANCE STATEMENT: The metabotropic glutamate receptors are attractive therapeutic targets for a range of psychiatric and neurological disorders. Over the past three decades, intense discovery efforts have yielded diverse pharmacological tools acting either competitively or allosterically, which have enabled dissection of fundamental biological process modulated by metabotropic glutamate receptors and established proof of concept for many therapeutic indications. We review metabotropic glutamate receptor molecular pharmacology and highlight emerging areas that are offering new avenues to selectively modulate neurotransmission.
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Affiliation(s)
- Karen J Gregory
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.) and Institut de Génomique Fonctionnelle (IGF), University of Montpellier, Centre National de la Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale (INSERM), Montpellier, France (C.G.)
| | - Cyril Goudet
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.) and Institut de Génomique Fonctionnelle (IGF), University of Montpellier, Centre National de la Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale (INSERM), Montpellier, France (C.G.)
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21
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Kalbfleisch JJ, Reed CW, Park C, Spearing PK, Quitalig MC, Jenkins MT, Rodriguez AL, Blobaum AL, Conn PJ, Niswender CM, Lindsley CW. Synthesis and SAR of a series of mGlu 7 NAMs based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinoline carboxylate core. Bioorg Med Chem Lett 2020; 30:127529. [PMID: 32890686 PMCID: PMC7686273 DOI: 10.1016/j.bmcl.2020.127529] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/24/2020] [Accepted: 08/27/2020] [Indexed: 10/23/2022]
Abstract
A High-Throughput Screening (HTS) campaign identified a fundamentally new mGlu7 NAM chemotype, based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinolone carboxylate core. The initial hit, VU0226390, was a potent mGlu7 NAM (IC50 = 647 nM, 6% L-AP4 min) with selectivity versus the other group III mGlu receptors (>30 μM vs. mGlu4 and mGlu8). A multi-dimensional optimization effort surveyed all regions of this new chemotype, and found very steep SAR, reminiscent of allosteric modulators, and unexpected piperazine mimetics (whereas classical bioisosteres failed). While mGlu7 NAM potency could be improved (IC50s ~ 350 nM), the necessity of the ethyl ester moiety and poor physiochemical and DMPK properties precluded optimization towards in vivo tool compounds or clinical candidates. Still, this hit-to-lead campaign afforded key medicinal chemistry insights and new opportunities.
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Affiliation(s)
- Jacob J Kalbfleisch
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
| | - Carson W Reed
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Charlotte Park
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Paul K Spearing
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Marc C Quitalig
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Matthew T Jenkins
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Alice L Rodriguez
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Anna L Blobaum
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - P Jeffrey Conn
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - Colleen M Niswender
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
| | - Craig W Lindsley
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
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22
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Luscombe VB, Lucy D, Bataille CJR, Russell AJ, Greaves DR. 20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor? DNA Cell Biol 2020; 39:1926-1937. [PMID: 33001759 DOI: 10.1089/dna.2020.5846] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
GPR84 is an inflammation-induced receptor highly expressed on immune cells, yet its endogenous ligand is still unknown. This makes any interpretation of its physiological activity in vivo difficult. However, experiments with potent synthetic agonists have highlighted what the receptor can do, namely, enhance proinflammatory signaling and macrophage effector functions such as phagocytosis. Developing drugs to block these effects has attracted interest from the scientific community with the aim of decreasing disease activity in inflammatory disorders or enhancing inflammation resolution. In this review, we critically reassess the widely held belief that the major role of GPR84 is that of being a medium-chain fatty acid (MCFA) receptor. While MCFAs have been shown to activate GPR84, it remains to be demonstrated that they are present in relevant tissues at appropriate concentrations. In contrast to four other "full-time" free fatty acid receptor subtypes, GPR84 is not expressed by enteroendocrine cells and has limited expression in the gastrointestinal tract. Across multiple tissues and cell types, the highest expression levels of GPR84 are observed hours after exposure to an inflammatory stimulus. These factors obscure the relationship between ligand and receptor in the human body and do not support the exclusive physiological pairing of MCFAs with GPR84. To maximize the chances of developing efficacious drugs for inflammatory diseases, we must advance our understanding of GPR84 and what it does in vivo.
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Affiliation(s)
- Vincent B Luscombe
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
| | - Daniel Lucy
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.,Department of Chemistry and University of Oxford, Oxford, United Kingdom
| | | | - Angela J Russell
- Department of Chemistry and University of Oxford, Oxford, United Kingdom.,Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - David R Greaves
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
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23
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Reed C, Kalbfleisch JJ, Wong MJ, Washecheck JP, Hunter A, Rodriguez AL, Blobaum AL, Conn PJ, Niswender CM, Lindsley CW. Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu 7 Positive Allosteric Modulator Tool Compound. ACS Med Chem Lett 2020; 11:1773-1779. [PMID: 32944146 PMCID: PMC7488291 DOI: 10.1021/acsmedchemlett.0c00432] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 08/20/2020] [Indexed: 01/07/2023] Open
Abstract
Herein, we report the discovery of the first selective and CNS penetrant mGlu7 PAM (VU6027459) derived from a "molecular switch" within a selective mGlu7 NAM chemotype. VU6027459 displayed CNS penetration in both mice (Kp = 2.74) and rats (Kp= 4.78), it was orally bioavailable in rats (%F = 69.5), and undesired activity at DAT was ablated.
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Affiliation(s)
- Carson
W. Reed
- Department
of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Jacob J. Kalbfleisch
- Department
of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Madison J. Wong
- Department
of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Jordan P. Washecheck
- Department
of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Ashton Hunter
- Warren
Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Alice L. Rodriguez
- Department
of Pharmacology, Vanderbilt University School
of Medicine, Nashville, Tennessee 37232, United States
- Warren
Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Anna L. Blobaum
- Department
of Pharmacology, Vanderbilt University School
of Medicine, Nashville, Tennessee 37232, United States
- Warren
Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - P. Jeffrey Conn
- Department
of Pharmacology, Vanderbilt University School
of Medicine, Nashville, Tennessee 37232, United States
- Warren
Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
- Vanderbilt
Kennedy Center, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Colleen M. Niswender
- Department
of Pharmacology, Vanderbilt University School
of Medicine, Nashville, Tennessee 37232, United States
- Warren
Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
- Vanderbilt
Kennedy Center, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Craig W. Lindsley
- Department
of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States
- Department
of Pharmacology, Vanderbilt University School
of Medicine, Nashville, Tennessee 37232, United States
- Warren
Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
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24
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Fisher NM, Gould RW, Gogliotti RG, McDonald AJ, Badivuku H, Chennareddy S, Buch AB, Moore AM, Jenkins MT, Robb WH, Lindsley CW, Jones CK, Conn PJ, Niswender CM. Phenotypic profiling of mGlu 7 knockout mice reveals new implications for neurodevelopmental disorders. GENES, BRAIN, AND BEHAVIOR 2020; 19:e12654. [PMID: 32248644 PMCID: PMC8034495 DOI: 10.1111/gbb.12654] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/03/2020] [Accepted: 03/26/2020] [Indexed: 12/17/2022]
Abstract
Neurodevelopmental disorders are characterized by deficits in communication, cognition, attention, social behavior and/or motor control. Previous studies have pointed to the involvement of genes that regulate synaptic structure and function in the pathogenesis of these disorders. One such gene, GRM7, encodes the metabotropic glutamate receptor 7 (mGlu7 ), a G protein-coupled receptor that regulates presynaptic neurotransmitter release. Mutations and polymorphisms in GRM7 have been associated with neurodevelopmental disorders in clinical populations; however, limited preclinical studies have evaluated mGlu7 in the context of this specific disease class. Here, we show that the absence of mGlu7 in mice is sufficient to alter phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep. Moreover, Grm7 knockout mice exhibit an attenuated response to amphetamine. These findings provide rationale for further investigation of mGlu7 as a potential therapeutic target for neurodevelopmental disorders such as idiopathic autism, attention deficit hyperactivity disorder and Rett syndrome.
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Affiliation(s)
- Nicole M. Fisher
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
| | - Robert W. Gould
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
| | - Rocco G. Gogliotti
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
| | - Annalise J. McDonald
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
| | - Hana Badivuku
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
| | - Susmita Chennareddy
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
| | - Aditi B. Buch
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
| | - Annah M. Moore
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
| | - Matthew T. Jenkins
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
| | - W. Hudson Robb
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
| | - Craig W. Lindsley
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee
| | - Carrie K. Jones
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - P. Jeffrey Conn
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Colleen M. Niswender
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee
- Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee
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25
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Lenart J, Augustyniak J, Lazarewicz JW, Zieminska E. Altered expression of glutamatergic and GABAergic genes in the valproic acid-induced rat model of autism: A screening test. Toxicology 2020; 440:152500. [DOI: 10.1016/j.tox.2020.152500] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 05/07/2020] [Accepted: 05/11/2020] [Indexed: 12/20/2022]
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26
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Shortall SE, Brown AM, Newton-Mann E, Dawe-Lane E, Evans C, Fowler M, King MV. Calbindin Deficits May Underlie Dissociable Effects of 5-HT 6 and mGlu 7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia. Mol Neurobiol 2020; 57:3439-3457. [PMID: 32533466 PMCID: PMC7340678 DOI: 10.1007/s12035-020-01938-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/13/2020] [Indexed: 12/11/2022]
Abstract
Despite several compounds entering clinical trials for the negative and cognitive symptoms of schizophrenia, few have progressed beyond phase III. This is partly attributed to a need for improved preclinical models, to understand disease and enable predictive evaluation of novel therapeutics. To this end, one recent approach incorporates "dual-hit" neurodevelopmental insults like neonatal phencyclidine plus isolation rearing (PCP-Iso). Glutamatergic dysfunction contributes to schizophrenia pathophysiology and may represent a treatment target, so we used enzyme-based microsensors to evaluate basal- and drug-evoked glutamate release in hippocampal slices from rats that received neonatal PCP and/or isolation rearing. 5-HT6 antagonist-evoked glutamate release (thought to be mediated indirectly via GABAergic disinhibition) was reduced in PCP-Iso, as were cognitive effects of a 5-HT6 antagonist in a hippocampal glutamate-dependent novel object discrimination task. Yet mGlu7 antagonist-evoked glutamatergic and cognitive responses were spared. Immunohistochemical analyses suggest these findings (which mirror the apparent lack of clinical response to 5-HT6 antagonists in schizophrenia) are not due to reduced hippocampal 5-HT input in PCP-Iso, but may be explained by reduced calbindin expression. This calcium-binding protein is present in a subset of GABAergic interneurons receiving preferential 5-HT innervation and expressing 5-HT6 receptors. Its loss (in schizophrenia and PCP-Iso) would be expected to reduce interneuron firing and potentially prevent further 5-HT6 antagonist-mediated disinhibition, without impacting on responses of VIP-expressing interneurons to mGlu7 antagonism. This research highlights the importance of improved understanding for selection of appropriate preclinical models, especially where disease neurobiology impacts on cells mediating the effects of potential therapeutics.
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Affiliation(s)
- Sinead E Shortall
- School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, Nottingham, NG7 2UH, UK
| | - Angus M Brown
- School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, Nottingham, NG7 2UH, UK
| | - Eliot Newton-Mann
- School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, Nottingham, NG7 2UH, UK
| | - Erin Dawe-Lane
- School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, Nottingham, NG7 2UH, UK
| | - Chanelle Evans
- School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, Nottingham, NG7 2UH, UK
| | - Maxine Fowler
- School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, Nottingham, NG7 2UH, UK
| | - Madeleine V King
- School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, Nottingham, NG7 2UH, UK.
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27
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Marafi D, Mitani T, Isikay S, Hertecant J, Almannai M, Manickam K, Abou Jamra R, El-Hattab AW, Rajah J, Fatih JM, Du H, Karaca E, Bayram Y, Punetha J, Rosenfeld JA, Jhangiani SN, Boerwinkle E, Akdemir ZC, Erdin S, Hunter JV, Gibbs RA, Pehlivan D, Posey JE, Lupski JR. Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy. Ann Clin Transl Neurol 2020; 7:610-627. [PMID: 32286009 PMCID: PMC7261753 DOI: 10.1002/acn3.51003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 02/10/2020] [Accepted: 02/11/2020] [Indexed: 01/29/2023] Open
Abstract
Objective Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G‐protein‐coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods Exome sequencing and family‐based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop‐gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal‐ or infantile‐onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic–pituitary–axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood. Conclusion Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.
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Affiliation(s)
- Dana Marafi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.,Department of Pediatrics, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110, Safat, Kuwait
| | - Tadahiro Mitani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030
| | - Sedat Isikay
- Department of Physiotherapy and Rehabilitation, School of Health Sciences, Hasan Kalyoncu University, Gaziantep, 27000, Turkey
| | - Jozef Hertecant
- Pediatric Metabolic and Genetics Division, Tawam Hospital, Al Ain, Abu Dhabi, United Arab Emirates
| | - Mohammed Almannai
- Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, 11525, Saudi Arabia
| | - Kandamurugu Manickam
- Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio
| | - Rami Abou Jamra
- Institute of Human Genetics, University Medical Center Leipzig, 04103, Leipzig, Germany
| | - Ayman W El-Hattab
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Jaishen Rajah
- Sheikh Khalifa Medical City (SKMC), P.O. Box: 51900, Abu Dhabi, United Arab Emirates
| | - Jawid M Fatih
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030
| | - Haowei Du
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030
| | - Ender Karaca
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030
| | - Yavuz Bayram
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030
| | - Jaya Punetha
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030
| | - Jill A Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030
| | - Shalini N Jhangiani
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030
| | - Eric Boerwinkle
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030.,Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas
| | - Zeynep C Akdemir
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030
| | - Serkan Erdin
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Jill V Hunter
- Texas Children's Hospital, Houston, Texas, 77030.,Department of Radiology, Baylor College of Medicine, Houston, Texas, 77030
| | - Richard A Gibbs
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.,Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030
| | - Davut Pehlivan
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.,Texas Children's Hospital, Houston, Texas, 77030.,Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030
| | - Jennifer E Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030
| | - James R Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.,Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030.,Texas Children's Hospital, Houston, Texas, 77030.,Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030
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28
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Elsayed NA, Yamamoto KM, Froehlich TE. Genetic Influence on Efficacy of Pharmacotherapy for Pediatric Attention-Deficit/Hyperactivity Disorder: Overview and Current Status of Research. CNS Drugs 2020; 34:389-414. [PMID: 32133580 PMCID: PMC8083895 DOI: 10.1007/s40263-020-00702-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Multiple stimulant and non-stimulant medications are approved for the treatment of attention-deficit/hyperactivity disorder (ADHD), one of the most prevalent childhood neurodevelopmental disorders. Choosing among the available agents and determining the most effective ADHD medication for a given child can be a time-consuming process due to the high inter-individual variability in treatment efficacy. As a result, there is growing interest in identifying predictors of ADHD medication response in children through the burgeoning field of pharmacogenomics. This article reviews childhood ADHD pharmacogenomics efficacy studies published during the last decade (2009-2019), which have largely focused on pharmacodynamic candidate gene investigations of methylphenidate and atomoxetine response, with a smaller number investigating pharmacokinetic candidate genes and genome-wide approaches. Findings from studies which have advanced the field of ADHD pharmacogenomics through investigation of meta-analytic approaches and gene-gene interactions are also overviewed. Despite recent progress, no one genetic variant or currently available pharmacogenomics test has demonstrated clinical utility in pinpointing the optimal ADHD medication for a given individual patient, highlighting the need for further investigation.
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Affiliation(s)
- Nada A Elsayed
- Division of Developmental and Behavioral Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 4002, Cincinnati, OH, 45229, USA
- Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kaila M Yamamoto
- Division of Developmental and Behavioral Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 4002, Cincinnati, OH, 45229, USA
| | - Tanya E Froehlich
- Division of Developmental and Behavioral Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 4002, Cincinnati, OH, 45229, USA.
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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29
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Liang W, Yu H, Su Y, Lu T, Yan H, Yue W, Zhang D. Variants of GRM7 as risk factor and response to antipsychotic therapy in schizophrenia. Transl Psychiatry 2020; 10:83. [PMID: 32127521 PMCID: PMC7054263 DOI: 10.1038/s41398-020-0763-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 01/07/2020] [Accepted: 02/12/2020] [Indexed: 11/09/2022] Open
Abstract
Genome-wide association study (GWAS) has determined the metabotropic glutamate receptor 7 (GRM7) gene as potential locus for schizophrenia risk variants; However, the relationship between the GRM7 variants and the risk of schizophrenia is still uncertain, and there are significant individual variations in response to the antipsychotic drugs. In order to identify susceptible gene and drug-response-related markers, 2413 subjects in our research were chosen for determining drug-response-related markers in schizophrenia. The rs1516569 variant (OR = 0.95, P < 3.47 × 10-4) was a significant risk factor, and a single-nucleotide polymorphism of GRM7 gene- rs9883258 (OR = 0.84, P = 2.18 × 10-3) has been determined as potential biomarkers for therapeutic responses of seven commonly used antipsychotic drugs (aripiprazole, haloperidol, olanzapine, perphenazine, quetiapine, risperidone and ziprasidone) in Chinese Han population; Significant associations with treatment response for several single-nucleotide polymorphisms in every antipsychotic drugs, such as rs779746 (OR = 1.39, P = 0.03), rs480409 (OR = 0.73, P = 0.04), rs78137319 (OR = 3.09, P = 0.04), rs1154370 (OR = 1.51, P = 0.006) have been identified in our study. Hence our research elucidates that GRM7 variants play the critical role of predicting the risk of schizophrenia and antipsychotic effect of seven common drugs.
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Affiliation(s)
- Wei Liang
- grid.459847.30000 0004 1798 0615Institute of Mental Health, Peking University Sixth Hospital, 100191 Beijing, China ,grid.453135.50000 0004 1769 3691NHC Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University Sixth Hospital), 100191 Beijing, China
| | - Hao Yu
- grid.449428.70000 0004 1797 7280Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Department of Psychiatry, Jining Medical University, 272067 Jining, Shandong China
| | - Yi Su
- grid.459847.30000 0004 1798 0615Institute of Mental Health, Peking University Sixth Hospital, 100191 Beijing, China ,grid.453135.50000 0004 1769 3691NHC Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University Sixth Hospital), 100191 Beijing, China
| | - Tianlan Lu
- grid.459847.30000 0004 1798 0615Institute of Mental Health, Peking University Sixth Hospital, 100191 Beijing, China ,grid.453135.50000 0004 1769 3691NHC Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University Sixth Hospital), 100191 Beijing, China
| | - Hao Yan
- grid.459847.30000 0004 1798 0615Institute of Mental Health, Peking University Sixth Hospital, 100191 Beijing, China ,grid.453135.50000 0004 1769 3691NHC Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University Sixth Hospital), 100191 Beijing, China
| | - Weihua Yue
- Institute of Mental Health, Peking University Sixth Hospital, 100191, Beijing, China. .,NHC Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University Sixth Hospital), 100191, Beijing, China. .,PKU-IDG/McGovern Institute for Brain Research, Peking University, 100871, Beijing, China. .,Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, 100191, Beijing, China.
| | - Dai Zhang
- Institute of Mental Health, Peking University Sixth Hospital, 100191, Beijing, China. .,NHC Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University Sixth Hospital), 100191, Beijing, China. .,PKU-IDG/McGovern Institute for Brain Research, Peking University, 100871, Beijing, China.
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30
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Jullié D, Stoeber M, Sibarita JB, Zieger HL, Bartol TM, Arttamangkul S, Sejnowski TJ, Hosy E, von Zastrow M. A Discrete Presynaptic Vesicle Cycle for Neuromodulator Receptors. Neuron 2020; 105:663-677.e8. [PMID: 31837915 PMCID: PMC7035187 DOI: 10.1016/j.neuron.2019.11.016] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 08/02/2019] [Accepted: 11/11/2019] [Indexed: 01/27/2023]
Abstract
A major function of GPCRs is to inhibit presynaptic neurotransmitter release, requiring ligand-activated receptors to couple locally to effectors at terminals. The current understanding of how this is achieved is through receptor immobilization on the terminal surface. Here, we show that opioid peptide receptors, GPCRs that mediate highly sensitive presynaptic inhibition, are instead dynamic in axons. Opioid receptors diffuse rapidly throughout the axon surface and internalize after ligand-induced activation specifically at presynaptic terminals. We delineate a parallel regulated endocytic cycle for GPCRs operating at the presynapse, separately from the synaptic vesicle cycle, which clears activated receptors from the surface of terminals and locally reinserts them to maintain the diffusible surface pool. We propose an alternate strategy for achieving local control of presynaptic effectors that, opposite to using receptor immobilization and enforced proximity, is based on lateral mobility of receptors and leverages the inherent allostery of GPCR-effector coupling.
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Affiliation(s)
- Damien Jullié
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco School of Medicine, San Francisco, California 94158, USA,Department of Psychiatry, University of California, San Francisco School of Medicine, San Francisco, California 94158, USA
| | - Miriam Stoeber
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco School of Medicine, San Francisco, California 94158, USA,Department of Psychiatry, University of California, San Francisco School of Medicine, San Francisco, California 94158, USA,Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland
| | - Jean-Baptiste Sibarita
- Interdisciplinary Institute for Neuroscience, UMR 5297, Centre National de la Recherche Scientifique, 33077 Bordeaux, France,Interdisciplinary Institute for Neuroscience, University of Bordeaux, 33077 Bordeaux, France
| | - Hanna L. Zieger
- Interdisciplinary Institute for Neuroscience, UMR 5297, Centre National de la Recherche Scientifique, 33077 Bordeaux, France,Interdisciplinary Institute for Neuroscience, University of Bordeaux, 33077 Bordeaux, France
| | - Thomas M. Bartol
- Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037, USA
| | - Seksiri Arttamangkul
- The Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
| | - Terrence J. Sejnowski
- Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037, USA
| | - Eric Hosy
- Interdisciplinary Institute for Neuroscience, UMR 5297, Centre National de la Recherche Scientifique, 33077 Bordeaux, France,Interdisciplinary Institute for Neuroscience, University of Bordeaux, 33077 Bordeaux, France
| | - Mark von Zastrow
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco School of Medicine, San Francisco, California 94158, USA,Department of Psychiatry, University of California, San Francisco School of Medicine, San Francisco, California 94158, USA,Lead contact,Correspondence:
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31
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Srivastava A, Das B, Yao AY, Yan R. Metabotropic Glutamate Receptors in Alzheimer's Disease Synaptic Dysfunction: Therapeutic Opportunities and Hope for the Future. J Alzheimers Dis 2020; 78:1345-1361. [PMID: 33325389 PMCID: PMC8439550 DOI: 10.3233/jad-201146] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of neuritic plaques and neurofibrillary tangles. The impaired synaptic plasticity and dendritic loss at the synaptic level is an early event associated with the AD pathogenesis. The abnormal accumulation of soluble oligomeric amyloid-β (Aβ), the major toxic component in amyloid plaques, is viewed to trigger synaptic dysfunctions through binding to several presynaptic and postsynaptic partners and thus to disrupt synaptic transmission. Over time, the abnormalities in neural transmission will result in cognitive deficits, which are commonly manifested as memory loss in AD patients. Synaptic plasticity is regulated through glutamate transmission, which is mediated by various glutamate receptors. Here we review recent progresses in the study of metabotropic glutamate receptors (mGluRs) in AD cognition. We will discuss the role of mGluRs in synaptic plasticity and their modulation as a possible strategy for AD cognitive improvement.
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Affiliation(s)
- Akriti Srivastava
- Department of Neuroscience, University of Connecticut Health, Farmington, CT, USA
| | - Brati Das
- Department of Neuroscience, University of Connecticut Health, Farmington, CT, USA
| | - Annie Y. Yao
- Department of Neuroscience, University of Connecticut Health, Farmington, CT, USA
| | - Riqiang Yan
- Department of Neuroscience, University of Connecticut Health, Farmington, CT, USA
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32
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Surveying heterocycles as amide bioisosteres within a series of mGlu7 NAMs: Discovery of VU6019278. Bioorg Med Chem Lett 2019; 29:1211-1214. [DOI: 10.1016/j.bmcl.2019.03.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/18/2019] [Accepted: 03/13/2019] [Indexed: 12/19/2022]
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33
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Llinas Del Torrent C, Pérez-Benito L, Tresadern G. Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors. Molecules 2019; 24:molecules24061098. [PMID: 30897742 PMCID: PMC6470756 DOI: 10.3390/molecules24061098] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 11/16/2022] Open
Abstract
Metabotropic glutamate (mGlu) receptors are a family of eight GPCRs that are attractive drug discovery targets to modulate glutamate action and response. Here we review the application of computational methods to the study of this family of receptors. X-ray structures of the extracellular and 7-transmembrane domains have played an important role to enable structure-based modeling approaches, whilst we also discuss the successful application of ligand-based methods. We summarize the literature and highlight the areas where modeling and experiment have delivered important understanding for mGlu receptor drug discovery. Finally, we offer suggestions of future areas of opportunity for computational work.
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Affiliation(s)
- Claudia Llinas Del Torrent
- Laboratori de Medicina Computacional Unitat de Bioestadistica, Facultat de Medicina, Universitat Autónoma de Barcelona, 08193 Bellaterra, Spain.
| | - Laura Pérez-Benito
- Computational Chemistry, Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium.
| | - Gary Tresadern
- Computational Chemistry, Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium.
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34
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Reed CW, Yohn SE, Washecheck JP, Roenfanz HF, Quitalig MC, Luscombe VB, Jenkins MT, Rodriguez AL, Engers DW, Blobaum AL, Conn PJ, Niswender CM, Lindsley CW. Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu 7 Negative Allosteric Modulator (NAM) in Vivo Tool Compound: N-(2-(1 H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962). J Med Chem 2019; 62:1690-1695. [PMID: 30608678 DOI: 10.1021/acs.jmedchem.8b01810] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu7) negative allosteric modulator (NAM) that achieves exposure in cerebral spinal fluid (CSF) 2.5× above the in vitro IC50 at minimum effective doses (MEDs) of 3 mg/kg in preclinical anxiety models.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - P Jeffrey Conn
- Vanderbilt Kennedy Center , Vanderbilt University School of Medicine , Nashville , Tennessee 37232 , United States
| | - Colleen M Niswender
- Vanderbilt Kennedy Center , Vanderbilt University School of Medicine , Nashville , Tennessee 37232 , United States
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