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Pharmacology of Metabotropic Glutamate Receptor 2 Homo‐ and Heterodimers
Author(s) -
McCullock Tyler William,
Kammermeier Paul
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06302
Subject(s) - metabotropic glutamate receptor 2 , metabotropic glutamate receptor , g protein coupled receptor , neuroscience , class c gpcr , biology , metabotropic glutamate receptor 1 , metabotropic glutamate receptor 6 , agonist , receptor , metabotropic receptor , glutamate receptor , computational biology , chemistry , biochemistry
Metabotropic Glutamate Receptors (mGluRs) are a family of class C g‐protein coupled receptors (GPCRs) that respond to glutamate as their native agonist. The eight members of the mGluR family are widely expressed across the nervous and are primarily charged with shaping and fine‐tuning neuronal excitability and synaptic efficacy. Like most class C GPCRs, mGluRs are obligate dimer proteins. All mGluRs maintain the capacity to homodimerize, but recent work has demonstrated that heterodimeric mGluRs can form and exist natively. Further, studies of the mGluR2‐4 heterodimer have demonstrated that this heterodimeric receptor exhibits a distinct and unpredicted pharmacological profile compared to either the mGluR2 homodimer or the mGluR4 homodimer. These findings underscore the importance of better understanding mGluR heterodimer pharmacology, particularly with preclinical studies showing promising results for leveraging mGluRs as therapeutic targets for a wide variety of conditions. To develop a better understanding of the behavior of mGluR2, we used a multifaceted approach to investigate mGluR2s dimerization preferences, whole cell signaling, and individual receptor signaling when expressed by itself, or with other mGluRs. To test dimerization preference, we utilize a split luciferase assay. To test whole cell signaling, we utilize a bioluminescent resonance energy transfer (BRET) based G‐protein Beta‐Gamma sensor. Finally, to detect and determine the pharmacological profile of specific mGluR2 heterodimers, we combine the split luciferase technique with BRET, allowing us to isolate signals from a specific dimer within a population of receptors. These studies will help define the pharmacological profile of various mGluR2 containing heterodimers, as well as develop new tools to help further interrogate the pharmacology of other dimer complexes. These new tools are also high‐throughput compatible, allowing for the development of more advanced drug screens to identify new molecules that specifically target mGluR heterodimers. Support or Funding Information University of Rochester Harold C Hodge Memorial Fund and the University of Rochester Drug Targets and Mechanism Pilot Award