title: Chloride is an Agonist of Group II and III Metabotropic Glutamate Receptors.
abstract: The elemental anion chloride is generally considered a passive participant in neuronal excitability, and has never been shown to function as an agonist in its own right. We show that the antagonist-mediated, glutamate-independent inverse agonism of group II and III metabotropic glutamate (mGlu) receptors results from inhibition of chloride-mediated activation. In silico molecular modeling, site-directed mutagenesis, and functional assays demonstrate (1) that chloride is an agonist of mGlu3, mGlu4, mGlu6, and mGlu8 receptors with its own orthosteric site, and (2) that chloride is not an agonist of mGlu2 receptors. Molecular modeling-predicted and site-directed mutagenesis supported that this unique property of mGlu2 receptors results from a single divergent amino acid, highlighting a molecular switch for chloride insensitivity that is transduced through an arginine flip. Ultimately, these results suggest that activation of group II and III mGlu receptors is mediated not only by glutamate, but also by physiologically relevant concentrations of chloride.
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia (J.O.D., E.J.M., D.C.L.); and Department of Pharmacology, Georgetown University, Washington, DC (J.O.D., C.B.-D., B.W., M.J., E.G., B.B.W., J.T.W.).
authors.forename: John O
authors.initials: JO
authors.lastname: DiRaddo
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia (J.O.D., E.J.M., D.C.L.); and Department of Pharmacology, Georgetown University, Washington, DC (J.O.D., C.B.-D., B.W., M.J., E.G., B.B.W., J.T.W.).
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Miller
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia (J.O.D., E.J.M., D.C.L.); and Department of Pharmacology, Georgetown University, Washington, DC (J.O.D., C.B.-D., B.W., M.J., E.G., B.B.W., J.T.W.).
authors.forename: Carrie
authors.initials: C
authors.lastname: Bowman-Dalley
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia (J.O.D., E.J.M., D.C.L.); and Department of Pharmacology, Georgetown University, Washington, DC (J.O.D., C.B.-D., B.W., M.J., E.G., B.B.W., J.T.W.).
authors.forename: Barbara
authors.initials: B
authors.lastname: Wroblewska
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia (J.O.D., E.J.M., D.C.L.); and Department of Pharmacology, Georgetown University, Washington, DC (J.O.D., C.B.-D., B.W., M.J., E.G., B.B.W., J.T.W.).
authors.forename: Monica
authors.initials: M
authors.lastname: Javidnia
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia (J.O.D., E.J.M., D.C.L.); and Department of Pharmacology, Georgetown University, Washington, DC (J.O.D., C.B.-D., B.W., M.J., E.G., B.B.W., J.T.W.).
authors.forename: Ewa
authors.initials: E
authors.lastname: Grajkowska
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia (J.O.D., E.J.M., D.C.L.); and Department of Pharmacology, Georgetown University, Washington, DC (J.O.D., C.B.-D., B.W., M.J., E.G., B.B.W., J.T.W.).
authors.forename: Barry B
authors.initials: BB
authors.lastname: Wolfe
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia (J.O.D., E.J.M., D.C.L.); and Department of Pharmacology, Georgetown University, Washington, DC (J.O.D., C.B.-D., B.W., M.J., E.G., B.B.W., J.T.W.).
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia (J.O.D., E.J.M., D.C.L.); and Department of Pharmacology, Georgetown University, Washington, DC (J.O.D., C.B.-D., B.W., M.J., E.G., B.B.W., J.T.W.) wroblewj@georgetown.edu.
authors.forename: Jarda T
authors.initials: JT
authors.lastname: Wroblewski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002712:Chlorides / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D018698:Glutamic Acid / Q000494:pharmacology; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D002712:Chlorides; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid