title: Selectivity and evolutionary divergence of metabotropic glutamate receptors for endogenous ligands and G proteins coupled to phospholipase C or TRP channels.
abstract: To define the upstream and downstream signaling specificities of metabotropic glutamate receptors (mGluR), we have examined the ability of representative mGluR of group I, II, and III to be activated by endogenous amino acids and catalyze activation of G proteins coupled to phospholipase C (PLC), or activation of G(i/o) proteins coupled to the ion channel TRPC4β. Fluorescence-based assays have allowed us to observe interactions not previously reported or clearly identified. We have found that the specificity for endogenous amino acids is remarkably stringent. Even at millimolar levels, structurally similar compounds do not elicit significant activation. As reported previously, the clear exception is L-serine-O-phosphate (L-SOP), which strongly activates group III mGluR, especially mGluR4,-6,-8 but not group I or II mGluR. Whereas L-SOP cannot activate mGluR1 or mGluR2, it acts as a weak antagonist for mGluR1 and a potent antagonist for mGluR2, suggesting that co-recognition of L-glutamate and L-SOP arose early in evolution, and was followed later by divergence of group I and group II mGluR versus group III in l-SOP responses. mGluR7 has low affinity and efficacy for activation by both L-glutamate and L-SOP. Molecular docking studies suggested that residue 74 corresponding to lysine in mGluR4 and asparagine in mGluR7 might play a key role, and, indeed, mutagenesis experiments demonstrated that mutating this residue to lysine in mGluR7 enhances the potency of L-SOP. Experiments with pertussis toxin and dominant-negative Gα(i/o) proteins revealed that mGluR1 couples strongly to TRPC4β through Gα(i/o), in addition to coupling to PLC through Gα(q/11).
authors.affiliation: From the Graduate Program in Structural and Computational Biology and Molecular Biophysics.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: From the Graduate Program in Structural and Computational Biology and Molecular Biophysics.
authors.forename: Kit
authors.initials: K
authors.lastname: Menlove
authors.affiliation: From the Graduate Program in Structural and Computational Biology and Molecular Biophysics, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, and Department of Bioengineering, Rice University, Houston, Texas 77005.
authors.forename: Jianpeng
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, and.
authors.forename: Angela
authors.initials: A
authors.lastname: Wilkins
authors.affiliation: From the Graduate Program in Structural and Computational Biology and Molecular Biophysics, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lichtarge
authors.affiliation: From the Graduate Program in Structural and Computational Biology and Molecular Biophysics, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, and twensel@bcm.edu.
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Wensel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D019143:Evolution, Molecular; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005799:Genes, Dominant; D018698:Glutamic Acid / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010768:Phosphoserine / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050051:Transient Receptor Potential Channels / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D008024:Ligands; D021122:Protein Subunits; D018094:Receptors, Metabotropic Glutamate; D050051:Transient Receptor Potential Channels; D010768:Phosphoserine; D018698:Glutamic Acid; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D002118:Calcium
keywords: G Protein; G Protein-coupled Receptor (GPCR); Metabotropic Glutamate Receptor (mGluR); Signal Transduction; Transient Receptor Potential Channels (TRP Channels)