Molecular Determinants for G Protein Modulation of Ionotropic Glycine Receptors*
Journal - Journal of Biological Chemistry
The ligand-gated ion channel superfamily plays a critical rolein neuronal excitability. The functions of glycine receptor(GlyR) and nicotinic acetylcholine receptor are modulated byG protein subunits. The molecular determinants for this functionalmodulation, however, are still unknown. Studying mutant receptors,we identified two basic amino acid motifs within the large intracellularloop of the GlyR 1 subunit that are critical for binding andfunctional modulation by G. Mutations within these sequencesdemonstrated that all of the residues detected are importantfor G modulation, although both motifs are necessary for fullbinding. Molecular modeling predicts that these sites are -helixesnear transmembrane domains 3 and 4, near to the lipid bilayerand highly electropositive. Our results demonstrate for thefirst time the sites for G protein subunit modulation on GlyRsand provide a new framework regarding the ligand-gated ion channelsuperfamily regulation by intracellular signaling.* This work was supported by the National Institute on AlcoholAbuse and Alcoholism Grant RO1 AA15150-01, FONDECYT Grant 1020475,CONICYT Grant AT-4040102, funds from the Andes Foundation, andDeutsche Forschungsgemeinschaft Grants Schm536/4-l and 4-2.The costs of publication of this article were defrayed in partby the payment of page charges. This article must thereforebe hereby marked "advertisement" in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.