Yevenes Gonzalo E, Moraga-Cid Gustavo, Guzmán Leonardo, Haeger Svenja, Oliveira Laerte, Olate Juan, Schmalzing Günther, Aguayo Luis G
Laboratory of Neurophysiology, Department of Physiology, University of Concepción, Concepción, Chile.
J Biol Chem. 2006 Dec 22;281(51):39300-7. doi: 10.1074/jbc.M608272200. Epub 2006 Oct 12.
The ligand-gated ion channel superfamily plays a critical role in neuronal excitability. The functions of glycine receptor (GlyR) and nicotinic acetylcholine receptor are modulated by G protein betagamma subunits. The molecular determinants for this functional modulation, however, are still unknown. Studying mutant receptors, we identified two basic amino acid motifs within the large intracellular loop of the GlyR alpha(1) subunit that are critical for binding and functional modulation by Gbetagamma. Mutations within these sequences demonstrated that all of the residues detected are important for Gbetagamma modulation, although both motifs are necessary for full binding. Molecular modeling predicts that these sites are alpha-helixes near transmembrane domains 3 and 4, near to the lipid bilayer and highly electropositive. Our results demonstrate for the first time the sites for G protein betagamma subunit modulation on GlyRs and provide a new framework regarding the ligand-gated ion channel superfamily regulation by intracellular signaling.
配体门控离子通道超家族在神经元兴奋性中起关键作用。甘氨酸受体（GlyR）和烟碱型乙酰胆碱受体的功能受G蛋白βγ亚基调节。然而，这种功能调节的分子决定因素仍不清楚。通过研究突变受体，我们在GlyR α(1)亚基的大细胞内环中鉴定出两个碱性氨基酸基序，它们对于Gβγ的结合和功能调节至关重要。这些序列中的突变表明，所有检测到的残基对于Gβγ调节都很重要，尽管两个基序对于完全结合都是必需的。分子建模预测，这些位点是靠近跨膜结构域3和4的α螺旋，靠近脂质双层且高度带正电。我们的结果首次证明了G蛋白βγ亚基在GlyRs上的调节位点，并为细胞内信号传导对配体门控离子通道超家族的调节提供了一个新框架。
