Molecular determinants for G protein betagamma modulation of ionotropic glycine receptors.
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.
Yevenes
Gonzalo E
GE
Laboratory of Neurophysiology, Department of Physiology, University of Concepción, Concepción, Chile.
Moraga-Cid
Gustavo
G
Guzmán
Leonardo
L
Haeger
Svenja
S
Oliveira
Laerte
L
Olate
Juan
J
Schmalzing
Günther
G
Aguayo
Luis G
LG
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002460:Cell Line; D004594:Electrophysiology; D044387:GTP-Binding Protein beta Subunits / Q000737:chemistry / Q000502:physiology*; D044388:GTP-Binding Protein gamma Subunits / Q000737:chemistry / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000737:chemistry; D006801:Humans; D008051:Lipid Bilayers; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D018009:Receptors, Glycine / Q000737:chemistry* / Q000502:physiology*; D015398:Signal Transduction
D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D008051:Lipid Bilayers; D018009:Receptors, Glycine; D019204:GTP-Binding Proteins