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J. Biol. Chem., Vol. 281, Issue 51, 39300-39307, December 22, 2006
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Modulation of Ionotropic Glycine Receptors*





1
From the
Laboratory of Neurophysiology, Department of Physiology, University of Concepción, Concepción, Chile, the
Department of Molecular Pharmacology, Medical School of the Technical University of Aachen, Aachen, Germany, the ¶Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil, and the ||Laboratory of Molecular Genetics, Department of Biochemistry and Molecular Biology, University of Concepción, Concepción, Chile
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 
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
1 subunit that are critical for binding and functional modulation by G
. Mutations within these sequences demonstrated that all of the residues detected are important for G
modulation, although both motifs are necessary for full binding. Molecular modeling predicts that these sites are
-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 
subunit modulation on GlyRs and provide a new framework regarding the ligand-gated ion channel superfamily regulation by intracellular signaling.
Received for publication, August 29, 2006 , and in revised form, October 4, 2006.
* This work was supported by the National Institute on Alcohol Abuse and Alcoholism Grant RO1 AA15150-01, FONDECYT Grant 1020475, CONICYT Grant AT-4040102, funds from the Andes Foundation, and Deutsche Forschungsgemeinschaft Grants Schm536/4-l and 4-2. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Dept. of Physiology, University of Concepción, P.O. Box 160-C, Concepción, Chile. Tel.: 56-41-2203380; Fax: 56-41-2245975; E-mail: laguayo{at}udec.cl.
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