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J. Biol. Chem., Vol. 278, Issue 36, 34079-34083, September 5, 2003

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A Highly Conserved Aspartic Acid Residue in the Signature Disulfide Loop of the 1 Subunit Is a Determinant of Gating in the Glycine Receptor^*

Claude M. Schofield  , Andrew Jenkins ¶ and Neil L. Harrison ||

From the Graduate Program in Neuroscience and the ^||Departments of Anesthesiology and Pharmacology, Weill Medical College of Cornell University, New York, New York 10021 and the ^¶Department of Anesthesiology, Emory University, Atlanta, Georgia 30322

Ligand-gated ion channels (LGICs) mediate rapid chemical neurotransmission. This gene superfamily includes the nicotinic acetylcholine, GABA_A/C, 5-hydroxytryptamine type 3, and glycine receptors. A signature disulfide loop (Cys loop) in the extracellular domain is a structural motif common to all LGIC member subunits. Here we report that a highly conserved aspartic acid residue within the Cys loop at position 148 (Asp-148) of the glycine receptor 1 subunit is critical in the process of receptor activation. Mutation of this acidic residue to the basic amino acid lysine produces a large decrease in the potency of glycine, produces a decrease in the Hill slope, and converts taurine from a full agonist to a partial agonist; these data are consistent with a molecular defect in the receptor gating mechanism. Additional mutation of Asp-148 shows that alterations in the EC₅₀ for agonists are dependent upon the charge of the side chain at this position and not molecular volume, polarity, or hydropathy. This study implicates negative charge at position Asp-148 as a critical component of the process in which agonist binding is coupled to channel gating. This finding adds to an emerging body of evidence supporting the involvement of the Cys loop in the gating mechanism of the LGICs.

Received for publication, March 10, 2003 , and in revised form, May 22, 2003.

^* 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.

To whom correspondence should be addressed: C. V. Starr Laboratory for Molecular Neuropharmacology, Dept. of Anesthesiology, Rm. A1040, Weill Medical College of Cornell University, 525 E. 68th St., New York, NY 10021. Tel.: 212-746-1150; Fax: 212-746-4879; E-mail: cms2002{at}med.cornell.edu.

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