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J. Biol. Chem., Vol. 280, Issue 45, 37877-37884, November 11, 2005

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Molecular Basis for Zinc Potentiation at Strychnine-sensitive Glycine Receptors^*

From the Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom

The divalent cation Zn²⁺ is a potent potentiator at the strychnine-sensitive glycine receptor (GlyR). This occurs at nanomolar concentrations, which are the predicted endogenous levels of extracellular neuronal Zn²⁺. Using structural modeling and functional mutagenesis, we have identified the molecular basis for the elusive Zn²⁺ potentiation site on GlyRs and account for the differential sensitivity of GlyR ₁ and GlyR ₂ to Zn²⁺ potentiation. In addition, juxtaposed to this Zn²⁺ site, which is located externally on the N-terminal domain of the subunit, another residue was identified in the nearby Cys loop, a region that is critical for receptor gating in all Cys loop ligand-gated ion channels. This residue acted as a key control element in the allosteric transduction pathway for Zn²⁺ potentiation, enabling either potentiation or overt inhibition of receptor activation depending upon the moiety resident at this location. Overall, we propose that Zn²⁺ binds to a site on the extracellular outer face of the GlyR subunit and exerts its positive allosteric effect via an interaction with the Cys loop to increase the efficacy of glycine receptor gating.

Received for publication, July 28, 2005

^* This work was supported by the Medical Research Council and the Wellcome Trust. 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 A Wellcome Trust four year Ph.D. postgraduate student.

² To whom correspondence should be addressed: Dept. of Pharmacology, University College London, Gower St., London, WC1E 6BT, United Kingdom. Tel.: 0207-679-2013; Fax: 0207-679-7298; E-mail: t.smart{at}ucl.ac.uk.

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