HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 566/3/657    most recent jphysiol.2005.088575v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miller, P. S Articles by Smart, T. G Search for Related Content PubMed PubMed Citation Articles by Miller, P. S Articles by Smart, T. G

¹ Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK
² Department of Pharmacology, School of Pharmacy, 29–39 Brunswick Square, London WC1N 1AX, UK

Glycine receptors exhibit a biphasic sensitivity profile in response to Zn²⁺-mediated modulation, with low Zn²⁺ concentrations potentiating (< 10 µM), and higher Zn²⁺ concentrations inhibiting submaximal responses to glycine. Here, a substantial 30-fold increase in sensitivity to Zn²⁺-mediated inhibition was apparent for the homomeric glycine receptor (GlyR) 1 subunit compared to either GlyR 2 or 3 subtypes. Swapping the divergent histidine (H107) residue in GlyR 1, which together with the conserved H109 forms part of an intersubunit Zn²⁺-binding site, for the equivalent asparagine residue present in GlyR 2 and 3, reversed this phenotype. Co-expression of heteromeric GlyR 1 or 2 with the ancillary ß subunit yielded receptors that maintained their distinctive sensitivities to Zn²⁺ inhibition. However, GlyR 2ß heteromers were consistently 2-fold more sensitive to inhibition compared to the GlyR 2 homomer. Comparative studies to elucidate the specific residue in the ß subunit responsible for this differential sensitivity revealed instead threonine 133 in the 1 subunit as a new vital component for Zn²⁺-mediated inhibition. Further studies on heteromeric receptors demonstrated that a mutated ß subunit could indeed affect Zn²⁺-mediated inhibition but only from one side of the intersubunit Zn²⁺-binding site, equivalent to the GlyR 1 H107 face. This strongly suggests that the subunit is responsible for Zn²⁺-mediated inhibition and that this is effectively transduced, asymmetrically, from the side of the Zn²⁺-binding site where H109 and T133 are located.

(Received 15 April 2005; accepted after revision 18 May 2005; first published online 19 May 2005)
Corresponding author T. G. Smart: Department of Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK. Email: t.smart{at}ucl.ac.uk

This article has been cited by other articles:

				M. Moroni, R. Vijayan, A. Carbone, R. Zwart, P. C. Biggin, and I. Bermudez Non-Agonist-Binding Subunit Interfaces Confer Distinct Functional Signatures to the Alternate Stoichiometries of the {alpha}4{beta}2 Nicotinic Receptor: An {alpha}4-{alpha}4 Interface Is Required for Zn2+ Potentiation J. Neurosci., July 2, 2008; 28(27): 6884 - 6894. [Abstract] [Full Text] [PDF]

				H. X. Zhang and L. L. Thio Zinc Enhances the Inhibitory Effects of Strychnine-Sensitive Glycine Receptors in Mouse Hippocampal Neurons J Neurophysiol, December 1, 2007; 98(6): 3666 - 3676. [Abstract] [Full Text] [PDF]

				P. S. Miller, H. M. A. Da Silva, and T. G. Smart Molecular Basis for Zinc Potentiation at Strychnine-sensitive Glycine Receptors J. Biol. Chem., November 11, 2005; 280(45): 37877 - 37884. [Abstract] [Full Text] [PDF]