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J. Biol. Chem., Vol. 282, Issue 35, 25623-25630, August 31, 2007

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Transducing Agonist Binding to Channel Gating Involves Different Interactions in 5-HT₃ and GABA_C Receptors^*

Kerry L. Price, Katherine S. Millen, and Sarah C. R. Lummis, A Wellcome Trust Senior Research Fellow in Basic Biomedical Science¹

From the Department of Biochemistry, University of Cambridge and Neurobiology Division, MRC-LMB, Hills Rd., Cambridge CB2 2QH, United Kingdom

5-Hydroxytryptamine (5-HT)₃ and -aminobutyric acid, type C (GABA_C) receptors are members of the Cys-loop superfamily of neurotransmitter receptors, which also includes nicotinic acetylcholine, GABA_A, and glycine receptors. The details of how agonist binding to these receptors results in channel opening is not fully understood but is known to involve charged residues at the extracellular/transmembrane interface. Here we have examined the roles of such residues in 5-HT₃ and GABA_C receptors. Charge reversal experiments combined with data from activation by the partial agonist -alanine show that in GABA_C receptors there is a salt bridge between Glu-92 (in loop 2) and Arg-258 (in the pre-M1 region), which is involved in receptor gating. The equivalent residues in the 5-HT₃ receptor are important for receptor expression, but charge reversal experiments do not restore function, indicating that there is not a salt bridge here. There is, however, an interaction between Glu-215 (loop 9) and Arg-246 (pre-M1) in the 5-HT₃ receptor, although the coupling energy determined from mutant cycle analysis is lower than might be expected for a salt bridge. Overall the data show that charged residues at the extracellular/transmembrane domain interfaces in 5-HT₃ and GABA_C receptors are important and that specific, but not equivalent, molecular interactions between them are involved in the gating process. Thus, we propose that the molecular details of interactions in the transduction pathway between the binding site and the pore can differ between different Cys-loop receptors.

Received for publication, March 23, 2007 , and in revised form, May 30, 2007.

^* This work was supported by a Biotechnology and Biological Sciences Research Council, Swindon, United Kingdom studentship (to K. S. M.) and by the Wellcome Trust (to K. L. P. and S. C. R. L.). 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 Biochemistry, University of Cambridge, Tennis Ct. Rd., Cambridge, UK. Tel.: 44-1223-765950; Fax: 44-1223-333345; E-mail: sl120{at}cam.ac.uk.

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