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J. Biol. Chem., Vol. 282, Issue 38, 27944-27952, September 21, 2007

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The Role of Distal S6 Hydrophobic Residues in the Voltage-dependent Gating of Ca_V2.3 Channels^*

From the Département de Physiologie and the Membrane Protein Research Group, Université de Montréal, Montréal, Québec H3C 3J7, Canada

The hydrophobic locus VAVIM is conserved in the S6 transmembrane segment of domain IV (IVS6) in Ca_V1 and Ca_V2 families. Herein we show that glycine substitution of the VAVIM motif in Ca_V2.3 produced whole cell currents with inactivation kinetics that were either slower (A1719G V1720G), similar (V1718G), or faster (I1721G M1722G) than the wild-type channel. The fast kinetics of I1721G were observed with a +10 mV shift in its voltage dependence of activation (E_0.5,act). In contrast, the slow kinetics of A1719G and V1720G were accompanied by a significant shift of -20 mV in their E_0.5,act indicating that the relative stability of the channel closed state was decreased in these mutants. Glycine scan performed with Val ³⁴⁹ in IS6, Ile⁷⁰¹ in IIS6, and Leu¹⁴²⁰ in IIIS6 at positions predicted to face Val¹⁷²⁰ in IVS6 also produced slow inactivating currents with hyperpolarizing shifts in the activation and inactivation potentials, again pointing out a decrease in the stability of the channel closed state. Mutations to other hydrophobic residues at these positions nearly restored the channel gating. Altogether these data indicate that residues at positions equivalent to 1720 exert a critical control upon the relative stability of the channel closed and open states and more specifically, that hydrophobic residues at these positions promote the channel closed state. We discuss a three-dimensional homology model of Ca_V2.3 based upon Kv1.2 where hydrophobic residues at positions facing Val¹⁷²⁰ in IS6, IIS6, and IIIS6 play a critical role in stabilizing the closed state in Ca_V2.3.

Received for publication, May 11, 2007 , and in revised form, July 6, 2007.

^* This work was supported by Canadian Institutes of Health Research Grant MOP13390 and a grant from the Canadian Heart and Stroke Foundation (to L. P.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2 and Figs. S1–S6.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: P.O. Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada. Tel.: 514-343-6673; Fax: 514-343-7146; E-mail: lucie.parent{at}umontreal.ca.

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