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J. Biol. Chem., Vol. 281, Issue 51, 39424-39436, December 22, 2006

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The Role of the GX₉GX₃G Motif in the Gating of High Voltage-activated Ca²⁺ Channels^*

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

The putative hinge point revealed by the crystal structure of the MthK potassium channel is a glycine residue that is conserved in many ion channels. In high voltage-activated (HVA) Ca_V channels, the mid-S6 glycine residue is only present in IS6 and IIS6, corresponding to G422 and G770 in Ca_V1.2. Two additional glycine residues are found in the distal portion of IS6 (Gly⁴³² and Gly⁴³⁶ in Ca_V1.2) to form a triglycine motif unique to HVA Ca_V channels. Lethal arrhythmias are associated with mutations of glycine residues in the human L-type Ca²⁺ channel. Hence, we undertook a mutational analysis to investigate the role of S6 glycine residues in channel gating. In Ca_V1.2, -helix-breaking proline mutants (G422P and G432P) as well as the double G422A/G432A channel did not produce functional channels. The macroscopic inactivation kinetics were significantly decreased with Ca_V1.2 wild type > G770A > G422A G436A >> G432A (from the fastest to the slowest). Mutations at position Gly⁴³² produced mostly nonfunctional mutants. Macroscopic inactivation kinetics were markedly reduced by mutations of Gly⁴³⁶ to Ala, Pro, Tyr, Glu, Arg, His, Lys, or Asp residues with stronger effects obtained with charged and polar residues. Mutations within the distal GX₃G residues blunted Ca²⁺-dependent inactivation kinetics and prevented the increased voltage-dependent inactivation kinetics brought by positively charged residues in the I-II linker. In Ca_V2.3, mutation of the distal glycine Gly³⁵² impacted significantly on the inactivation gating. Altogether, these data highlight the role of the GX₃G motif in the voltage-dependent activation and inactivation gating of HVA Ca_V channels with the distal glycine residue being mostly involved in the inactivation gating.

Received for publication, August 3, 2006 , and in revised form, September 26, 2006.

^* 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.

¹ To whom correspondence should be addressed: Dépt. de Physiologie, Université de Montréal, 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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