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J. Biol. Chem., Vol. 282, Issue 10, 7276-7286, March 9, 2007

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Regulation of the Gating of BK_Ca Channel by Lipid Bilayer Thickness^*

Chunbo Yuan, Robert J. O'Connell, Robert F. Jacob, R. Preston Mason, and Steven N. Treistman¹

From the Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01604 and Elucida Research, Beverly, Massachusetts 01915

Transmembrane segments of ion channels tend to match the hydrophobic thickness of lipid bilayers to minimize mismatch energy and to maintain their proper organization and function. To probe how ion channels respond to mismatch with lipid bilayers of different thicknesses, we examined the single channel activities of BK_Ca (hSlo -subunit) channels in planar bilayers of binary mixtures of DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) with phosphatidylcholines (PCs) of varying chain lengths, including PC 14:1, PC 18:1, PC 22:1, PC 24:1, and with porcine brain sphingomyelin. Bilayer thickness and structure was measured with small angle x-ray diffraction and atomic force microscopy. The open probability (P_o) of the BK_Ca channel was finely tuned by bilayer thickness, first decreasing with increases in bilayer thickness from PC 14:1 to PC 22:1 and then increasing from PC 22:1 to PC 24:1 and to porcine brain sphingomyelin. Single channel kinetic analyses revealed that the mean open time of the channel increased monotonically with bilayer thickness and, therefore, could not account for the biphasic changes in P_o. The mean closed time increased with bilayer thickness from PC 14:1 up to PC 22:1 and then decreased with further increases in bilayer thickness to PC 24:1 and sphingomyelin, correlating with changes in P_o. This is consistent with the proposition that bilayer thickness affects channel activity mainly through altering the stability of the closed state. We suggest a simple mechanical model that combines forces of lateral stress within the lipid bilayer with local hydrophobic mismatch between lipids and the protein to account for the biphasic modulation of BK_Ca gating.

Received for publication, August 9, 2006 , and in revised form, January 2, 2007.

^* This work was supported by National Institutes of Health Grant AA12054 (to S. N. T.). 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: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, 303 Belmont St., Worcester, MA 01604. Tel.: 508-856-6985; Fax: 508-856-6266; E-mail: Steven.Treistman{at}umassmed.edu.

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