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J. Biol. Chem., Vol. 282, Issue 43, 31558-31568, October 26, 2007

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BK Channels Are Linked to Inositol 1,4,5-Triphosphate Receptors via Lipid Rafts

A NOVEL MECHANISM FOR COUPLING [Ca²⁺]_i TO ION CHANNEL ACTIVATION^*

From the Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294

Glioma cells prominently express a unique splice variant of a large conductance, calcium-activated potassium channel (BK channel). These channels transduce changes in intracellular calcium to changes of K⁺ conductance in the cells and have been implicated in growth control of normal and malignant cells. The Ca²⁺ increase that facilitates channel activation is thought to occur via activation of intracellular calcium release pathways or influx of calcium through Ca²⁺-permeable ion channels. We show here that BK channel activation involves the activation of inositol 1,4,5-triphosphate receptors (IP₃R), which localize near BK channels in specialized membrane domains called lipid rafts. Disruption of lipid rafts with methyl--cyclodextrin disrupts the functional association of BK channel and calcium source resulting in a >50% reduction in K⁺ conductance mediated by BK channels. The reduction of BK current by lipid raft disruption was overcome by the global elevation of intracellular calcium through inclusion of 750 nM Ca²⁺ in the pipette solution, indicating that neither the calcium sensitivity of the channel nor their overall number was altered. Additionally, pretreatment of glioma cells with 2-aminoethoxydiphenyl borate to inhibit IP₃Rs negated the effect of methyl--cyclodextrin, providing further support that IP₃Rs are the calcium source for BK channels. Taken together, these data suggest a privileged association of BK channels in lipid raft domains and provide evidence for a novel coupling of these Ca²⁺-sensitive channels to their second messenger source.

Received for publication, April 4, 2007 , and in revised form, August 20, 2007.

^* This work was supported by National Institutes of Health Grants RO1-NS36692 and RO1-NS31234. 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 Fig. 1.

¹ To whom correspondence should be addressed: 1719 6th Ave. S., CIRC 425, Birmingham, AL 35294. Tel.: 205-975-5805; Fax: 205-975-5518; E-mail: hws{at}uab.edu.

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