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J. Biol. Chem., Vol. 279, Issue 1, 444-452, January 2, 2004

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Differential Recruitment of Kv1.4 and Kv4.2 to Lipid Rafts by PSD-95^*

Wei Wong¶ and Lyanne C. Schlichter||**

From the Division of Cellular and Molecular Biology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada, the Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and the ^||Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

The activity of voltage-gated potassium (Kv) channels, and consequently their influence on cellular functions, can be substantially altered by phosphorylation. Several protein kinases that modulate Kv channel activity are found in membrane subdomains known as lipid rafts, which are thought to organize signaling complexes in the cell. Thus, we asked whether Kv1.4 and Kv4.2, two channels with critical roles in excitable cells, are found in lipid rafts. Acylation can target proteins to raft regions; however, Kv channels are not acylated, and therefore, a different mechanism must exist to bring them into these membrane subdomains. Because both Kv1.4 and Kv4.2 interact with postsynaptic density protein 95 (PSD-95), which is acylated (specifically, palmitoylated), we examined whether PSD-95 can recruit these channels to lipid rafts. We found that a portion of Kv1.4 and Kv4.2 protein in rat brain membranes is raft-associated. Lipid raft patching and immunostaining confirmed that some Kv4.2 is in Thy-1-containing rafts in rat hippocampal neurons. Using a heterologous expression system, we determined that palmitoylation of PSD-95 was crucial to its localization to lipid rafts. We then assessed the contribution of PSD-95 to the raft association of these channels. Co-expression of PSD-95 increased the amount of Kv1.4, but not Kv4.2, in lipid rafts. Deleting the PSD-95 binding motif of Kv1.4 eliminated this recruitment, as did substituting a palmitoylation-deficient PSD-95 mutant. This work represents the first evidence that PSD-95 binding can recruit Kv channels into lipid rafts, a process that could facilitate interactions with the protein kinases that affect channel activity.

Received for publication, May 5, 2003 , and in revised form, October 10, 2003.

^* This work was funded by grants from the Canadian Institutes of Health Research (CIHR) (MT-13657), the Heart and Stroke Foundation of Ontario (T-3726) (to L. C. S.), and an Ontario Graduate Scholarship and a University of Toronto Connaught Scholarship (to W. W.). Parts of this work were previously published as an abstract (97). 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.

^¶ Current address: Vollum Institute, Howard Hughes Medical Institute/Oregon Health & Sciences University, S.W. 3181 Sam Jackson Park Rd., L-474, Portland, OR 97239.

^** To whom correspondence should be addressed: MC9–415, Toronto Western Hospital, 399 Bathurst St., Toronto, ON M5T 2S8. Tel.: 416-603-5970; Fax: 416-603-5745; E-mail: schlicht{at}uhnres.utoronto.ca.

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