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J. Biol. Chem., Vol. 283, Issue 13, 8756-8764, March 28, 2008

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Kv1.5 Association Modifies Kv1.3 Traffic and Membrane Localization^*

Rubén Vicente¹, Núria Villalonga¹, Maria Calvo, Artur Escalada^¶1, Carles Solsona^¶, Concepció Soler^¶, Michael M. Tamkun^||2, and Antonio Felipe²³

From the Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona, Avenida Diagonal 645, E-08028 Barcelona, Spain, the Departament de Biologia Cellular, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, 08036 Barcelona, Spain, the ^¶Departament de Patologia i Terapèutica Experimental, Universitat de Barcelona-Campus de Bellvitge, E-08907 Hospitalet de Llobregat, Spain, and the ^||Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523

Kv1.3 activity is determined by raft association. In addition to Kv1.3, leukocytes also express Kv1.5, and both channels control physiological responses. Because the oligomeric composition may modify the channel targeting to the membrane, we investigated heterotetrameric Kv1.3/Kv1.5 channel traffic and targeting in HEK cells. Kv1.3 and Kv1.5 generate multiple heterotetramers with differential surface expression according to the subunit composition. FRET analysis and pharmacology confirm the presence of functional hybrid channels. Raft association was evaluated by cholesterol depletion, caveolae colocalization, and lateral diffusion at the cell surface. Immunoprecipitation showed that both Kv1.3 and heteromeric channels associate with caveolar raft domains. However, homomeric Kv1.3 channels showed higher association with caveolin traffic. Moreover, FRAP analysis revealed higher mobility for hybrid Kv1.3/Kv1.5 than Kv1.3 homotetramers, suggesting that heteromers target to distinct surface microdomains. Studies with lipopolysaccharide-activated macrophages further supported that different physiological mechanisms govern Kv1.3 and Kv1.5 targeting to rafts. Our results implicate the traffic and localization of Kv1.3/Kv1.5 heteromers in the complex regulation of immune system cells.

Received for publication, October 3, 2007 , and in revised form, January 14, 2008.

^* This work was supported by Ministerio de Educación y Ciencia Grants BFI2002-00764 and BFU2005-00695 (to A. F.) and SAF2005-00736 and BFU2006-06076 (to C. S.) and National Institutes of Health Grants HL49330 and NS41542 (to M. M. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Movies S1-S4.

¹ Recipients of fellowships from the Universitat de Barcelona, the Ministerio de Educación y Ciencia, and the Fundació Marató TV3.

² Both authors contributed equally to this work.

³ To whom correspondence should be addressed: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Avda. Diagonal 645, E-08028 Barcelona, Spain. Tel.: 34-934034616; Fax: 34-934021559; E-mail: afelipe{at}ub.edu.

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