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J. Biol. Chem., Vol. 281, Issue 49, 37675-37685, December 8, 2006

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Association of Kv1.5 and Kv1.3 Contributes to the Major Voltage-dependent K⁺ Channel in Macrophages^*

Rubén Vicente¹², Artur Escalada¹³, Nuria Villalonga⁴, Laura Texidó, Meritxell Roura-Ferrer⁵, Mireia Martín-Satué, Carmen López-Iglesias^¶, Concepció Soler^||6, Carles Solsona⁷, Michael M. Tamkun^**18, and Antonio Felipe, Supported by the Ministerio de Educación y Ciencia, Spain (BFI2002-00764, BFU2005-00695)¹⁹

From the Molecular Physiology Laboratory, Departament de Bioquiámica i Biologia Molecular, ^||Departament de Fisiologia, and ^¶Unitat de Reconeixement Molecular in situ, Serveis Cientificotècnics Universitat de Barcelona, E-08028 Barcelona, Spain, Cellular and Molecular Neurobiology Laboratory, Departament de Patologia i Terapèutica Experimental (IDIBELL), Universitat de Barcelona-Campus de Bellvitge, E-08907 Hospitalet de Llobregat, Spain, and ^**Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523

Voltage-dependent K⁺ (Kv) currents in macrophages are mainly mediated by Kv1.3, but biophysical properties indicate that the channel composition could be different from that of T-lymphocytes. K⁺ currents in mouse bone marrow-derived and Raw-264.7 macrophages are sensitive to Kv1.3 blockers, but unlike T-cells, macrophages express Kv1.5. Because Shaker subunits (Kv1) may form heterotetrameric complexes, we investigated whether Kv1.5 has a function in Kv currents in macrophages. Kv1.3 and Kv1.5 co-localize at the membrane, and half-activation voltages and pharmacology indicate that K⁺ currents may be accounted for by various Kv complexes in macrophages. Co-expression of Kv1.3 and Kv1.5 in human embryonic kidney 293 cells showed that the presence of Kv1.5 leads to a positive shift in K⁺ current half-activation voltages and that, like Kv1.3, Kv1.3/Kv1.5 heteromers are sensitive to r-margatoxin. In addition, both proteins co-immunoprecipitate and co-localize. Fluorescence resonance energy transfer studies further demonstrated that Kv1.5 and Kv1.3 form heterotetramers. Electrophysiological and pharmacological studies of different ratios of Kv1.3 and Kv1.5 co-expressed in Xenopus oocytes suggest that various hybrids might be responsible for K⁺ currents in macrophages. Tumor necrosis factor--induced activation of macrophages increased Kv1.3 with no changes in Kv.1.5, which is consistent with a hyperpolarized shift in half-activation voltage and a lower IC₅₀ for margatoxin. Taken together, our results demonstrate that Kv1.5 co-associates with Kv1.3, generating functional heterotetramers in macrophages. Changes in the oligomeric composition of functional Kv channels would give rise to different biophysical and pharmacological properties, which could determine specific cellular responses.

Received for publication, June 12, 2006 , and in revised form, September 28, 2006.

^* 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 These authors contributed equally to this work.

² Holds a fellowship from the Universitat de Barcelona.

³ Supported by a fellowship from the Fundació Marató TV3.

⁴ Holds a fellowship from the Ministerio de Educación y Ciencia.

⁵ Hold a fellowship from the Generalitat de Catalunya.

⁶ Supported by the Fondo de Investigaciones Sanitarias (PI021192) and the Ramón y Cajal program of the Ministerio de Educación y Ciencia.

⁷ Supported by the Fundació August Pi i Sunyer, Generalitat de Catalunya, and the Ministerio de Educación y Ciencia (BFI2001-3331, SAF2005-00736).

⁸ Supported by National Institutes of Health Grants HL49330 and NS41542.

⁹ To whom correspondence should be addressed: Molecular Physiology Laboratory, Departament de Bioquiámica i Biologia Molecular, Universitat de Barcelona, Avda. Diagonal 645, E-08028 Barcelona, Spain. Tel.: 34-93-4034616; Fax: 34-93-4021559; E-mail: afelipe{at}ub.edu.

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