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J. Biol. Chem., Vol. 278, Issue 47, 46307-46320, November 21, 2003

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Differential Voltage-dependent K⁺ Channel Responses during Proliferation and Activation in Macrophages^*

From the ^aMolecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, ^g Unitat de Reconeixement Molecular in Situ, Serveis Cientificotcnics, ^fMacrophage Biology Group, Biomedical Research Institute of Barcelona, ^hDepartament de Fisiologia, Universitat de Barcelona, E-08028 Barcelona, Spain and the ^dCellular and Molecular Neurobiology Laboratory, Departament de Biologia Cellular i Anatomia Patològica, Universitat de Barcelona-Campus de Bellvitge, E-08907 Hospitalet de Llobregat, Spain

Voltage-dependent K⁺ channels (VDPC) are expressed in most mammalian cells and involved in the proliferation and activation of lymphocytes. However, the role of VDPC in macrophage responses is not well established. This study was undertaken to characterize VDPC in macrophages and determine their physiological role during proliferation and activation. Macrophages proliferate until an endotoxic shock halts cell growth and they become activated. By inducing a schedule that is similar to the physiological pattern, we have identified the VDPC in non-transformed bone marrow-derived macrophages and studied their regulation. Patch clamp studies demonstrated that cells expressed outward delayed and inwardly rectifying K⁺ currents. Pharmacological data, mRNA, and protein analysis suggest that these currents were mainly mediated by Kv1.3 and Kir2.1 channels. Macrophage colony-stimulating factor-dependent proliferation induced both channels. Lipopolysaccharide (LPS)-induced activation differentially regulated VDPC expression. While Kv1.3 was further induced, Kir2.1 was down-regulated. TNF- mimicked LPS effects, and studies with TNF- receptor I/II double knockout mice demonstrated that LPS regulation mediates such expression by TNF--dependent and -independent mechanisms. This modulation was dependent on mRNA and protein synthesis. In addition, bone marrow-derived macrophages expressed Kv1.5 mRNA with no apparent regulation. VDPC activities seem to play a critical role during proliferation and activation because not only cell growth, but also inducible nitric-oxide synthase expression were inhibited by blocking their activities. Taken together, our results demonstrate that the differential regulation of VDPC is crucial in intracellular signals determining the specific macrophage response.

Received for publication, April 28, 2003 , and in revised form, July 31, 2003.

^* 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.

^b Both authors contributed equally to this work.

^c Supported by a fellowship from the Universitat de Barcelona.

^e Supported by a fellowship from the Fundació Marató TV3.

ⁱ Supported by Fondo de Investigaciones Sanitarias Grant PI021192 and the "Ramón y Cajal" program from Ministerio de Ciencia y Tecnología (MCYT), Spain.

^j Supported by The Fundació August Pi i Sunyer, Generalitat de Catalunya and MCYT Grant BFI2001-3331.

^k Supported by MCYT Grant BMC2001-3040. To whom correspondence may be addressed: Macrophage Biology Group, Biomedical Research Institute of Barcelona, Barcelona Science Park, University of Barcelona, Josep Samitier 1–5, Barcelona E-08028, Spain. Tel.: 34-934037165; Fax: 34-934034747; E-mail: acelada{at}ub.edu. ^l Supported by the Universitat de Barcelona and MCYT Grant BFI2002-00764. To whom correspondence may be addressed: Molecular Physiology Laboratory, Departament de Bioquímica 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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