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J. Biol. Chem., Vol. 281, Issue 19, 13588-13595, May 12, 2006

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TRPC3 and TRPC4 Associate to Form a Redox-sensitive Cation Channel

EVIDENCE FOR EXPRESSION OF NATIVE TRPC3-TRPC4 HETEROMERIC CHANNELS IN ENDOTHELIAL CELLS^*

Michael Poteser¹, Annarita Graziani¹, Christian Rosker, Petra Eder, Isabella Derler, Heike Kahr, Michael X. Zhu^¶, Christoph Romanin, and Klaus Groschner²

From the Institute of Pharmaceutical Sciences, Pharmacology and Toxicology, Karl-Franzens-University of Graz, Universitaetsplatz 2, A-8010 Graz, Austria, the ^¶Department of Neuroscience and Center for Molecular Neurobiology, The Ohio State University, Columbus, Ohio 43210, and the Institute of Biophysics, University of Linz, A-4020 Linz, Austria

Canonical transient receptor potential proteins (TRPC) have been proposed to form homo- or heteromeric cation channels in a variety of tissues, including the vascular endothelium. Assembly of TRPC multimers is incompletely understood. In particular, heteromeric assembly of distantly related TRPC isoforms is still a controversial issue. Because we have previously suggested TRPC proteins as the basis of the redox-activated cation conductance of porcine aortic endothelial cells (PAECs), we set out to analyze the TRPC subunit composition of endogenous endothelial TRPC channels and report here on a redox-sensitive TRPC3-TRPC4 channel complex. The ability of TRPC3 and TRPC4 proteins to associate and to form a cation-conducting pore complex was supported by four lines of evidence as follows: 1) Co-immunoprecipitation experiments in PAECs and in HEK293 cells demonstrated the association of TRPC3 and TRPC4 in the same complex. 2) Fluorescence resonance energy transfer analysis demonstrated TRPC3-TRPC4 association, involving close proximity between the N terminus of TRPC4 and the C terminus of TRPC3 subunits. 3) Co-expression of TRPC3 and TRPC4 in HEK293 cells generated a channel that displayed distinct biophysical and regulatory properties. 4) Expression of dominant-negative TRPC4 proteins suppressed TRPC3-related channel activity in the HEK293 expression system and in native endothelial cells. Specifically, an extracellularly hemagglutinin (HA)-tagged TRPC4 mutant, which is sensitive to blockage by anti-HA-antibody, was found to transfer anti-HA sensitivity to both TRPC3-related currents in the HEK293 expression system and the redox-sensitive cation conductance of PAECs. We propose TRPC3 and TRPC4 as subunits of native endothelial cation channels that are governed by the cellular redox state.

Received for publication, November 14, 2005 , and in revised form, March 6, 2006.

^* This work was funded by FWF (Austrian Science Fund) Project P18280 [GenBank] (to K. G.), FWF Project P18475 [GenBank] (to M. P.), FWF Project P16537 [GenBank] (to C. R.), and National Institutes of Health Grant NS42183 (to M. X. Z.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 43-316-380-5570; Fax: 43-316-380-9890; E-mail: klaus.groschner{at}uni-graz.at.

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