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Molecular and Cellular Biology, August 2005, p. 6980-6989, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.6980-6989.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Increased Vascular Smooth Muscle Contractility in TRPC6–/– Mice

Alexander Dietrich,1 Michael Mederos y Schnitzler,1 Maik Gollasch,2,{dagger} Volkmar Gross,2 Ursula Storch,1 Galyna Dubrovska,2 Michael Obst,2 Eda Yildirim,3 Birgit Salanova,2 Hermann Kalwa,1 Kirill Essin,2 Olaf Pinkenburg,1 Friedrich C. Luft,2 Thomas Gudermann,1* and Lutz Birnbaumer3

Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Marburg, Germany,1 Franz-Volhard Klinik, HELIOS Klinikum-Berlin, Medizinische Fakultät der Charité, Max-Delbrück-Centrum, Berlin, Germany,2 National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 277093

Received 17 February 2005/ Returned for modification 24 March 2005/ Accepted 29 May 2005

Among the TRPC subfamily of TRP (classical transient receptor potential) channels, TRPC3, -6, and -7 are gated by signal transduction pathways that activate C-type phospholipases as well as by direct exposure to diacylglycerols. Since TRPC6 is highly expressed in pulmonary and vascular smooth muscle cells, it represents a likely molecular candidate for receptor-operated cation entry. To define the physiological role of TRPC6, we have developed a TRPC6-deficient mouse model. These mice showed an elevated blood pressure and enhanced agonist-induced contractility of isolated aortic rings as well as cerebral arteries. Smooth muscle cells of TRPC6-deficient mice have higher basal cation entry, increased TRPC-carried cation currents, and more depolarized membrane potentials. This higher basal cation entry, however, was completely abolished by the expression of a TRPC3-specific small interference RNA in primary TRPC6–/– smooth muscle cells. Along these lines, the expression of TRPC3 in wild-type cells resulted in increased basal activity, while TRPC6 expression in TRPC6–/– smooth muscle cells reduced basal cation influx. These findings imply that constitutively active TRPC3-type channels, which are up-regulated in TRPC6-deficient smooth muscle cells, are not able to functionally replace TRPC6. Thus, TRPC6 has distinct nonredundant roles in the control of vascular smooth muscle tone.

* Corresponding author. Mailing address: Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Karl-von-Frisch-Str. 1, 35043 Marburg, Germany, Phone: 49 6421 2865000. Fax: 49 6421 2865600. E-mail: guderman{at}staff.uni-marburg.de.

{dagger} Present address: Medizinische Klinik mit Schwerpunkt Nephrologie und internistische Intensivmedizin, Charité Campus Virchow Klinikum, Berlin, Germany.

Molecular and Cellular Biology, August 2005, p. 6980-6989, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.6980-6989.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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