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.The TRP (transient receptor potential) family of ion channels is a growing group of structurally and evolutionarily related cation channels formed of several subfamilies that include the TRPC, TRPM, and TRPV classes of channels (6, 22). TRP-type ion channels are presumed to be homo-or heterotetramers (13,14), each spanning the plasma membrane six times. The founding members of this channel family are the insect TRP and TRPL channels, which are responsible for photoreceptor depolarization in response to light. Mammalian TRPCs (C stands for canonical or classical) (23, 32) are the closest mammalian structural relatives of insect TRPs. Among the TRPC channels, TRPC3, -6, and -7 are 75% identical and gated by signal transduction pathways that activate C-type phospholipases (3, 32) as well as by direct exposure to diacylglycerols (DAG) (15). TRPC3, -6, and -7 interact physically and, upon coexpression, coassemble to form functional channels (14). Expression of TRPC3 and TRPC7 in HEK 293 cells, but not of TRPC6, reveals constitutively active cation channels that are permeable not only to monovalent but also to divalent cations such as Ca 2ϩ , Ba 2ϩ , and Mn 2ϩ (7,23,33). In contrast to members of other TRP families, the functional importance of most members of the TRPC subfamily is still poorly understood. A TRPC channel for which considerable evidence has accumulated for a specific role is TRPC6, which has been proposed to regulate smooth muscle function. The TRPC6 mRNA was originally isolated from mouse brain and was also identified in lung cells (4). By comparative biophysical characterization and gene suppression using antisense oligonucleot...

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