Increased vascular smooth muscle contractility in TRPC6-/- mice.
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.
Dietrich
Alexander
A
Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Germany.
Mederos Y Schnitzler
Michael
M
Gollasch
Maik
M
Gross
Volkmar
V
Storch
Ursula
U
Dubrovska
Galyna
G
Obst
Michael
M
Yildirim
Eda
E
Salanova
Birgit
B
Kalwa
Hermann
H
Essin
Kirill
K
Pinkenburg
Olaf
O
Luft
Friedrich C
FC
Gudermann
Thomas
T
Birnbaumer
Lutz
L
D000818:Animals; D001011:Aorta / Q000473:pathology; D001158:Arteries / Q000166:cytology; D001464:Barium / Q000494:pharmacology; D001794:Blood Pressure; D015153:Blotting, Western; D015220:Calcium Channels / Q000235:genetics* / Q000502:physiology*; D002412:Cations; D018076:DNA, Complementary / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004594:Electrophysiology; D018274:Electroporation; D005822:Genetic Vectors; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D009132:Muscles / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D018408:Patch-Clamp Techniques; D010656:Phenylephrine / Q000494:pharmacology; D011312:Pressure; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; D013997:Time Factors
D015220:Calcium Channels; D002412:Cations; D018076:DNA, Complementary; D007473:Ion Channels; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D010656:Phenylephrine; D001464:Barium