Molecular Mechanisms Of Regulation Of TRPC1 Channel By Endothelin-1 In Human Atrial Myocytes

Background:Our previous study showed that the non-selective cation current mediated by TRPC1 channels is present in human atrial myocytes and activated by endothelin-1(ET-1).The present study is to investigate whether TRPC1 channel is upregulated in human atria in patients with persistent atrial fibrillation(AF)and how ET-1 regulatesTRPC1 channel in human atrial myocytes.Methods:Real-time PCR and Western blot analysis were used to determine gene and protein expression of TRPC channels and ET receptors,and a conventional whole-cell patch voltage-clamp technique was employed to recoerd TRPC current in human atrial myocytes.Results:Messager RNA and protein levels of TRPC 1 and ETA receptor,but not ETB receptor,were significantly increased in human atria from AF patients.TRPC1 current activated by ET-1 was greater in AF myocytes than in sinus rhythm(SR)myocytes(n=10,P<0.05 vs.control).ET-1-evoked TRPC1 current was inhibited by both ETA and ETB receptor antagonists BQ-123 and BQ788 or protein kinase C(PKC)inhibitor chelerythrine.ETA receptor-mediated TRPC1 channel activation was selectively inhibited by phosphoinositol-3-kinase(PI-3-kinase)inhibitors wortmannin,while ETB receptor-mediated TRPC1 channel activation was inhibited by the PI-phospholipase C(PI-PLC)inhibitor U73122.Conclusion:Our results demonstrate for the first time thatTRPC1 and ETA receptor are upregulated in atria of AF patients.Increase of TRPC 1 current by ET-1 is likely involved in atrial electrical remodelingin AF patients via activating PKC through the distinct phospholipids pathways PI-3 kinase and PLC.