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Regulation of the TRPC1 channel by endothelin-1 in human atrial myocytes.

Authors :: Zhang K
Wu WY
Li G
Zhang YH
Sun Y
Qiu F
Yang Q
Xiao GS
Li GR
Wang Y
Source :: Heart rhythm [Heart Rhythm] 2019 Oct; Vol. 16 (10), pp. 1575-1583. Date of Electronic Publication: 2019 Apr 04.
Publication Year :: 2019
Abstract: Background: Our recent study demonstrated that the nonselective cation current mediated by the transient receptor potential canonical 1 (TRPC1) channel is activated by endothelin-1 (ET-1) in human atrial myocytes; however, the related signal molecules involved are unknown. Objective: The purpose of this study was to investigate how the TRPC1 channel is regulated by ET-1 and whether it is upregulated in human atria from patients with atrial fibrillation (AF). Methods: Whole-cell patch technique and molecular biology techniques were used in the study. Results: The ET-1-evoked TRPC1 current was inhibited by the ET-1 type A (ET <subscript>A</subscript> ) receptor antagonist BQ123 and the ET-1 type B (ET <subscript>B</subscript> ) receptor antagonist BQ788 as well as the protein kinase C inhibitor chelerythrine. ET <subscript>A</subscript> receptor-mediated TRPC1 channel activity was selectively inhibited by the phosphoinositide-3-kinase inhibitor wortmannin, while ET <subscript>B</subscript> receptor-mediated TRPC1 activity was inhibited by the phospholipase C inhibitor U73122. The messenger RNAs and proteins of the TRPC1 channel and ET <subscript>A</subscript> receptor, but not the ET <subscript>B</subscript> receptor, were significantly upregulated in atria from patients with AF. The basal TRPC1 current increased in AF myocytes, and the response to ET-1 was greater in AF myocytes than in sinus rhythm myocytes. ET-1 induced a delayed repolarization in 20% of AF myocytes. Conclusion: These results demonstrate for the first time that TRPC1 activation by ET-1 is mediated by protein kinase C through the distinct phospholipids pathways phosphoinositide-3-kinase and phospholipase C and that the TRPC1 channel and ET <subscript>A</subscript> receptor are upregulated in AF atria, which are likely involved in atrial electrical remodeling in patients with AF. (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)