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Scientific article
Open access
English

Activation of transient receptor potential canonical 3 (TRPC3)-mediated Ca2+ entry by A1 adenosine receptor in cardiomyocytes disturbs atrioventricular conduction

Published inThe Journal of biological chemistry, vol. 287, no. 32, p. 26688-26701
Publication date2012
Abstract

Although the activation of the A(1)-subtype of the adenosine receptors (A(1)AR) is arrhythmogenic in the developing heart, little is known about the underlying downstream mechanisms. The aim of this study was to determine to what extent the transient receptor potential canonical (TRPC) channel 3, functioning as receptor-operated channel (ROC), contributes to the A(1)AR-induced conduction disturbances. Using embryonic atrial and ventricular myocytes obtained from 4-day-old chick embryos, we found that the specific activation of A(1)AR by CCPA induced sarcolemmal Ca(2+) entry. However, A(1)AR stimulation did not induce Ca(2+) release from the sarcoplasmic reticulum. Specific blockade of TRPC3 activity by Pyr3, by a dominant negative of TRPC3 construct, or inhibition of phospholipase Cs and PKCs strongly inhibited the A(1)AR-enhanced Ca(2+) entry. Ca(2+) entry through TRPC3 was activated by the 1,2-diacylglycerol (DAG) analog OAG via PKC-independent and -dependent mechanisms in atrial and ventricular myocytes, respectively. In parallel, inhibition of the atypical PKCζ by myristoylated PKCζ pseudosubstrate inhibitor significantly decreased the A(1)AR-enhanced Ca(2+) entry in both types of myocytes. Additionally, electrocardiography showed that inhibition of TRPC3 channel suppressed transient A(1)AR-induced conduction disturbances in the embryonic heart. Our data showing that A(1)AR activation subtly mediates a proarrhythmic Ca(2+) entry through TRPC3-encoded ROC by stimulating the phospholipase C/DAG/PKC cascade provide evidence for a novel pathway whereby Ca(2+) entry and cardiac function are altered. Thus, the A(1)AR-TRPC3 axis may represent a potential therapeutic target.

Keywords
  • Animals
  • Atrial Function
  • Blotting, Western
  • Calcium/metabolism
  • Chick Embryo
  • Myocardium/metabolism
  • Polymerase Chain Reaction
  • Receptor, Adenosine A1/metabolism
  • TRPC Cation Channels/metabolism
  • Ventricular Function
Citation (ISO format)
SABOURIN, Jessica et al. Activation of transient receptor potential canonical 3 (TRPC3)-mediated Ca2+ entry by A1 adenosine receptor in cardiomyocytes disturbs atrioventricular conduction. In: The Journal of biological chemistry, 2012, vol. 287, n° 32, p. 26688–26701. doi: 10.1074/jbc.M112.378588
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Article (Published version)
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ISSN of the journal0021-9258
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