Abstract 12979: A Key Role of Transient Receptor Potential Canonical (TRPC) Channels in the Regulation of Ventricular Electrical Activity of the Developing Heart
It is well established that ventricular electrical activity is controlled by a series of voltage-dependent channels in the fetal and adult heart. However, the involvement of voltage-insensitive cationic TRPC channels remains unclear. We assessed the hypothesis that TRPC channels play a crucial role in the ventricular spontaneous activity of the developing heart. The TRPC channels expression and their role were investigated in isolated hearts obtained from 4-day-old chick embryos. Using RT-PCR, western blot and co-immunoprecipitation, we report for the first time that TRPC1, 3, 4, 5, 6 and 7 isoforms are expressed at the mRNA and protein levels and that they can form a macromolecular complex with the α1C subunit of the L-type voltage-gated calcium channel (LCC, Cav1.2) in ventricle. Using ex vivo electrocardiogram and electrogram of isolated ventricles, we found that inhibition of TRPC channels by SKF-96365 (SKF) provokes ventricular arrhythmias characterised by tachycardia (+31%), prolonged QT interval (+35%) and widening of QRS (+68%). Interestingly, the prolongation of QT interval was predominantly due to LCC overactivity since exposure to SKF and nifedipine (LCC inhibitor) in combination reversed the effect of SKF alone on QT interval. This suggests that TRPC channels can regulate negatively LCC, directly or indirectly. Intracellular Ca2+ changes measured by Fura-2 fluorescence in embryonic chick ventricular myocytes confirmed that a LCC-dependent Ca2+ overload is induced by SKF. These results give new insights into the key role that TRPC channels, via interaction with the Cav1.2 channel, play in regulation of ventricular electrical activity during cardiogenesis. Overall, TRPC channels may constitute new potential therapeutic targets to reduce ventricular arrhythmias observed during fetal and adult life.
- © 2011 by American Heart Association, Inc.