Abstract
It is well established that dysfunction of voltage-dependent ion channels results in arrhythmias and conduction disturbances in the foetal and adult heart. However, the involvement of voltage-insensitive cationic TRPC (transient receptor potential canonical) channels remains unclear. We assessed the hypothesis that TRPC channels play a crucial role in the spontaneous activity of the developing heart. TRPC isoforms were investigated in isolated hearts obtained from 4-day-old chick embryos. Using RT-PCR, western blotting 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 (Cav1.2) in atria and ventricle. Using ex vivo electrocardiograms, electrograms of isolated atria and ventricle and ventricular mechanograms, we found that inhibition of TRPC channels by SKF-96365 leads to negative chrono-, dromo-, and inotropic effects, prolongs the QT interval, and provokes first- and second-degree atrioventricular blocks. Pyr3, a specific antagonist of TRPC3, affected essentially atrioventricular conduction. On the other hand, specific blockade of the L-type calcium channel with nifedipine rapidly stopped ventricular contractile activity without affecting rhythmic electrical activity. These results give new insights into the key role that TRPC channels, via interaction with the Cav1.2 channel, play in regulation of cardiac pacemaking, conduction, ventricular activity, and contractility during cardiogenesis.
Highlights
Intracellular calcium signalling plays an important role in the cardiac physiology and development.[1]
The present study shows for the first time that TRPC channels play a key role in regulation of pacemaking, conduction, and contractility in the developing heart
TRPC1, 3, 4, 5, 6, and 7 transcripts were detected in the whole heart as well as in retina (Figure 1A)
Summary
Intracellular calcium signalling plays an important role in the cardiac physiology and development.[1] In the adult mammalian myocardium, depolarizing current resulting in a relatively small calcium influx across the sarcolemma contributes to the initiation of action potential in atrial pacemaker cells or to the plateau phase in ventricular myocytes This entry is followed by a further calcium release from the sarcoplasmic reticulum (SR) via a mechanism termed Ca2+-induced Ca2+ release, which leads to contraction, the so-called excitation –contraction (EC) coupling.[2] in the mammalian embryo/foetus, calcium appears to come exclusively through sarcolemmal calcium influx because of immature SR.[3]. In the embryonic chick heart, all the components necessary for a functioning SR and EC coupling are expressed early such as ryanodine receptor (RyR2), SR Ca2+-ATPase (SERCA2), Land T-type voltage-dependent calcium channels, and Na+/Ca2+ exchanger.[4,5,6,7,8] Brotto and Creazzo have estimated in the embryonic chick heart that 70% of the calcium available for the transient comes through sarcolemmal calcium channels, while the remainder is from SR calcium release.[7]
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