TRPC channels, an overarching Ca2+ paradigm in the developing heart

This editorial refers to ‘A key role of TRPC channels in the regulation of electromechanical activity of the developing heart’ by J. Sabourin et al., pp. 226–236, this issue. It is well established that in the adult mammalian heart, small amounts of Ca2+ entry via voltage-dependent sarcolemmal Cav1.2 L-type Ca2+ channels can trigger the release of a significant amount of Ca2+ from the sarcoplasmic reticulum (SR) that is followed by muscle contraction, a process known as excitation–contraction (EC) coupling.1 However, for the developing mammalian and avian hearts, earlier studies proposed that EC coupling relies essentially on transsarcolemmal influx of Ca2+ through L-type Ca2+ channels, mainly Cav1.2, and that the contribution of the SR is minimal.2 In the embryonic chick heart, Ca2+ channel density is maximal at 3 days and decreases at 17 days,3 whereas Ca2+ channel density is low in the foetal heart and increases with development in guinea-pig,4 rabbit,5 and human,6 consistent with the need for additional Ca2+ entry through other sarcolemmal voltage-dependent proteins such as the T-type Ca2+ channel, the Cav1.3 L-type Ca2+ channel, and the Na/Ca2+ exchanger (NCX).2,6–8 Other candidate channels suspected to provide Ca2+ entry into the immature myocyte have been associated with voltage-independent channels, canonical transient receptor potential (TRPC) channels.9 TRPC channels are composed of four subunits with each containing six membrane-spanning regions lacking the voltage sensors in the fourth domain (thus voltage-independent). TRPC channels possess multiple regulatory and protein interaction sites, a property that allows them to associate and form homotetramers or heterotetramers. TRPC channels are activated following stimulation of receptors coupled to phospholipase C pathways through inositol trisphosphate and diacylglycerol (receptor-operated channels or ROCs), by depletion of internal calcium stores (store-operated channels or SOCs), and by membrane stretching (stretch-activated channels).9 The functional role of TRPC channels in the immature heart is just emerging. In this context, Sabourin et al.10 demonstrated that transarcolemmal Ca2+ entry via TRPC channels regulates not only contractility but also pacemaker activity and conduction in hearts from 4-day-old chick embryos. Sabourin et al.10 first showed that the transcript and proteins of TRPC 1, 3, 4, 5, 6, and 7 isoforms, but not TRPC 2, are present in the heart of the chick embryo. The expression of these multiple TRPC isoforms in the same embryonic myocyte suggests unique and discrete roles. Next, Sabourin et al.10 used co-immunoprecipitation technique to demonstrate that TRPC channels can form a macromolecular complex with the Ca1.2 α1C subunit of the L-type Ca2+ channel, in line with previous studies showing that TRPC channels can also form macromolecules with NCX,11 Na+/K+ pump,12 and SERCA pump.13 Although it is not clear what are the functional consequences of these co-associations, the ability of TRPC channels to interact with multiple Ca2+ modulators may create a microenvironment facilitating the fine tuning of Ca2+ homeostasis and EC-coupling. The observation that inhibition of TRPC channels by SKF, a blocker of TRPC channels, resulted in a decreased spontaneous beating rate in the whole embryonic heart and isolated atria suggests a potential role of TRPC channels in the pacemaker activity; however, the expression of TRPC channels in the sino-atrial (SA) node and the atrioventricular (AV) node of the embryonic chick heart was not investigated.10 Because inhibition of TRPC channels with SKF prevented tachycardia induced by SR Ca2+-ATPase blockade, it was suggested10 that substantial Ca2+ influx generating inward currents could be induced by SR store depletion, a characteristic of SOC activity. SOCs formed by TRPC channels have been recently proposed to provide a pacemaker current in the mouse SA node,14 thus supporting the concept that in the embryonic chick heart, TRPC channels may also contribute to the pacemaker activity as SOCs. However, the extent to which SOCs participate along with other channels to control the diastolic depolarization remains unknown. Inhibition of TRPC channels also resulted in conduction abnormalities such as first- and second-degree AV block, invoking a potential functional link to Cx43 as demonstrated in endothelial cells.15 SKF only partially diminished the myocardial shortening, indicating that TRPC channels may have only a complementary role in the control of Ca2+ entry and Ca2+ homeostasis. Collectively, the proposal that TRPC channels can act as SOCs and form a functional unit with the Cav1.2 L-type Ca2+ channel, thereby generating inward current that will contribute to the diastolic depolarization during the pacemaker phase, is intriguing. SOCs are known to be activated on depletion of intracellular Ca2+ stores; thus, it is not clear how the co-association with Cav1.2 L-type Ca2+ channels that rather cause Ca2+ entry to the immature cell can be reconciled. The more plausible scenario proposed by Sabourin et al.10 is illustrated in Fig 6C of their paper in which the Cav1.2 L-type Ca2+ channel regulates the Ca2+ transient for contraction while TRPC channels play a complementary role by contributing to the refilling of the modest SR Ca2+ stores of the immature myocyte. Alternatively, the potential association between TRPC and the newly described Cav1.3 L-type Ca2+ channel in the heart cannot be ruled out and should be explored. The Cav1.3 L-type Ca2+ channel has been recently shown to be highly expressed in myocytes of foetal human16 and rat17 hearts and plays an important role in the pacemaker activity and conduction as well.16,17 Given the high homology (>80%) between Cav1.2 and Cav1.3 and the role of the Cav1.3 L-type Ca2+ channel in foetal cardiac automaticity and conduction, it is conceivable that Cav1.3 L-type Ca2+ channel individually or in association with TRPC channels may also contribute to Ca2+ homeostatic and EC-coupling of the immature heart. Studies designed to test the functional role of the complex TRPC/Cav1.2 L-type Ca2+ or TRPC/Cav1.3 L-type Ca2+ channels are warranted. In summary, the study by Sabourin et al.10 has profound implications for the current understanding of Ca2+ homeostasis and EC coupling of the developing heart. In addition to the conventional L- and T-type Ca2+ channels and NCX, TRPC channels may offer a novel pathway for Ca2+ influx and contribute to the modulation of myocardial contractility, pacemaking, and impulse conduction. Provided that the results of this study are reproduced in the foetal human heart, the important role of voltage-independent TRPC channels in the functioning of immature myocytes should be recognized, especially now that emerging evidence has already demonstrated the importance of TRPC channels in hypertrophy and heart failure,18 where re-expression of foetal genes occurs. Conflict of interest: none declared.