Ontogeny of excitation-contraction coupling in the mammalian myocardium

It is well known that in adult mammalian cardiomyocytes that the relatively small amount of Ca2+ that enters via the activation of L-type Ca2+ channels triggers a larger amount of Ca2+ release from the sarcoplasmic recticulum (SR) in a process known as Ca2+-induced Ca2+ release (CICR). The subsequent rise in cytosolic [Ca2+] ([Ca2+]i), initiates its binding with troponin C causing cell contraction. During cell relaxation, the Na+- Ca2+ exchanger (NCX), SR Ca2+ pump (SERCA2a) and the “slow removal system”, made up of the sarcolemmal Ca2+-ATPase (PMCA) and mitochondrial Ca2+ uniporter, contribute to the decline of [Ca2+]i, resulting in cell relaxation. However, much less is known about cardiac E-C coupling and the relative importance of the Ca2+ transporters to cell relaxation in neonatal cardiomyocytes. It is commonly accepted that the SR does not play an appreciable role in either E-C coupling or cell relaxation in the neonate heart. Using the perforated patch-clamp technique and simultaneous measurement of the Ca2+ transient in developing rabbit ventricular myocytes, we found that the NCX activity decreased with age while the functional coupling between dihydropyridine receptors (DHPRs) and ryanodine receptors (RyRs) increased with age. Surprisingly, the younger age groups possessed the greatest SR Ca2+ content, which declined significantly with development. Studies on SR Ca2+ loading source revealed the presence of a store-operated Ca2+ entry (SOCE) and further showed that reverse mode NCX, along with the SOCE, play a prominent role in SR Ca2+ loading at early development. The L-type Ca2+ current (ICa), on the other hand, was found to be the main source of SR Ca2+ loading at later stages of development. In addition, we demonstrated that the lower efficiency NCX-mediated CICR was the predominant mode of CICR at earliest developmental stages. With ontogeny, the more efficient L-type Ca2+ channel-mediated CICR increased in prominence, becoming the dominant mode of E-C coupling in the mature heart. These findings provide a more detailed understanding of the underlying developmental changes in heart function and therefore will likely contribute to the treatment of neonatal heart diseases.