Abstract
Cardiac contractility is regulated by changes in intracellular Ca concentration ([Ca2+]i). Normal function requires that [Ca2+]i be sufficiently high in systole and low in diastole. Much of the Ca needed for contraction comes from the sarcoplasmic reticulum and is released by the process of calcium-induced calcium release. The factors that regulate and fine-tune the initiation and termination of release are reviewed. The precise control of intracellular Ca cycling depends on the relationships between the various channels and pumps that are involved. We consider 2 aspects: (1) structural coupling: the transporters are organized within the dyad, linking the transverse tubule and sarcoplasmic reticulum and ensuring close proximity of Ca entry to sites of release. (2) Functional coupling: where the fluxes across all membranes must be balanced such that, in the steady state, Ca influx equals Ca efflux on every beat. The remainder of the review considers specific aspects of Ca signaling, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca2+]i.
Highlights
The process of excitation–contraction (E–C) coupling links the electric excitation of the surface membrane to contraction
The depolarization produced by the action potential opens L-type Ca channels situated in the surface membrane and transverse tubules
Ca must be removed from the cytoplasm. This requires that the RyRs close and that Ca is pumped (1) back into the SR, by the SERCA (SR CaATPase) and (2) out of the cell, largely by the sodium–calcium exchange (NCX)
Summary
Transverse (t-) tubules are 150- to 300-nm-wide[8,9] deep invaginations of the surface sarcolemma occurring at the junction of each sarcomere (z-line). The cardiac dyad is a specialized signaling nexus concerned primarily with the initiation of cardiac contraction It consists of clusters of L-type Ca2+ channels on the sarcolemma closely apposed (≈15 nm) across the dyadic cleft to clusters of RyRs on the SR membrane. In addition to these basic requirements for excitation–contraction coupling, the cardiac dyad may be considered as containing additional structures that may contribute to or modulate Ca2+ release from the SR during systole (Figure 1). This position, reductions in SERCA activity (via either reduced expression or hypophosphorylation of phospholamban45,46) in the diseased heart, especially if coupled to increased RyR density[35] and thence an increased probability of Ca2+ spark occurrence,[32,33] may impair the protective firebreak and facilitate the formation of Ca2+ waves and triggered activity
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