Calcium signaling in cardiac myocytes

Intracellular calcium regulation in excitation-contraction coupling

Intracellular calcium (Ca2+) regulation is crucial for intact cellular function. In cardiac cells, Ca2+ is a critical mediator of excitation–contraction coupling and is an important second messenger for Ca2+-dependent signaling that regulates vital cell functions. 

Ca2+-induced Ca2+ release (CICR) in cardiac myocyte

Cardiac myocyte excitation–contraction coupling is governed by Ca2+-induced Ca2+ release (CICR). Activation of voltage-gated L-type Ca2+ channels (LTCCs) by membrane depolarization leads to an influx of external Ca2+ into the cytoplasm. This triggers a much larger release of Ca2+ from the sarcoplasmic reticulum (SR) Ca2+ storage complex via the SR-Ca2+ release channel, ryanodine receptor 2 (RyR2).

The open probability of RyR2 is regulated by its phosphorylation-state, which is enhanced primarily via Ca2+-calmodulin–dependent kinase type II (CaMKII) and protein kinase A, and downregulated by protein phosphatases (PP) such as PP1 and PP type 2A (PP2A). These protein kinases and phosphatases also interact with LTCC complexes and regulate LTCC activity, contributing to the control of Ca2+ current density and the activation of Ca2+ signaling.

CICR produces a rapid, transient rise in intracellular Ca2+, initiating contraction when cytosolic Ca2+ binds to the Ca2+-sensitive myofilaments including troponin, actin, and myosin. Diastolic relaxation occurs as Ca2+ is released from the myofilaments, pumped back into the SR via the SR Ca2+-ATPase (SERCA2a) and extruded from the cell via the sarcolemmal Na+/Ca2+ exchanger (NCX). SERCA2a is under regulatory inhibition by the SERCA2a-binding protein phospholamban. Phospholamban-phosphorylation by CaMKII and protein-kinase A causes it to unbind from SERCA2a, enhancing SERCA2a-activity.

Browse L-type Ca2+ channel ( LTCC) blockers & antibodies

Browse  RyR2 modulators & antibodies

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Browse NCX inhibitors & antibodies

ROS and calcium signaling

Recent advances show that reactive oxygen species (ROS) such as superoxide anion (O2-) and hydrogen peroxide (H2O2) critically regulate cardiac Ca2+ signaling. ROS-dependent modifications have been found on virtually all Ca2+ signaling components in cardiac myocytes. For example, ROS has been shown to downregulate LTCC and NCX in ventricular myocytes. SERCA activity was inhibited by reagents that oxidize thiols. In contrast, H2O2 has been found to enhance Ca2+ release from SR in isolated ventricular myocytes. In purified cardiac RyR channels incorporated into planar lipid bilayers, H2O2 increases the channel open probability and this effect is reversed by the  SH-reducing agent dithiothreitol (DTT). It is safe to conclude that ROS signaling adds a new layer of regulation to cardiac excitation-contraction coupling, in addition to the classic phosphorylation mechanism mediated by kinases and phosphatases.


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