Intracellular Regulation of Excitation-Contraction Coupling by Calcium Ions
The ability to modify the intracellular concentrations of divalent calcium ions is vital to normal cell functioning. In the cells of the cardiac muscle, calcium ions play a crucial role in coupling excitation and contraction. It is thus one of the most important second messengers since it regulates calcium-dependent cell signaling and in turn essential cell functions.
Calcium-Induced Calcium Release (CICR) Within Cardiac Myocytes
Excitation-contraction coupling occurs within cardiac muscle cells in response to calcium-induced calcium release, CICR. When L-type calcium channels that are voltage-gated are activated by the depolarization of the myocyte membrane, they allow calcium ions from outside the cell to sweep into the cytoplasm.
This in turn sparks off a more massive calcium ion release from the sarcoplasmic reticulum (SR) calcium ion storage complex, through other channels, the SR-calcium ion release channel. These are called ryanodine receptor 2, or RyR2.
The open probability of RyR2 depends on the occurrence of phosphorylation, which in turn is positively regulated chiefly through calcium ion-calmodulin-dependent kinase type II (CaCKII) and protein kinase A. It is downregulated by protein phosphatases (PP) like PP1 and PP2A.
Both protein kinases and phosphatases act on LTCC complexes as well, controlling their activity levels, and this results in more precise regulation of calcium current density as well as the activation of calcium signaling.
CICR causes the concentration of calcium inside the cell to rise rapidly but for a very brief time. This leads to the beginning of contraction by the binding of calcium in the cytosol with calcium-sensitive myofilaments like actin, myosin and troponin.
When calcium ions are released by these myofilaments, and pumped back into the sarcoplasmic reticulum through the SR calcium ATPase (SERCA2a) enzyme, and finally expelled from the myocyte through the sarcolemmal sodium/calcium exchanger (NCX), the muscle relaxes to cause diastole of the heart muscle.
The SERCA2a is controlled by phospholamban, a regulatory inhibitor protein which binds SERCA2a. When phospholamban is phosphorylated by CaMKII and protein kinase a, it is released from SERCA2a, which increases the level of activity of SERCA2a.
ROS and Calcium Signaling
We now know that reactive oxygen species (ROS) like superoxide anion (O2-) or hydrogen peroxide (H2O2) are critical regulators of the process of cardiac signaling via calcium ions. The modifications of components of the cardiac myocytes that contribute to calcium signaling that depend upon ROS are present in almost all these cells.
One instance is the downregulation of the expression of LTCC and NCX in cardiac myocytes in the ventricles. Reagents that oxidize thiols are shown to inhibit SERCA activity. On the other hand, H2O2 increases the release of calcium from the SR when studied in isolated ventricular muscle cells. When RyR channels from the cardiac myocytes are purified and integrated into planar lipid bilayers, the action of H2O2 is to enhance the probability of the channel open state, and this is counteracted by dithiothreitol (DTT) which reduces SH.
Signaling via ROS seems to be one more layer of control of excitation-contraction coupling in heart muscle cells, in addition to the classic mode of regulation already exerted by kinases and phosphatases using phosphorylation.
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