![]() ![]() The binding of cAMP to the R subunits releases the active catalytic subunits, resulting in the phosphorylation of substrates within the consensus motif R-R-X-S/T-X ( 28). PKA is a broad specificity tetrameric serine/threonine kinase consisting of two catalytic subunits maintained in an inactive state by association with a regulatory (R) subunit dimer. Finally, the phosphorylation of sarcomeric proteins including cardiac troponin I (cTnI) and myosin-binding protein C (cMyBP-C) also promotes relaxation by decreasing myofilament Ca 2+ responsiveness ( 14, 57, 62, 108).Īnchoring of PKA Through A-Kinase Anchoring Proteins This promotes SERCA2 activation and favors myocyte relaxation. On the other hand, the phosphorylation of phospholamban (PLB), a regulatory transmembrane protein that inhibits SERCA2 activity, induces the dissociation of PLB from SERCA2 ( 39). In this respect, the phosphorylation of L-type Ca 2+ channels and RyR2s increases their open probability and, as a consequence, Ca 2+ mobilization from intracellular stores ( 48, 72). Activated β-ARs enhance cAMP/PKA signaling, which directly or indirectly regulates the phosphorylation and activity of proteins controlling Ca 2+ cycling and sarcomere contraction. The sympathetic nervous system enhances contractile force (inotropy), heart rate (chronotropy), and myocardial relaxation (lusitropy) through the release of the catecholamines norepinephrine and epinephrine, which stimulate β-adrenergic receptors (β-ARs) located on the sarcolemma of cardiomyocytes. In humans, ∼75% of cytosolic Ca 2+ is transported back to the lumen of the sarcoplasmic reticulum by the ATP-dependent Ca 2+-pump, sarco(endo)plasmic reticulum Ca 2+-ATPase (SERCA2), whereas the remaining 25% is exported out of the cell by the Na +/Ca 2+ exchanger ( Fig. Relaxation occurs when L-type Ca 2+ channels inactivate and Ca 2+ is removed from the cytosol. At the sarcomere, binding of Ca 2+ ions to troponin C induces a conformational change in the troponin complex that exposes binding sites for myosin on the actin filaments and allows contraction to occur ( 24). 1), producing a global increase in Ca 2+ concentration. This induces a local increase in cytosolic Ca 2+ concentration which, in turn, activates the release of Ca 2+ from intracellular stores through the ryanodine receptor 2 (RyR2) at the sarcoplasmic reticulum ( 4, 23, 84) ( Fig. This process initiates when voltage-gated L-type Ca 2+ channels in the transverse tubules (T tubules) open in response to membrane depolarization. In cardiomyocytes, the coupling of membrane depolarization to contraction is achieved through a process known as excitation-contraction coupling. While inward Na + and Ca 2+ currents initiate and maintain membrane depolarization, respectively, the delayed rectifier K + current mediates repolarization of the plasma membrane to the resting state ( 82). ![]() Action potentials reflect the sequential activation and inactivation of ion channels carrying inward Na + and Ca 2+ and outward K + currents. To perform this function, myocytes in the atria and ventricles contract in response to action potentials that originate in the sinoatrial node. The heart pumps blood to the systemic and pulmonary circulation to ensure that oxygen is delivered to the brain and peripheral organs. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at. This article is part of a collection on G Protein Kinase A Signaling in Cardiovascular Physiology and Disease. ![]()
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