Altered sarcoplasmic reticulum calcium cycling--targets for heart failure therapy

Abstract

Cardiac myocyte function is dependent on the synchronized movements of Ca(2+) into and out of the cell, as well as between the cytosol and sarcoplasmic reticulum. These movements determine cardiac rhythm and regulate excitation-contraction coupling. Ca(2+) cycling is mediated by a number of critical Ca(2+)-handling proteins and transporters, such as L-type Ca(2+) channels (LTCCs) and sodium/calcium exchangers in the sarcolemma, and sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), ryanodine receptors, and cardiac phospholamban in the sarcoplasmic reticulum. The entry of Ca(2+) into the cytosol through LTCCs activates the release of Ca(2+) from the sarcoplasmic reticulum through ryanodine receptor channels and initiates myocyte contraction, whereas SERCA2a and cardiac phospholamban have a key role in sarcoplasmic reticulum Ca(2+) sequesteration and myocyte relaxation. Excitation-contraction coupling is regulated by phosphorylation of Ca(2+)-handling proteins. Abnormalities in sarcoplasmic reticulum Ca(2+) cycling are hallmarks of heart failure and contribute to the pathophysiology and progression of this disease. Correcting impaired intracellular Ca(2+) cycling is a promising new approach for the treatment of heart failure. Novel therapeutic strategies that enhance myocyte Ca(2+) homeostasis could prevent and reverse adverse cardiac remodeling and improve clinical outcomes in patients with heart failure.

Figure 1

Excitation–contraction coupling. During systole, the action potential depolarizes the sarcolemma. This depolarization enables a small amount of extracellular Ca²⁺ to enter the cytosol through the LTCCs. Ca²⁺ entry triggers the release of Ca²⁺ from the SR through RyR2 channels. The intracellular Ca²⁺ concentration increases and binding of Ca²⁺ to TN-C activates myofilaments, resulting in muscle contraction. Removal of cytosolic Ca²⁺ during diastole is primarily facilitated by SERCA2a, which returns Ca²⁺ to the SR. Some Ca²⁺ also exits the cell through NCX. The decrease in intracellular Ca²⁺ leads to dissociation of Ca²⁺ from TN-C and muscle relaxation. Abbreviations: LTCC, voltage-dependent L-type Ca²⁺ channel; NCX, Na⁺/Ca²⁺ exchanger; RyR2, ryanodine receptor 2; SERCA2, sarcoplasmic/endoplasmic reticulum calcium ATPase 2; SR, sarcoplasmic reticulum; TN-C, troponin C.

Figure 2

Abnormal intracellular Ca²⁺ handling in failing cardiomyocytes results in reduced contractile force and prolonged relaxation. a. Reduced SR Ca²⁺ storage and release cause abnormal systolic cardiomyocyte function. Abnormal β-AR and GPCR signaling increase the expression of PKA and CaMKII, which hyperphosphorylate and alter the function of RyR2 and LTCC. FKBP12.6 also contributes to stabilization of the RyR2 open probability. Impaired SERCA2a function decreases SR Ca²⁺ loading, resulting in reduced SR Ca²⁺ content and release and, therefore, reduced contractility. Alterations in LTCC function and STIM1–ORAI1-mediated store-operated Ca²⁺ influx can also result in abnormal Ca²⁺ handling during systole. b. Reduced SR Ca²⁺ resequestration is a key abnormality in diastole. Decreased SERCA2a activity, downregulation of SERCA2a, a decreased PLB:SERCA2a ratio, or PLB hypophosphorylation cause prolonged intracellular Ca²⁺ transients, reduced SR Ca²⁺ loading, and slowed cardiomyocyte relaxation. An increase in levels of NCX might be a compensatory response to prevent Ca²⁺ overloading. While increased NCX activity would be initially adaptive, excessive or sustained NCX activation could contribute to decreased sarcoplasmic reticulum Ca²⁺ content by removing cytosolic Ca²⁺, and reducing systolic Ca²⁺ transients and contractile function. SR Ca²⁺ leak resulting from impaired RyR2 function and increased expression of PP1 can reduce SR Ca²⁺ content and increase cytosolic Ca²⁺ concentration during diastole. On activation, the β-AR–AC–GPCR complex synthesizes cAMP, which activates PKA. Hyperactive PKA decreases the Ca²⁺ sensitivity of the myofilaments and prolongs relaxation. Intracellular Ca²⁺ overload stimulates CaMKII, which contributes to SR diastolic Ca²⁺ leak by hyperphosphorylating RyR2 and induces the transduction of pathological Ca²⁺ signaling. Abbreviations: AC, adenylate cyclase; β-AR, β-adrenergic receptor; CaMKII, calcium and calmodulin-dependent protein kinase type II; FKBP12.6, FK506 binding protein; GPCR, G-protein-coupled receptor; LTCC, voltage-dependent L-type Ca²⁺ channel; NCX, Na⁺/Ca²⁺ exchanger; Orai-1, calcium-release activated calcium channel protein 1; P, phosphorylation; PLB, cardiac phospholamban; PP1, protein phosphatase 1; RyR2, ryanodine receptor 2; SERCA2a, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a; STIM1, stromal interaction molecule 1.