Multiple Roles for the Membrane-Associated Ca²⁺/Calmodulin-Dependent Protein Kinase in the Regulation of Sarcoplasmic Reticulum Function in Heart Muscle

Abstract

By regulating the cytosolic Ca²⁺ concentration, the sarcoplasmic reticulum (SR) plays a central role in the contraction-relaxation cycle of heart muscle. Following excitation, Ca²⁺ is released from the SR through a Ca²⁺ release channel (the ryanodine receptor), and the consequent increase in cytoplasmic Ca²⁺ produces myofilament activation and muscle contraction [1–4]. Subsequently, active sequestration of Ca²⁺ back into the SR lumen by a Ca²⁺-pumping ATPase (Ca²⁺-ATPase) in the SR lowers the cytoplasmic Ca²⁺, thus promoting muscle relaxation [2,3,5,6]. The Ca²⁺-pumping function of this ATPase is well known to be regulated by another cardiac SR-specific protein called phospholamban [2,7–9]. Current evidence suggests that nonphosphorylated phospholamban interacts with the ATPase and serves to inhibit the Ca²⁺ pump and that phosphorylation of phospholamban by cAMP-dependent protein kinase (PKA) or Ca²⁺/calmodulin-dependent protein kinase (CaM kinase) results in disruption of the ATPase-phospholamban interaction leading to removal of inhibition and consequent activation of the Ca²⁺ pump [7–14]. In cardiac SR, the Ca²⁺ channel also undergoes phosphorylation by CaM kinase [15,16], and Ca²⁺ channel phosphorylation appears to result in stimulation of Ca²⁺ release from the SR [15].