Does Ca 2+ /Calmodulin-Dependent Protein Kinase δ c Activate or Inhibit the Cardiac Ryanodine Receptor Ion Channel?

Abstract

See related article, pages 399–407 The multifunctional Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) modulates cardiac muscle function by regulating Ca2+ transport proteins and nuclear signaling molecules. Aberrant activity of CaMKIIδ is implicated in heart disease. In this issue, Yang et al1 report that acute overexpression of constitutively active splice variant CaMKIIδC phosphorylates the cardiac ryanodine receptor ion channel (RyR2) to decrease the rate of occurrence of local Ca2+ release events (Ca2+ sparks) and Ca2+ waves in cultured rat cardiomyocytes. A dominant negative form of CaMKIIδC was shown to have opposite effects. The cardiac ryanodine receptors are cation selective channels that release Ca2+ from an intracellular Ca2+ storing compartment, the sarcoplasmic reticulum (SR), during a cardiac muscle action potential, in a process known as excitation-contraction coupling.2 Released Ca2+ cause cardiac muscle to contract. Sequestration of released Ca2+ by the SR Ca2+-transporting ATPase and extrusion by the Na+-Ca2+ exchanger restore the myofibrillar Ca2+ concentration from 10−6 - 10−5 to ≈10−7 M, causing muscle to relax. The RyR2s are regulated by a variety of effectors.3 During a cardiac action potential, closely apposed dihydropyridine-sensitive L-type Ca2+ channels in the surface membrane and T-tubule mediate influx of Ca2+, which triggers massive release of Ca2+ from SR by opening RyR2s. In addition to Ca2+, endogenous effectors such as Mg2+, ATP, reactive oxygen and nitrogen …