Modulation of ryanodine receptor by luminal calcium and accessory proteins in health and cardiac disease.
The cardiac ryanodine receptor (RyR2) is the sarcoplasmic reticulum (SR) Ca(2+) release channel which is responsible for generation of the cytosolic Ca(2+) transient required for activation of cardiac contraction. RyR2 functional activity is governed by changes in [Ca(2+)] on both the cytosolic and luminal phase of the RyR2 channel. Activation of RyR2 by cytosolic Ca(2+) results in Ca(2+)-induced Ca(2+) release (CICR) from the SR. The decline in luminal [Ca(2+)] following release contributes to termination of CICR and Ca(2+) signalling refractoriness through the process of luminal Ca(2+)-dependent deactivation of RyR2s. The control of RyR2s by luminal Ca(2+) involves coordinated interaction of the channel with several SR proteins, including the Ca(2+)-binding protein calsequestrin (CASQ2), and the integral proteins triadin 1 (TRD) and junctin (JCN). CASQ2 in addition to serving as a Ca(2+) storage site and a luminal Ca(2+) buffer modulates RyR2 function more directly as a putative luminal Ca(2+) sensor. TRD and JCN, stimulatory by themselves, mediate the interactions between CASQ2 and RyR2. Acquired and genetic defects in proteins of this junctional Ca(2+) signalling complex lead to disease states such as cardiac arrhythmia and heart failure by impairing luminal Ca(2+) regulation of RyR2.
Györke
Sandor
S
Department of Physiology and Cell Biology, 505 Davis Heart and Lung Research Institute, The Ohio State University, 473 West 12th Avenue, Columbus, OH 43210, USA. sandor.gyorke@osumc.edu
Terentyev
Dmitry
D
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002155:Calsequestrin / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D006331:Heart Diseases / Q000209:etiology* / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D006899:Mixed Function Oxygenases / Q000502:physiology*; D009124:Muscle Proteins / Q000502:physiology*; D011110:Polymorphism, Genetic; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
C443109:CASQ2 protein, human; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D002352:Carrier Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C070048:triadin; D006899:Mixed Function Oxygenases; C419389:ASPH protein, human; D002118:Calcium