Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging

Abstract

Calcium (Ca(2+)) release from intracellular stores controls numerous cellular processes, including cardiac and skeletal muscle contraction, synaptic transmission and metabolism. The ryanodine receptors (RyRs: RyR1, RyR2, RyR3) and inositol 1,4,5-trisphosphate receptors (IP3Rs: IP3R1, IP3R2, IP3R3) are the major Ca(2+) release channels (CRCs) on the endo/sarcoplasmic reticulum (ER/SR). RyRs and IP3Rs comprise macromolecular signaling complexes that include modulatory proteins which regulate channel activity in response to extracellular signals resulting in intracellular Ca(2+) release. Here we focus on the roles of CRCs in heart, skeletal muscle, brain, metabolism, and aging.

Calcium release channel RyR2 regulates insulin release and glucose homeostasis

“…Dissociation of calstabin2 from RyR2 results in intracellular Ca 2+ leak via RyR2 channels (20,23,27). We have demonstrated that CPVT-linked RYR2 mutations reduce the binding affinity of the stabilizing subunit calstabin2 to the RyR2 channel (17,20,23).…”

“…RyR channels are macromolecular complexes comprising 4 protomers, each with a molecular mass of 565 kDa (17). They are the largest known ion channels, and the structure of RyR1, which is highly homologous (~70%) to RyR2, has recently been solved, revealing that RyRs are members of the 6-transmembrane family of ion channels (18).…”

“…They are the largest known ion channels, and the structure of RyR1, which is highly homologous (~70%) to RyR2, has recently been solved, revealing that RyRs are members of the 6-transmembrane family of ion channels (18). RyR channels are widely expressed and regulate the release of intracellular Ca 2+ involved in vital organspecific functions (17)(18)(19)(20)(21)(22). We studied knockin mice harboring RyR2 containing mutations that were discovered in humans with a genetic form of exercise-induced sudden cardiac death syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT), which has a 50% mortality rate by 35 years of age (23)(24)(25).…”

Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1–Mediated Protein Kinase A/Uncoupling Protein 2 Pathway

“…Ca 2+ plays an important role in mitochondrial function. 41 In addition, PKA has been shown to play a crucial role in RyR2 (type 2 ryanodine receptor) phosphorylation and mitochondrial Ca 2+ overload, which affect mitochondrial function and cardiac performance. 42 This study showed that capsaicin-mediated PKA phosphorylation in endothelium might affect the mitochondrial Ca 2+ level in ECs.…”

Dantrolene requires Mg 2+ to arrest malignant hyperthermia

“…malignant hyperthermia | dantrolene | ryanodine receptor | magnesium | skeletal muscle fiber R yanodine receptors (RyRs) are essential regulators of cytoplasmic Ca 2+ in muscle, heart, and brain (1)(2)(3). Congenital or acquired mishandling of Ca 2+ by RyRs is associated with organ dysfunction, myopathy, and the increased risk of sudden death (1,(4)(5)(6)(7). Consequently, the search for drugs to modulate RyR function is an area of intense research (8)(9)(10).…”