Ryanodine receptors

Emichelle Capes,Randall Loaiza,Héctor H Valdivia

doi:10.1186/2044-5040-1-18

Abstract

Excitation-contraction coupling involves the faithful conversion of electrical stimuli to mechanical shortening in striated muscle cells, enabled by the ubiquitous second messenger, calcium. Crucial to this process are ryanodine receptors (RyRs), the sentinels of massive intracellular calcium stores contained within the sarcoplasmic reticulum. In response to sarcolemmal depolarization, RyRs release calcium into the cytosol, facilitating mobilization of the myofilaments and enabling cell contraction. In order for the cells to relax, calcium must be rapidly resequestered or extruded from the cytosol. The sustainability of this cycle is crucially dependent upon precise regulation of RyRs by numerous cytosolic metabolites and by proteins within the lumen of the sarcoplasmic reticulum and those directly associated with the receptors in a macromolecular complex. In addition to providing the majority of the calcium necessary for contraction of cardiac and skeletal muscle, RyRs act as molecular switchboards that integrate a multitude of cytosolic signals such as dynamic and steady calcium fluctuations, β-adrenergic stimulation (phosphorylation), nitrosylation and metabolic states, and transduce these signals to the channel pore to release appropriate amounts of calcium. Indeed, dysregulation of calcium release via RyRs is associated with life-threatening diseases in both skeletal and cardiac muscle. In this paper, we briefly review some of the most outstanding structural and functional attributes of RyRs and their mechanism of regulation. Further, we address pathogenic RyR dysfunction implicated in cardiovascular disease and skeletal myopathies.

Highlights

In striated and smooth muscle cells, fluctuations in the intracellular levels of Ca2+ ions greatly determine the magnitude and duration of contractile force
Ai et al [160] reported that RyR2S2808 phosphorylation was increased by approximately 50% in a rabbit model of heart failure (HF); a direct test of PKA phosphorylation of RyR2 in canine and human HF yielded no difference compared with control, and a phospho-antibody against RyR2-S2808 detected equal phosphorylation levels in control and HF samples [158,161]
Summary In addition to providing the majority of the Ca2+ necessary for contraction of cardiac and skeletal muscle, ryanodine receptors (RyRs) act as molecular switchboards that integrate a multitude of cytosolic signals such as dynamic and steady Ca2+ fluctuations, b-adrenergic stimulation, nitrosylation and metabolic states, and transduce these signals to the channel pore to release appropriate amounts of Ca2+

Summary

Introduction

In striated and smooth muscle cells, fluctuations in the intracellular levels of Ca2+ ions greatly determine the magnitude and duration of contractile force. Because infusion of catecholamines triggers CPVT, it is likely that activation of the b-adrenergic system plays an important role In this regard, it has been suggested that phosphorylation of RyR2 by PKA, the kinase linking b1-adrenergic receptor activation to cellular effects, dissociates FKBP12.6 [37,90,91,146]), an accessory protein that presumably stabilizes RyR2 in the closed state. Summary In addition to providing the majority of the Ca2+ necessary for contraction of cardiac and skeletal muscle, RyRs act as molecular switchboards that integrate a multitude of cytosolic signals such as dynamic and steady Ca2+ fluctuations, b-adrenergic stimulation (phosphorylation), nitrosylation and metabolic states, and transduce these signals to the channel pore to release appropriate amounts of Ca2+. Competing interests The authors declare that they have no competing interests

21. Serysheva II

Findings

32. Bers DM