Physiology and pathophysiology of excitation–contraction coupling: the functional role of ryanodine receptor

Abstract

Calcium (Ca2+) release from intracellular stores plays a key role in the regulation of skeletal muscle contraction. The type 1 ryanodine receptors (RyR1) is the major Ca2+ release channel on the sarcoplasmic reticulum (SR) of myocytes in skeletal muscle and is required for excitation-contraction (E–C) coupling. This article explores the role of RyR1 in the skeletal muscle physiology and pathophysiology.

Ryanodine Receptor Structure and Function in Health and Disease

“…They are required for excitation-contraction coupling, which translates an electrical signal into a mechanical output via the second messenger Ca 2+ (Santulli and Marks 2015). The closely related inositol 1,4,5-trisphosphate receptors (IP3Rs) are also found in most cell types and require the second messenger IP3 for activation (Harnick et al 1995; Yuan et al 2016; Santulli et al 2017a). In skeletal muscle there is a mechanical interaction between RyR1 on the sarcoplasmic reticulum (SR) membrane and the dihydropyridine receptor (Ca v 1.1) on specialized invaginations of the sarcolemma, called transverse tubules, leading to rapid Ca 2+ release (Rios and Brum 1987; Nelson et al 2013; Santulli et al 2017b).…”

“…RyRs have a high degree of sequence and structure homology with another intracellular Ca 2+ release channel, the IP3R (Santulli et al 2017a). IP3Rs are found in the ER and mediate the release of intracellular Ca 2+ in response to external stimuli.…”

“…IP3Rs are found in the ER and mediate the release of intracellular Ca 2+ in response to external stimuli. RyRs and IP3Rs have ∼40% homology in the core regions, indicating a common origin for Ca 2+ release channels (Santulli et al 2017a). However, the IP 3 R does not include much of the cytoplasmic shell and, most notably, lacks the large Bsol (Santulli et al 2017a).…”

“…RyRs and IP3Rs have ∼40% homology in the core regions, indicating a common origin for Ca 2+ release channels (Santulli et al 2017a). However, the IP 3 R does not include much of the cytoplasmic shell and, most notably, lacks the large Bsol (Santulli et al 2017a). Of particular interest, the extended pore helix, CTD and activation domain are conserved between these two channels, meaning that they have the same or very similar mechanisms of activation by Ca 2+ (Santulli et al 2017a).…”

Insight into muscle physiology through understanding mechanisms of muscle pathology

“…The review by Santulli and co-workers (Santulli et al 2017) covers the role of calcium (Ca2+) release from intracellular stores in the regulation of skeletal muscle contraction. The type 1 ryanodine receptors (RyR1) is the major Ca 2+ release channel on the sarcoplasmic reticulum (SR) of myocytes in skeletal muscle and is required for excitation-contraction (E-C) coupling.…”