Association of cardiac myosin-binding protein-C with the ryanodine receptor channel – putative retrograde regulation?

Abstract

The cardiac muscle ryanodine receptor-Ca2+ release channel (RyR2) constitutes the sarcoplasmic reticulum (SR) Ca2+ efflux mechanism that initiates myocyte contraction, while cardiac myosin-binding protein-C (cMyBP-C; also known as MYBPC3) mediates regulation of acto-myosin cross-bridge cycling. In this paper, we provide the first evidence for the presence of direct interaction between these two proteins, forming a RyR2–cMyBP-C complex. The C-terminus of cMyBP-C binds with the RyR2 N-terminus in mammalian cells and the interaction is not mediated by a fibronectin-like domain. Notably, we detected complex formation between both recombinant cMyBP-C and RyR2, as well as between the native proteins in cardiac tissue. Cellular Ca2+ dynamics in HEK293 cells is altered upon co-expression of cMyBP-C and RyR2, with lowered frequency of RyR2-mediated spontaneous Ca2+ oscillations, suggesting that cMyBP-C exerts a potential inhibitory effect on RyR2-dependent Ca2+ release. Discovery of a functional RyR2 association with cMyBP-C provides direct evidence for a putative mechanistic link between cytosolic soluble cMyBP-C and SR-mediated Ca2+ release, via RyR2. Importantly, this interaction may have clinical relevance to the observed cMyBP-C and RyR2 dysfunction in cardiac pathologies, such as hypertrophic cardiomyopathy.

Susceptibility Modules and Genes in Hypertrophic Cardiomyopathy by WGCNA and ceRNA Network Analysis

“…21 genes were targeted by these 3 miRNAs. Several hub genes obtaining from Limma analysis have been reported to be involved in HCM in previous study, such as RYR2,RBM20, XIRP2 (Helms et al, 2016;Okuda et al, 2018;Stanczyk et al, 2018;Fernlund et al, 2020). Importantly, RyR2 is an important receptor that controls calcium channels of sarcoplasmic reticulum.…”

“…Importantly, RyR2 is an important receptor that controls calcium channels of sarcoplasmic reticulum. Therefore, it is closely related to the systolic function of cardiomyocytes (Okuda et al, 2018;Stanczyk et al, 2018).…”

Inhibition of HSC70 alleviates hypertrophic cardiomyopathy pathology in human induced pluripotent stem cell‐derived cardiomyocytes with a MYBPC3 mutation

“…It has been reported that MYBPC3 may bind to RYR2 to form a complex for stabilizing RYR2‐dependent Ca 2+ release. 9 Notably, we found that largely enhanced RYR2‐mediated Ca 2+ leak contributed to Ca 2+ handling abnormalities in Ang II‐treated mutant iPSC‐CMs, whereas sarcoplasmic reticulum (SR) Ca 2+ load was unchanged (Figure 2L‐N , Figure S4E and Table S4 ).…”

Ca2+ Channels Mediate Bidirectional Signaling between Sarcolemma and Sarcoplasmic Reticulum in Muscle Cells

“…Interestingly, the phosphorylation of cMyBP-C enhances activation profiles nearby sites of Ca 2+ binding to troponin C, and thereby accelerates the rate of cooperative cross-bridge recruitment (as reviewed by Moss et al [111]). Moreover, a recent study showed that cMyBP-C also physically interacts with RyR2s, and this interaction decreases the frequency of spontaneous Ca 2+ oscillations, without significantly altering the rate of Ca 2+ release or the amplitude/duration of Ca 2+ transients [112]. These data were obtained in HEK293 cells, and thus their relevance for muscle pathophysiology remains to be elucidated.…”