Abstract
Cardiac ryanodine receptor (RyR2) mediates the sarcoplasmic reticulum (SR) Ca2+ efflux that induces cardiomyocyte contraction, whereas sarcomeric myosin binding protein-C (cMyBP-C) regulates actomyosin cross-bridge cycling. We report the first evidence for direct interaction between these two essential proteins using several complementary methods, suggesting existence of a RyR2:cMyBP-C complex. Our studies indicate the C-terminus of cMyBP-C binds to the RyR2 N-terminus in mammalian cells with minimal requirement of a fibronectin-like type 3 domain. Importantly, we observe that specific binding between both recombinant cMyBP-C and RyR2 also occurs with the native proteins extracted from cardiac tissue. Co-expression of cMyBP-C and RyR2 in HEK293 cells alters cellular Ca2+ dynamics, with reduced frequency of RyR2-mediated spontaneous Ca2+ oscillations, suggesting a potential inhibitory effect of cMyBP-C on RyR2 Ca2+ release. Our discovery of direct, functional cMyBP-C association with RyR2 provides novel evidence for putative linkage between sarcomeric cMyBP-C regulation of myofilament contraction and SR-mediated Ca2+ release via RyR2. A distinct mechanism for retrograde sarcomere regulation of SR RyR2 channels may exist, with significant relevance to cMyBP-C and RyR2 dysfunction observed in inherited cardiac disorders.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
