Abstract
Excitation-contraction coupling in skeletal muscle is believed to be triggered by direct protein-protein interactions between the sarcolemmal dihydropyridine-sensitive Ca2+ channel and the Ca2+ release channel/ryanodine receptor (RyR) of sarcoplasmic reticulum. A 138-amino acid cytoplasmic loop between repeats II and III of the alpha1 subunit of the skeletal dihydropyridine receptor (the II-III loop) interacts with a region of the RyR to elicit Ca2+ release. In addition, small segments (10-20 amino acid residues) of the II-III loop retain the capacity to activate Ca2+ release. Imperatoxin A, a 33-amino acid peptide from the scorpion Pandinus imperator, binds directly to the RyR and displays structural and functional homology with an activating segment of the II-III loop (Glu666-Leu690). Mutations in a structural motif composed of a cluster of basic amino acids followed by Ser or Thr dramatically reduce or completely abolish the capacity of the peptides to activate RyRs. Thus, the Imperatoxin A-RyR interaction mimics critical molecular characteristics of the II-III loop-RyR interaction and may be a useful tool to elucidate the molecular mechanism that couples membrane depolarization to sarcoplasmic reticulum Ca2+ release in vivo.
Highlights
In cardiac and skeletal muscle, the dihydropyridine receptor (DHPR)1 of the external membrane and the Ca2ϩ release channel/ryanodine receptor (RyR) of sarcoplasmic reticulum (SR) are key components of excitation-contraction (E-C) coupling, the series of events that link an electrical stimulus to a mechanical contraction (1)
We have previously shown that Imperatoxin A (IpTxa), a 33-amino acid peptide from the scorpion Pandinus imperator, is a high-affinity activator of RyRs (13, 14)
We found that IpTxa and a synthetic peptide with an amino acid sequence corresponding to a segment of the II-III loop (Glu666-Leu690) (10) activate RyRs in a similar manner and appear to compete for a common binding site on the channel protein
Summary
In cardiac and skeletal muscle, the dihydropyridine receptor (DHPR)1 of the external membrane and the Ca2ϩ release channel/ryanodine receptor (RyR) of sarcoplasmic reticulum (SR) are key components of excitation-contraction (E-C) coupling, the series of events that link an electrical stimulus (depolarization) to a mechanical contraction (1). We found that IpTxa and a synthetic peptide with an amino acid sequence corresponding to a segment of the II-III loop (Glu666-Leu690) (10) activate RyRs in a similar manner and appear to compete for a common binding site on the channel protein.
Sign-in/Register to view highlights & summary 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.
