Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling

Kimura, Takashi, Lueck, John D., Harvey, Peta J., Pace, Suzy M., Ikemoto, Noriaki, Casarotto, Marco G., Kirksen, Robert T. and Dulhunty, Angela F. (2009) Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling. Cell Calcium, 45 3: 264-274. doi:10.1016/j.ceca.2008.11.005

Author Kimura, Takashi
Lueck, John D.
Harvey, Peta J.
Pace, Suzy M.
Ikemoto, Noriaki
Casarotto, Marco G.
Kirksen, Robert T.
Dulhunty, Angela F.
Title Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling
Journal name Cell Calcium   Check publisher's open access policy
ISSN 0143-4160
Publication date 2009-03
Sub-type Article (original research)
DOI 10.1016/j.ceca.2008.11.005
Volume 45
Issue 3
Start page 264
End page 274
Total pages 11
Place of publication Kidlington, United Kingdom
Publisher Churchill Livingstone
Language eng
Formatted abstract
Alternative splicing of ASI residues (Ala3481–Gln3485) in the skeletal muscle ryanodine receptor (RyR1) is developmentally regulated: the residues are present in adult ASI(+)RyR1, but absent in the juvenile ASI(−)RyR1 which is over-expressed in adult myotonic dystrophy type 1 (DM1). Although this splicing switch may influence RyR1 function in developing muscle and DM1, little is known about the properties of the splice variants. We examined excitation-contraction (EC) coupling and the structure and interactions of the ASI domain (Thr3471–Gly3500) in the splice variants. Depolarisation-dependent Ca2+ release was enhanced by >50% in myotubes expressing ASI(−)RyR1 compared with ASI(+)RyR1, although DHPR L-type currents and SR Ca2+ content were unaltered, while ASI(−)RyR1 channel function was actually depressed. The effect on EC coupling did not depend on changes in ASI domain secondary structure. Probing RyR1 function with peptides possessing the ASI domain sequence indicated that the domain contributes to an inhibitory module in RyR1. The action of the peptide depended on a sequence of basic residues and their alignment in an α-helix adjacent to the ASI splice site. This is the first evidence that the ASI residues contribute to an inhibitory module in RyR1 that influences EC coupling. Implications for development and DM1 are discussed.
Keyword Skeletal ryanodine receptor
Variably spliced residues
Excitation-contraction coupling
Myotonic dystrophy
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: ERA 2012 Admin Only
Institute for Molecular Bioscience - Publications
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Created: Fri, 14 Oct 2011, 09:25:11 EST by Peta Harvey on behalf of Institute for Molecular Bioscience