Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling
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Kimura, Takashi; Lueck, John D; Harvey, Peta; Pace, Suzy M; Ikemoto, Noriaki; Casarotto, Marco; Dirksen, Robert; Dulhunty, Angela
Description
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...[Show more]
dc.contributor.author | Kimura, Takashi | |
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dc.contributor.author | Lueck, John D | |
dc.contributor.author | Harvey, Peta | |
dc.contributor.author | Pace, Suzy M | |
dc.contributor.author | Ikemoto, Noriaki | |
dc.contributor.author | Casarotto, Marco | |
dc.contributor.author | Dirksen, Robert | |
dc.contributor.author | Dulhunty, Angela | |
dc.date.accessioned | 2015-12-07T22:41:44Z | |
dc.identifier.issn | 0143-4160 | |
dc.identifier.uri | http://hdl.handle.net/1885/24457 | |
dc.description.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. | |
dc.publisher | Elsevier | |
dc.source | Cell Calcium | |
dc.subject | Keywords: ryanodine receptor 1; alpha helix; alternative RNA splicing; animal cell; article; calcium transport; controlled study; depolarization; excitation contraction coupling; myotonic dystrophy; myotube; nonhuman; priority journal; protein domain; protein secon Development; Excitation-contraction coupling; Myotonic dystrophy; Nuclear magnetic resonance; Skeletal ryanodine receptor; Structure; Variably spliced residues | |
dc.title | Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 45 | |
dc.date.issued | 2009 | |
local.identifier.absfor | 060199 - Biochemistry and Cell Biology not elsewhere classified | |
local.identifier.ariespublication | u4693331xPUB32 | |
local.type.status | Published Version | |
local.contributor.affiliation | Kimura, Takashi, Hyogo College of Medicine | |
local.contributor.affiliation | Lueck, John D, University of Rochester | |
local.contributor.affiliation | Harvey, Peta, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Pace, Suzy M, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Ikemoto, Noriaki, Boston Biomedical Research Institute | |
local.contributor.affiliation | Casarotto, Marco, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Dirksen, Robert, University of Rochester | |
local.contributor.affiliation | Dulhunty, Angela, College of Medicine, Biology and Environment, ANU | |
local.description.embargo | 2037-12-31 | |
local.bibliographicCitation.issue | 3 | |
local.bibliographicCitation.startpage | 264 | |
local.bibliographicCitation.lastpage | 274 | |
local.identifier.doi | 10.1016/j.ceca.2008.11.005 | |
dc.date.updated | 2016-02-24T11:17:55Z | |
local.identifier.scopusID | 2-s2.0-61449183565 | |
local.identifier.thomsonID | 000264956800008 | |
Collections | ANU Research Publications |
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