Rapid Ca2+ efflux from intracellular stores during cardiac muscle excitation–contraction coupling is mediated by the ryanodine-sensitive calcium-release channel, a large homotetrameric complex present in the sarcoplasmic reticulum. We report here the identification, primary structure and topological analysis of the ryanodine receptor–calcium release channel from human cardiac muscle (hRyR-2). Consistent with sedimentation and immunoblotting studies on the hRyR-2 protein, sequence analysis of ten overlapping cDNA clones reveals an open reading frame of 14901 nucleotides encoding a protein of 4967 amino acid residues with a predicted molecular mass of 564569 Da for hRyR-2. In-frame insertions corresponding to eight and ten amino acid residues were found in two of the ten cDNAs isolated, suggesting that novel, alternatively spliced transcripts of the hRyR-2 gene might exist. Six hydrophobic stretches, which are present within the hRyR-2 C-terminal 500 amino acids and are conserved in all RyR sequences, may be involved in forming the transmembrane domain that constitutes the Ca2+-conducting pathway, in agreement with competitive ELISA studies with a RyR-2-specific antibody. Sequence alignment of hRyR-2 with other RyR isoforms indicates a high level of overall identity within the RyR family, with the exception of two important regions that exhibit substantial variability. Phylogenetic analysis suggests that the RyR-2 isoform diverged from a single ancestral gene before the RyR-1 and RyR-3 isoforms to form a distinct branch of the RyR family tree.
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September 1996
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Research Article|
September 01 1996
The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis
Richard E. A. TUNWELL;
Richard E. A. TUNWELL
‡
*MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, U.K.
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Colin WICKENDEN;
Colin WICKENDEN
§
*MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, U.K.
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Bénédicte M. A. BERTRAND;
Bénédicte M. A. BERTRAND
*MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, U.K.
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Valery I. SHEVCHENKO;
Valery I. SHEVCHENKO
*MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, U.K.
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Martina B. WALSH;
Martina B. WALSH
*MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, U.K.
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Paul D. ALLEN;
Paul D. ALLEN
†Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, U.S.A.
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F. Anthony LAI
F. Anthony LAI
‖
*MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, U.K.
‖To whom correspondence should be addressed.
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Publisher: Portland Press Ltd
Received:
January 10 1996
Revision Received:
May 07 1996
Accepted:
May 10 1996
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1996
1996
Biochem J (1996) 318 (2): 477–487.
Article history
Received:
January 10 1996
Revision Received:
May 07 1996
Accepted:
May 10 1996
Citation
Richard E. A. TUNWELL, Colin WICKENDEN, Bénédicte M. A. BERTRAND, Valery I. SHEVCHENKO, Martina B. WALSH, Paul D. ALLEN, F. Anthony LAI; The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis. Biochem J 1 September 1996; 318 (2): 477–487. doi: https://doi.org/10.1042/bj3180477
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