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Three residues in the luminal domain of triadin impact on Trisk 95 activation of skeletal muscle ryanodine receptors
Triadin isoforms, splice variants of one gene, maintain healthy Ca 2+ homeostasis in skeletal muscle by subserving several functions including an influence on Ca 2+ release through the ligand-gated ryanodine receptor (RyR1) ion channels. The predominant triadin isoform in skeletal muscle, Trisk 95,...
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Published in: | Pflügers Archiv 2016-11, Vol.468 (11-12), p.1985-1994 |
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Main Authors: | , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Triadin isoforms, splice variants of one gene, maintain healthy Ca
2+
homeostasis in skeletal muscle by subserving several functions including an influence on Ca
2+
release through the ligand-gated ryanodine receptor (RyR1) ion channels. The predominant triadin isoform in skeletal muscle, Trisk 95, activates RyR1 in vitro via binding to previously unidentified amino acids between residues 200 and 232. Here, we identify three amino acids that influence Trisk 95 binding to RyR1 and ion channel activation, using peptides encompassing residues 200–232. Selective alanine substitutions show that K
218
, K
220
, and K
224
together facilitate normal Trisk 95 binding to RyR1 and channel activation. Neither RyR1 binding nor activation are altered by alanine substitution of K
220
alone or of K
218
and K
224
. Therefore K
218
, K
220
, and K
224
contribute to a robust binding and activation site that is disrupted only when the charge on all three residues is neutralized. We suggest that charged pair interactions between acidic RyR1 residues D
4878
, D
4907
, and E
4908
and Trisk 95 residues K
218
, K
220
, and K
224
facilitate Trisk 95 binding to RyR1 and channel activation. Since K
218
, K
220
, and K
224
are also required for CSQ binding to RyRs (Kobayashi et al.
17
,
J Biol Chem
275, 17639–17646), the results suggest that Trisk 95 may not simultaneously bind to RyR1 and CSQ, contrary to the widely held belief that triadin monomers form a quaternary complex with junctin, CSQ and RyR1. Therefore, the in vivo role of triadin monomers in modulating RyR1 activity is likely unrelated to CSQ. |
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ISSN: | 0031-6768 1432-2013 |
DOI: | 10.1007/s00424-016-1869-7 |