The calmodulin binding region of the skeletal ryanodine receptor acts as a self-modulatory domain

被引:33
作者
Zhu, XS
Ghanta, J
Walker, JW
Allen, PD
Valdivia, CH
机构
[1] Univ Wisconsin, Sch Med, Dept Physiol, Madison, WI 53706 USA
[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Anesthesia Res, Boston, MA 02115 USA
关键词
Ca2+ release channel; excitation-contraction coupling; calmodulin; sarcoplasmic reticulum;
D O I
10.1016/j.ceca.2003.09.002
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
A synthetic peptide (CaMBP) matching amino acids 3614-3643 of the skeletal ryanodine receptor (RyR1) binds to both Ca2+-free calmodulin (CaM) and Ca2+-bound CaM with nanomolar affinity [J. Biol. Chem. 276 (2001) 2069]. We report here that CaMBP increases [H-3]ryanodine binding to RyR1 in a dose- and Ca2+-dependent manner; it also induces Ca2+ release from SR vesicles, and increases open probability (P-o) of single RyR channels reconstituted in planar lipid bilayers. Further, CaMBP removes CaM associated with SR vesicles and increases [H-3]ryanodine binding to purified RyR1, suggesting that its mechanism of action is two-fold: it removes endogenous inhibitors and also interacts directly with complementary regions in RyR1. Remarkably, the N-terminus of CaMBP activates RyRs while the C-terminus of CaMBP inhibits RyR activity, suggesting the presence of two discrete functional subdomains within this region. A ryr1 mutant lacking this region, RyR1-Delta3614-3643, was constructed and expressed in dyspedic myoblasts (RyR1-knockout). The depolarization-, caffeine and 4-chloro-m-cresol (4-CmC)-induced Ca2+ transients in these cells were dramatically reduced compared with cells expressing wild type RyR1. Deletion of the 3614-3643 region also resulted in profound changes in unitary conductance and channel gating. We thus propose that the RyR1 3614-3643 region acts not only as the CaM binding site, but also as an important modulatory domain for RyR1 function. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:165 / 177
页数:13
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