Physical interaction of junctophilin and the Ca(V)1.1 C terminus is crucial for skeletal muscle contraction

Nakada Tsutomu; Kashihara Toshihide; Komatsu MasatoshiKojima KatsuhikoTakeshita ToshikazuYamada Mitsuhiko

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Physical interaction of junctophilin and the Ca(V)1.1 C terminus is crucial for skeletal muscle contraction

机译：Physical interaction of junctophilin and the Ca(V)1.1 C terminus is crucial for skeletal muscle contraction

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Close physical association of Ca(V)1.1 L-type calcium channels (LTCCs) at the sarcolemmal junctional membrane (JM) with ryanodine receptors (RyRs) of the sarcoplasmic reticulum (SR) is crucial for excitation-contraction coupling (ECC) in skeletal muscle. However, the molecular mechanism underlying the JM targeting of LTCCs is un-explored. Junctophilin 1 (JP1) and JP2 stabilize the JM by bridging the sarcolemmal and SR membranes. Here, we examined the roles of JPs in localization and function of LTCCs. Knockdown of JP1 or JP2 in cultured myotubes inhibited LTCC clustering at the JM and suppressed evoked Ca2+ transients without disrupting JM structure. Coimmunoprecipitation and GST pull-down assays demonstrated that JPs physically interacted with 12-aa residues in the proximal C terminus of the CaV1.1. A JP1 mutant lacking the C terminus including the transmembrane domain (JP1 Delta CT) interacted with the sarcolemmal/T-tubule membrane but not the SR membrane. Expression of this mutant in adult mouse muscles in vivo exerted a dominant-negative effect on endogenous JPs, impairing LTCC-RyR coupling at triads without disrupting JM morphology, and substantially reducing Ca2+ transients without affecting SR Ca2+ content. Moreover, the contractile force of the JP1 Delta CT-expressedmuscle was dramatically reduced compared with the control. Taken together, JPs recruit LTCCs to the JM through physical interaction and ensure robust ECC at triads in skeletal muscle.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2018年第17期|4507-4512|共6页
作者
Nakada Tsutomu; Kashihara Toshihide; Komatsu MasatoshiKojima KatsuhikoTakeshita ToshikazuYamada Mitsuhiko;
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作者单位

Shinshu Univ, Sch Med, Dept Microbiol & Immunol, Matsumoto, Nagano 3908621, Japan;

Shinshu Univ, Sch Med, Dept Mol Pharmacol, Matsumoto, Nagano 3908621, Japan;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
skeletal muscle; dihydropyridine receptor; junctophilin; triad; ryanodine receptor;

Physical interaction of junctophilin and the Ca(V)1.1 C terminus is crucial for skeletal muscle contraction

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