Physical interaction of junctophilin and the Ca V 1.1 C terminus is crucial for skeletal muscle contraction
| Autor: | Toshihide Kashihara, Tsutomu Nakada, Katsuhiko Kojima, Masatoshi Komatsu, Mitsuhiko Yamada, Toshikazu Takeshita |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Calcium Channels L-Type Mutant Muscle Proteins Cell Line Mice 03 medical and health sciences Cav1.1 Sarcolemma Protein Domains medicine Animals Calcium Signaling Muscle Skeletal Multidisciplinary biology Voltage-dependent calcium channel Myogenesis Chemistry Ryanodine receptor Endoplasmic reticulum Membrane Proteins Skeletal muscle Biological Sciences musculoskeletal system Cell biology Transmembrane domain 030104 developmental biology medicine.anatomical_structure biology.protein Calcium Muscle Contraction |
| Zdroj: | Proceedings of the National Academy of Sciences. 115:4507-4512 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1716649115 |
| Popis: | Close physical association of CaV1.1 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 unexplored. 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 (JP1ΔCT) 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 JP1ΔCT-expressed muscle 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. Article Proceedings of the National Academy of Sciences of the United States of America. 115(17) : 4507-4512(2018) |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|