Role of junctophilins on excitation-contraction coupling of skeletal muscles

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08491
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: Shinshu University
• Principal Investigator: Nakada Tsutomu 信州大学, 学術研究院総合人間科学系, 准教授 (70452141)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 興奮収縮連関 / 骨格筋 / L型カルシウムチャネル / ジャンクトフィリン / リアノジン受容体

Outline of Final Research Achievements

Close physical association of CaV1.1 L-type calcium channels (LTCCs) at the sarcolemmal junctional membrane (JM) with ryanodine receptors of the sarcoplasmic reticulum (SR) is crucial for excitation-contraction coupling in skeletal muscle. However, the molecular mechanism underlying the JM targeting of LTCCs is unexplored. Junctophilins (JPs) 1 and 2 stabilize the JM by bridging the sarcolemmal and SR membranes. 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 impairing LTCC-JP coupling at triads, 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.

Free Research Field

生理学

Academic Significance and Societal Importance of the Research Achievements

本研究では，骨格筋L型カルシウムチャネルの結合膜構造への集積が，ジャンクトフィリンとの直接的な結合によって調節されていることを，生体を用いた実験で初めて示した。骨格筋の収縮メカニズムを理解することは，正常状態の筋生理のみならず，様々な病態生理を説明する上で重要である。また，骨格筋と心筋の結合膜構造には多くの共通点があり，本研究で得られた知見は，心筋の収縮機構についても応用される可能性がある。