ジャンクトフィリンによるL型カルシウムチャネル調節機構

抄録

Functional coupling between L-type calcium channels (LTCCs) of the sarcolemma and ryanodine receptors (RyR) of the sarcoplasmic reticulum (SR) at the junctional membrane (JM) is crucial for the excitation–contraction coupling (ECC) of striated muscles. Junctophilins (JPs) stabilize the JM by bridging the sarcolemmal and SR membranes. We recently reported that expression of JP1 mutant lacking its C-terminal transmembrane domain in mouse skeletal muscles significantly reduced their contractile force without disrupting JM, revealing a novel role of JP1 to directly support the physical LTCC–RyR1 interaction. Thus, we next investigated by using an analogous JP2 mutant (JP2Δ427), a role of JP2 in cardiac myocytes where LTCCs regulate RyR2 not directly but indirectly through Ca²⁺-induced Ca²⁺ release (CICR). Nonetheless, JP2Δ427 also significantly reduced the peak twitch calcium transient of ventricular myocytes and the fractional shortening of the left ventricle from 43 to 31% without causing overt heart failure. Interestingly, it recruited LTCCs to the surface sarcolemma from T-tubules without disrupting T-tubules. Therefore, JP2 supports the cardiac ECC by aligning LTCC and RyR2 within an adequate distance for CICR. In this symposium, we will discuss how JPs regulates ECC of striated muscles.