A Toolkit Fine-Tuning the Dyadic “Fuzzy Space”?
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Cardiac excitation-contraction (E-C) coupling links action potentials to muscle contraction and is in essence a process of calcium ion mobilization.1 The central mechanism governing this process in ventricular myocytes is Ca2+-induced Ca2+ release, or CICR. It has been established for more than 20 years that CICR operates in a local control mode, taking place in a restricted junctional space of ≈12 to 15 nm between the transverse (T)-tubule and sarcoplasmic reticulum (SR) membranes, namely, the junctional membrane complexes or cardiac dyads.2,3 Within this dyadic “fuzzy space,”4 clusters of ryanodine receptor (RyR) Ca2+ release channels on the SR constitute the calcium release apparatus together with the directly apposed voltage-gated L-type Ca2+ channels (LTCCs) located primarily on the T-tubule membrane.5 On membrane depolarization, a small amount of Ca2+ influx through the opening of LTCCs locally activates adjacent RyRs to release a much larger (≈10 times) amount of Ca2+ from the SR.6,7 The normal, functional cross-talk between LTCCs and RyRs depends on a stable local ultrastructure—the cardiac dyad.
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The molecular mechanism underlying the formation of cardiac dyads remained a mystery until the pioneering work of Takeshima and colleagues.8 In their study, junctophilins were identified as key molecules that maintain junctional membrane complexes between the plasma membrane and the endoplasmic/sarcoplasmic reticulum (ER/SR) in excitable cells. The junctophilin protein family contains 4 members (JP1-4), and JP2 is the only subtype expressed in cardiac myocytes. Lack of JP2 in mice causes embryonic …