Regulation of cardiac excitation-contraction coupling by sorcin, a novel modulator of ryanodine receptors

• Main Authors: EMILY F FARRELL, ANAID ANTARAMIAN, NANCY BENKUSKY, XINSHENG ZHU, ANGÉLICA RUEDA, ANA M GÓMEZ, HÉCTOR H VALDIVIA
• Format: Article
• Language: English
• Published: BMC 2004-01-01
• Series: Biological Research
• Subjects: Sorcin; ryanodine receptors; CICR; dihydropyridine receptor; sarcoplasmic reticulum
• Online Access: http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602004000400015

Activation of Ca2+ release channels/ryanodine receptors (RyR) by the inward Ca2+ current (I Ca) gives rise to Ca2+-induced Ca2+ release (CICR), the amplifying Ca2+ signaling mechanism that triggers contraction of the heart. CICR, in theory, is a high-gain, self-regenerating process, but an unidentified mechanism stabilizes it in vivo. Sorcin, a 21.6 kDa Ca2+-binding protein, binds to cardiac RyRs with high affinity and completely inhibits channel activity. Sorcin significantly inhibits both the spontaneous activity of RyRs in quiescent cells (visualized as Ca2+ sparks) and the I Ca-triggered activity of RyRs that gives rise to [Ca2+]i transients. Since sorcin decreases the amplitude of the [Ca2+]i transient without affecting the amplitude of I Ca, the overall effect of sorcin is to reduce the "gain" of excitation-contraction coupling. Immunocytochemical staining shows that sorcin localizes to the dyadic space of ventricular cardiac myocytes. Ca2+ induces conformational changes and promotes translocation of sorcin between soluble and membranous compartments, but the [Ca2+] required for the latter process (ED50 = ~200 mM) appears to be reached only within the dyadic space. Thus, sorcin is a potent inhibitor of both spontaneous and I Ca-triggered RyR activity and may play a role in helping terminate the positive feedback loop of CICR.