Regulation of cardiac excitation-contraction coupling by sorcin, a novel modulator of ryanodine receptors.
Activation of Ca2+ release channels/ryanodine receptors (RyR) by the inward Ca2+ current (I(Ca)) gives rise to Ca(2+)-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 Ca(2+)-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 = approximately 200 microM) 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.
Farrell
Emily F
EF
Department of Physiology, University of Wisconsin Medical School, Madison, WI 53706, USA.
Antaramian
Anaid
A
Benkusky
Nancy
N
Zhu
Xinsheng
X
Rueda
Angélica
A
Gómez
Ana M
AM
Valdivia
Héctor H
HH
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000502:physiology*; D007150:Immunohistochemistry; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium