Sorcin regulates excitation-contraction coupling in the heart.
Sorcin is a penta-EF hand Ca2+-binding protein that associates with both cardiac ryanodine receptors and L-type Ca2+ channels and has been implicated in the regulation of intracellular Ca2+ cycling. To better define the function of sorcin, we characterized transgenic mice in which sorcin was overexpressed in the heart. Transgenic mice developed normally with no evidence of cardiac hypertrophy and no change in expression of other calcium regulatory proteins. In vivo hemodynamics revealed significant reductions in global indices of contraction and relaxation. Contractile abnormalities were also observed in isolated adult transgenic myocytes, along with significant depression of Ca2+ transient amplitudes. Whole cell ICa density and the time course of activation were normal in transgenic myocytes, but the rate of inactivation was significantly accelerated. These effects of sorcin on L-type Ca2+ currents were confirmed in Xenopus oocyte expression studies. Finally, we examined the expression of sorcin in normal and failing hearts from spontaneous hypertensive heart failure rats. In normal myocardium, sorcin extensively co-localized with ryanodine receptors at the Z-lines, whereas in myopathic hearts the degree of co-localization was markedly disrupted. Together, these data indicate that sorcin modulates intracellular Ca2+ cycling and Ca2+ influx pathways in the heart.
Meyers
Marian B
MB
Department of Medicine and Pediatrics, New York University School of Medicine, New York, New York, 10016, USA.
Fischer
Avi
A
Sun
Yan-Jie
YJ
Lopes
Coeli M B
CM
Rohacs
Tibor
T
Nakamura
Tomoe Y
TY
Zhou
Ying-Ying
YY
Lee
Paul C
PC
Altschuld
Ruth A
RA
McCune
Sylvia A
SA
Coetzee
William A
WA
Fishman
Glenn I
GI
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D009202:Cardiomyopathies / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000032:analysis; D014162:Transfection; D014982:Xenopus laevis
D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C503113:SRI protein, human; C503114:Sri protein, mouse; D002118:Calcium