Abstract

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.

Highlights

  • Tracellular Ca2ϩ levels to diastolic levels is in turn accomplished by various efflux mechanisms involving key transport proteins such as SERCA2 and the Naϩ-Ca2ϩ exchanger [1]

  • Using anti-peptide antibodies specific for epitopes from the amino or carboxyl terminus of sorcin, we found that only the full-length, 22-kDa form of sorcin was overexpressed in transgenic hearts, whereas the abundance of the 18-kDa t-sorcin form was essentially equivalent in TG and WT hearts (Fig. 1B)

  • Full-length sorcin undergoes translocation, Ca2ϩ-mediated conformational changes, and dimerization [22, 23, 35,36,37]. These properties, many of them Ca2ϩ-dependent, in combination with our biochemical studies revealing a direct association of sorcin with both the cardiac and skeletal ryanodine receptors (RyRs) and the cardiac L-type Ca2ϩ channel, have led to the hypothesis that sorcin may play a regulatory role in intracellular calcium cycling

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Summary

The abbreviations used are

RyR, ryanodine receptor; SERCA2, sarco/endoplasmic reticulum Ca-ATPase; SHHF, spontaneous-hypertensive heart failure; TG, transgenic; WT, wild type; PBS, phosphatebuffered saline. The amplitude of L-type Ca2ϩ currents in sorcin-overexpressing myocytes was not different from control cells; the time course of inactivation of L-type. Using confocal immunomicroscopy, we found that the localization of both sorcin and RyRs was markedly perturbed in failing hearts from spontaneous hypertensive heart failure (SHHF) rats, a model of heart failure in which excitation-contraction coupling is abnormal [19]. Together, these data suggest that sorcin modulates cardiac excitation-contraction coupling

EXPERIMENTAL PROCEDURES
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