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Biphasic Modulation of Ryanodine Receptors by Sulfhydryl Oxidation in Rat Ventricular Myocytes

Unit of Cell Signal Transduction, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Correspondence: Address reprint requests to Professor Pei-Hong Zhu, Unit of Cell Signal Transduction, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Rd., Shanghai 200031, China. Tel.: 86-21-54920303; E-mail: phzhu{at}sibs.ac.cn.

To understand better the modulation of ryanodine receptors (RyRs) during oxidative stress, the effect of 4,4'-dithiodipyridine (DTDP), a cell-permeant and thiol-reactive oxidant, on global Ca²⁺ signal and spontaneous Ca²⁺ sparks of rat ventricular myocytes was investigated. It was shown that a brief Ca²⁺ transient was elicited by DTDP, when its concentration was raised to 100 µM DTDP. In addition a dose-dependent increase of cytoplasmic free Zn²⁺ concentration was induced by DTDP. An increase of the frequency of spontaneous Ca²⁺ sparks appeared at 3 µM DTDP, whereas higher concentration of DTDP caused a biphasic change of the frequency in both intact and permeabilized myocytes. Consistent with the biphasic effect, caffeine-induced Ca²⁺ transients were similarly affected. Because DTDP did not reduce the free Ca²⁺ concentration in the sarcoplasmic reticulum lumen, it is likely that the effects of DTDP on the frequency and caffeine-induced Ca²⁺ transients are due mainly to sulfhydryl oxidation-induced activation and subsequent inactivation of RyRs. Unlike the frequency, the spatio-temporal properties of Ca²⁺ sparks were not influenced by DTDP. The finding that DTDP does not affect the duration of Ca²⁺ sparks is inconsistent with that the DTDP-induced increase of the open time of reconstituted RyR channels. The mechanism underlying this discrepancy, especially the possible role of the interaction between arrayed RyRs in myocytes, is discussed. This study suggests that, even if oxidative stress is mild enough not to cause intracellular Ca²⁺ accumulation, it may affect signaling pathways through directly modulating the RyR or its complex and in turn changing the frequency of spontaneous Ca²⁺ sparks. Thus, the functional importance of moderate oxidative stress should not be overlooked.

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