CHANNELS, RECEPTORS, AND ELECTRICAL SIGNALING |
Biphasic modulation of ryanodine receptors by sulfhydryl
oxidation in rat ventricular myocytes
Hong Xie 1 and Pei-Hong Zhu 2*
1 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
2 Unit of Cell Signal Transduction, Shanghai Institutes for Biological Sciences, Chinese Academy of Sc
* To whom correspondence should be addressed. E-mail: phzhu{at}sibs.ac.cn.
Submitted on April 17, 2006
Revised on May 15, 2006
Accepted on 11 July 2006
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Abstract |
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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, while 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 (CaTs) were similarly affected. Since DTDP did not reduce the free Ca2+ concentration in the sarcoplasmic reticulum (SR) lumen, it is likely that the effects of DTDP on the frequency and CaTs 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 (1). 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.
Key Words:
4,4-dithiodipyridine, Ca2+ sparks, oxidative stress
