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  • Title: C(6)-ceramide inhibited Na(+) currents by intracellular Ca(2+) release in rat myoblasts.
    Author: Liu Z, Xu JG, Zhang H, Fang YJ, Mei YA.
    Journal: J Cell Physiol; 2007 Oct; 213(1):151-60. PubMed ID: 17458889.
    Abstract:
    Ceramides are novel second messengers that may mediate signaling leading to apoptosis and the regulation of cell cycle progression. Moreover, ceramide analogs have been reported to directly modulate K(+) and Ca(2+) channels in different cell types. In this report, the effect of C(6)-ceramide on the voltage-gated inward Na(+) currents (I(Na)) in cultured rat myoblasts was investigated using whole-cell current recording and a fluorescent Ca(2+) imaging experiment. At concentrations of 1-100 microM, ceramide produced a dose-independent and reversible inhibition of I(Na). Ceramide also significantly shifted the steady-state inactivation curve of I(Na) by 16 mV toward the hyperpolarizing potential, but did not alter the steady-state activation properties. C(2)-ceramide caused a similar inhibitory effect on I(Na) amplitude. However, dihydro-C(6)-ceramide, the inactive analog of ceramide, failed to modulate I(Na). The effect of C(6)-ceramide on I(Na) was abolished by intracellular infusion of the Ca(2+)-chelating agent BAPTA, but was mimicked by application of caffeine. Blocking the release of Ca(2+) from the sarcoplasmic reticulum with xestospongin C or heparin, an inositol 1,4,5-trisphosphate (IP(3)) receptor blocker, induced a gradual increase in I(Na) amplitude and eliminated the effect of ceramide on I(Na). In contrast, ruthenium red, which is a blocker of the ryanodine-sensitive Ca(2+) receptor did not affect the action of C(6)-ceramide on I(Na). Intracellular application of the G-protein agonist GTPgammaS also induced a gradual decrease in I(Na) amplitude, while the G-protein antagonist GDPbetaS eliminated the effect of C(6)-ceramide on I(Na). Calcium imaging showed that C(6)-ceramide could give rise to a significant elevation of intracellular calcium. Our data show that increased calcium release through the IP(3)-sensitive Ca(2+) receptor, which probably occurred through the G-protein and phospholipase C pathway, may be responsible for C(6)-ceramide-induced inhibition of the I(Na) of rat myoblasts.
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