Nitric oxide and S-nitrosothiols exert dual mechanism regulation on L-type calcium channels in ferret ventricular myocytes via cGMP-dependent inhibition and direct S-nitrosylation/oxidation activation.
Nitric oxide and S-nitrosothiols exert dual, opposing regulatory effects on L-type calcium channels in ventricular myocytes through indirect cGMP-dependent and direct redox mechanisms, respectively.
The effects of NO-related activity and cellular thiol redox state on basal L-type calcium current, ICa,L, in ferret right ventricular myocytes were studied using the patch clamp technique. SIN-1, which generates both NO. and O2-, either inhibited or stimulated ICa,L. In the presence of superoxide dismutase only inhibition was seen. 8-Br-cGMP also inhibited ICa,L, suggesting that the NO inhibition is cGMP-dependent. On the other hand, S-nitrosothiols (RSNOs), which donate NO+, stimulated ICa,L. RSNO effects were not dependent upon cell permeability, modulation of SR Ca2+ release, activation of kinases, inhibition of phosphatases, or alterations in cGMP levels. Similar activation of ICa,L by thiol oxidants, and reversal by thiol reductants, identifies an allosteric thiol-containing "redox switch" on the L-type calcium channel subunit complex by which NO/O2- and NO+ transfer can exert effects opposite to those produced by NO. In sum, our results suggest that: (a) both indirect (cGMP-dependent) and direct (S-nitrosylation/oxidation) regulation of ventricular ICa,L, and (b) sarcolemma thiol redox state may be an important determinant of ICa,L activity.
Campbell et al. (Tue,) reported a other. Nitric oxide and S-nitrosothiols was evaluated on Basal L-type calcium current (ICa,L). Nitric oxide and S-nitrosothiols exert dual mechanism regulation on L-type calcium channels in ferret ventricular myocytes via cGMP-dependent inhibition and direct S-nitrosylation/oxidation activation.