['This study was undertaken to analyze whether nitric oxide (NO) modulates the human potassium channel hKv1.5, which generates the ultrarapid delayed rectifier current (IKur) that determines the height and duration of atrial action potentials.', 'Currents were recorded using the whole-cell patch-clamp in Ltk- cells expressing hKv1.5 channels.', 'The NO donors (+/-)-S-Nitroso-N-acetylpenicillamine (SNAP) and sodium nitroprusside, a NO solution, and l-Arginine inhibited hKv1.5 currents in a concentration-dependent manner. The NO concentration in the cell chamber was monitored using a sensor, and the IC50 for NO-induced hKv1.5 block was 340+/-70 nM. SNAP also inhibited the IKur recorded in mouse ventricular myocytes. The NO effects were partially mediated by the activation of the soluble guanylate cyclase (sGC)/cGMP/cGMP-dependent protein kinase (PKG) pathway. The biotin-switch assay demonstrated the presence of S-nitrosylated cysteines (Cys) on the hKv1.5 protein in SNAP-treated cells. Molecular modeling of hKv1.5 channel structure suggests that S-nitrosylation of Cys331 (segment 2, S2) and Cys346 (S2) would be stabilized by hydrogen bridge bonds with Ile262 (S1) and Arg342 (S2), respectively.'] Does nitric oxide block hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism?