SUMMARY1. Macroscopic and single-channel currents were recorded from voltage-clamped neurones in the abdominal and pleural ganglia of Aplysia californica in order to investigate conductance changes elicited by application of the endogenous peptide FMRFamide (Phe-Met-Arg-Phe-NH2) and related neuropeptides to the cell surface.2. The Ca-dependent K current, IK(Ca) when elicited at a constant voltage by intracellular injection of Ca2+, was insensitive to FMRFamide or its derivative YGG-FMRFamide (Tyr-Gly-Gly-Phe-Met-Arg-Phe-NH2). Unclamped cells responded with a corresponding hyperpolarization. These responses reversed at about -75 mV. Ion substitution indicated that the current is carried by K+. 4. FMRFamide and YGG-FMRFamide were equally effective in activating the outward current, whereas FMRF, met-enkephalin and leu-enkephalin were ineffective.5. At voltages negative to -30 mV and, in the absence of extracellular Ca2+, also at more positive potentials, the FMRFamide-sensitive current showed no voltage dependence beyond that predicted from constant-field considerations.6. The response to FMRFamide was relatively insensitive to extracellular tetraethylammonium (TEA, KD -75 mm) and 4-aminopyridine (4-AP, KD 6 mM). It was suppressed in Ba-containing solutions, but was unaffected by injection of the Ca chelating agent EGTA. The response was blocked by serotonin and other agents known to elevate intracellular adenosine 3',5'-phosphate (cyclic AMP) levels, and by direct injection of cyclic AMP into the cell. 7. In its pharmacological properties and lack of voltage dependence, the FMRFamide-activated current resembles the 'S' current, IK(S)' a K current suppressed by application of serotonin in Aplysia neurones.8. The similarity between the FMRFamide-sensitive current and the 'S' current was confirmed in cell-attached patch-clamp studies, in which activity of 'S' channels was found to be reduced by serotonin, and enhanced by FMRFamide.* Address for reprint requests.