The ionic mechanism of the effect of extracellularly ejected calcitonin (CT) on the membrane of identified neurons R9 and R10 of Aplysia was investigated with voltage-clamp, micropressure ejection, and ion substitution techniques. Micropressure-ejected CT caused a marked hyperpolarization in the undamped neuron. Heat-inactivated CT was without effect. Clamping the same neuron at its resting potential level (-60 mV) and re-ejecting CT with the same dose produced a slow outward current (I,(CT), 3 0 4 0 sec in duration, 4-6 nA in amplitude) associated with a decrease in input membrane conductance. I, (CT) was decreased by depolarization and increased by hyperpolarization. The extrapolated reversal potential of I, (CT) was approximately +10 mV. I, (CT) was sensitive to changes in the external Na+ concentration but not to changes in K + , Ca2+, and C1-concentrations. Micropressure-ejected forskolin produced a slow outward current, which, like the current to CT, was associated with a decrease in input membrane conductance, and was sensitive to changes in the external Na+ concentration. I, (CT) was prolonged by bath-applied isobutylmethylxanthine (IBMX) but was not affected by I-oleoyl-2acetylglycerol (OAG) and calphostin C. Neither superfusion of the neuron with nordihydroguaiaretic acid (NDGA) nor superfusion with indomethacin caused any changes in I,(CT). These results suggest that extracellular CT can induce a slow outward current associated with a decrease in Na+ conductance, mediated by a receptor-controlled increase in intracellular cyclic adenosine 3', 5'-monophosphate.