Neurons may initiate behaviour or store information by translating prior activity into a lengthy change in excitability. For example, brief input to the bag cell neurons of Aplysia results in an approximate 30 min afterdischarge that induces reproduction. Similarly, momentary stimulation of cultured bag cells neurons evokes a prolonged depolarization lasting many minutes. Contributing to this is a voltage-independent cation current activated by Ca²⁺ entering during the stimulus. However, the cation current is relatively short-lived, and we hypothesized that a second, voltage-dependent persistent current sustains the prolonged depolarization. In bag cell neurons, the inward voltage-dependent current is carried by Ca²⁺; thus, we tested for persistent Ca²⁺ current in primary culture under voltage-clamp. The observed current activated between -40 and -50 mV, exhibited a very slow decay, presented a similar magnitude regardless of stimulus duration (10-60 sec), and, like the rapid Ca²⁺ current, was enhanced when Ba²⁺ was the permeant ion. The rapid and persistent Ca²⁺ current, but not the cation current, were Ni²⁺-sensitive. Consistent with the persistent current contributing to the response, Ni²⁺ reduced the amplitude of a prolonged depolarization evoked under current-clamp. Finally, protein kinase C activation enhanced the rapid and persistent Ca²⁺ current, as well as increased the prolonged depolarization when elicited by an action potential-independent stimulus. Thus, the prolonged depolarization arises from Ca²⁺ influx triggering a cation current, followed by voltage-dependent activation of a persistent Ca²⁺ current, and is subject to modulation. Such synergy between currents may represent a common means of achieving activity-dependent changes to excitability.