Enhancement of the defensive withdrawal reflex ofAplysia involves a prolongation of the action potentials of mechanosensory neurons, which contributes to facilitation of transmitter release from these cells. Recent reports have suggested that whereas cAMP-dependent modulation of K+ current increases sensory neuron excitability, a cAMP-independent decrease in K+ current may increase the action potential duration and, thus, facilitate transmitter release. We have tested this proposal using Walsh cAMP-dependent protein kinase inhibitor or activators of the cAMP cascade and found that cAMP plays a major role in the spike-broadening effects of facilitatory transmitter; however, broadening requires higher levels of activation of the cAMP-dependent kinase than does increasing excitability. A steeply voltage-dependent transient K+ current, termed IKv,ealy, and the slowly activating S-type K+ (S-K+) current are both reduced by activation of the cAMP cascade, although with different sensitivities to the second messenger, enabling excitability and spike duration to be regulated independently. Differences in cAMP sensitivity also suggested that the originally described S-K+ current actually consists of two independent components, a slowly activating component and a time-independent, "steady-state" current that is activated at rest.During both sensitization and classical conditioning of defensive withdrawal reflexes in Aplysia, increased transmitter release from sensory neurons (SNs) (1-4) contributes to the enhancement of withdrawal responses. One important mechanism for short-term facilitation of transmitter release is a prolongation of the presynaptic action potential (5-7), which increases the Ca2+ influx during each spike (8). This spike broadening results from a decrease in outward K+ current (5) triggered by facilitatory transmitters, primarily serotonin (5-HT) (9,19), that are released by sensitizing stimuli. Several K+ currents are modulated by 5-HT in the siphon and pleural SNs, which have similar properties (10)(11)(12)(13)(14). Klein et al. (11) first characterized the K+ current reduced by 5-HT and found it is partially active at rest and further activates slowly when the membrane is depolarized to potentials from -30 to 0 mV. The 5-HT-induced reduction in this S-type K+ (S-K+) current (IKS) is mediated by cAMP (10, 11). Because several "classical" K+ currents were unaffected by 5-HT (11), it was believed that the modulation of IKS probably accounted for spike broadening. However, more recently, Baxter and Byrne (14) discovered that 5-HT also modulates a distinct steeply voltage-dependent K+ current that activates rapidly with membrane depolarization above +20 mV and then inactivates; we have named this current IKv,,,wly to emphasize both its kinetics and steep voltage dependence (15). 5-HT slows both its activation and inactivation and reduces the peak current activated.It has been difficult to evaluate which of the K+ currents reduced by 5-HT is primarily responsible for slowing repolarization of the S...