1. The effect of electrical activity on the response to the neuromodulators serotonin (5-HT) and the neuropeptide egg-laying hormone (ELH) was studied in the Aplysia bursting pacemaker neuron R15. 2. Previous work has shown that 5-HT and ELH augment R15s bursting activity by enhancing two ionic currents, an inwardly rectifying K+ current (IR) and a voltage-gated Ca2+ current (ICa), and that the enhancement of the currents is mediated by the intracellular second-messenger adenosine 3',5'-cyclic monophosphate (cAMP). Here we show that both spontaneous action potentials and voltage-clamp depolarizations suppress the modulation by 5-HT and ELH of these currents. Both spontaneous and evoked depolarizations decrease the magnitude and dramatically speed the decay of the modulation of IR and ICa. 3. The depolarization-induced suppression is blocked by intracellular ethylene glycol-bis(beta-aminoethyl ether)N,N,N',N',-tetraacetic acid (EGTA), indicating that the suppression is Ca-dependent. The suppression is specific for responses mediated by cAMP; a non-cyclic AMP-mediated response to acetylcholine is not affected by depolarizing pulses. 4. The Ca-dependent suppression of IR modulation differs from the Ca-dependent suppression of ICa modulation. Ca2+ influx decreases the sensitivity of IR to neuromodulators without reducing the maximal response elicited by high concentrations of neuromodulators. In contrast, Ca2+ not only decreases the sensitivity of ICa but also reduces the maximal effect elicited by high concentrations of neuromodulators. We have shown previously that intracellular Ca2+ also inactivates the basal IR and ICa in neuron R15 by distinct mechanisms. The inactivation of IR is due to an antagonistic action of Ca2+ on cAMP metabolism, whereas the inactivation of the basal ICa is due primarily to a more direct action of Ca2+, perhaps on the Ca channels themselves. 5. We also studied the interaction between action potentials and neuromodulator released onto R15 from an endogenous source: bag cell neurons, which release large amounts of ELH during an intense "afterdischarge." IR and ICa become greatly enhanced during the afterdischarge, even though R15 continually fires action potentials. In addition, Ca-dependent inactivation of IR is suppressed during the afterdischarge. We suggest that the bag cells release an amount of ELH sufficient to temporarily saturate the cAMP-mediated enhancement of IR and that this temporarily prevents the suppressive effects of Ca2+ on IR. 6. The activity-dependent suppression of neuromodulation in neuron R15 is an example of neuronal plasticity that results from interactions between intracellular messengers.(ABSTRACT TRUNCATED AT 400 WORDS)
Comparison of the ionic currents modulated during activity-dependent and normal presynaptic facilitation
