A systems approach to regulation of neuronal excitation in the mollusc Pleurobranchaea has described novel interactions of cyclic AMP-gated cation current (INa,cAMP), Ca2+, pHi, and NO. INa,cAMP appears in many neurons of feeding and locomotor neuronal networks. It is likely one of the family of hyperpolarization-activated, cyclic-nucleotide-gated currents (h-current) of vertebrate and invertebrate pacemaker networks. There are two isoforms. Ca2+ regulates both voltage dependence and depolarization-sensitive inactivation in both isoforms. The Type 1 INa,cAMP of the feeding network is enhanced by intracellular acidification. A direct dependence of INa,cAMP on cAMP allows the current to be used as a reporter on cAMP concentrations in the cell, and from there to the intrinsic activities of the synthetic adenyl cyclase and the degradative phosphodiesterase. Type 2 INa,cAMP of the locomotor system is activated by serotonergic inputs, while Type 1 of the feeding network is thought to be regulated peptidergically. NO synthase activity is high in the CNS, where it differs from standard neuronal NO synthase in not being Ca2+ sensitive. NO acidifies pHi, potentiating Type 1, and may act to open proton channels. A cGMP pathway does not mediate NO effects as in other systems. Rather, nitrosylation likely mediates its actions. An integrated model of the action of cAMP, Ca2+, pHi, and NO in the feeding network postulates that NO regulates proton conductance to cause neuronal excitation in the cell body on the one hand, and relief of activity-induced hyperacidification in fine dendritic processes on the other.