Pituitary adenylate cyclase activating polypeptide (PACAP) peptides (Adcyap1) signaling at the selective PAC1 receptor (Adcyap1r1) participates in multiple homeostatic and stress-related responses, yet the cellular mechanisms underlying PACAP actions remain to be completely elucidated. PACAP/PAC1 receptor signaling increases excitability of neurons within the guinea pig cardiac ganglia and as these neurons are readily accessible, this neuronal system is particularly amenable to studying PACAP modulation of ionic conductances. The present study investigated how PACAP activation of MEK/ERK signaling contributed to the peptide-induced increase in cardiac neuron excitability. Treatment with the MEK inhibitor PD 98059 blocked PACAP-stimulated pERK and in parallel, suppressed the increase in cardiac neuron excitability. However, PD 98059 did not blunt the ability of PACAP to enhance two inward ionic currents, one flowing through hyperpolarization-activated nonselective cationic channels (I_h), and a second flowing through low voltage-activated calcium channels (I_T), which support the peptide-induced increase in excitability. Thus, a PACAP and MEK/ERK-sensitive, voltage-dependent conductance(s), in addition to I_h and I_T, modulate neuronal excitability. Despite prior work implicating PACAP down regulation of K_V4.2 in modulation of excitability in other cells, treatment with the K_V4.2 current blocker 4-aminopyridine did not replicate the PACAP-induced increase in excitability in cardiac neurons. However, cardiac neurons express the ERK target Na_V1.7 channel and treatment with the selective Na_V1.7 inhibitor PF-04856264 decreased the PACAP modulation of excitability. From these results, PACAP/PAC1 activation of MEK/ERK signaling may phosphorylate Na_V1.7, enhancing sodium currents near the threshold, an action contributing to repetitive firing of the cardiac neurons exposed to PACAP.