Prokineticin 2 (PK2) is a neuropeptide which acts as an signaling molecule regulating circadian rhythms in mammals. We have previously reported PK2 actions on subfornical organ (SFO) neurons identifying this circumventricular organ as a target at which PK2 acts to influence autonomic control. In this study we have examined the cellular mechanisms by which PK2 increases the excitability of SFO neurons. Whole cell patch recordings from dissociated rat SFO neurons demonstrated that the MAP kinase inhibitor PD98059 prevented PK2-induced depolarization and decreases in I_K. PK2 also increased [Ca²⁺]_i in 39% of dissociated SFO neurons (mean increase = 20.8 ± 5.5%), effects that were maintained in the presence of thapsigargin but abolished by both nifedipine, or the absence of extracellular Ca²⁺, suggesting that PK2 induced [Ca²⁺]_i transients resulted from Ca²⁺ entry through voltage-gated Ca²⁺ channels. Voltage clamp recordings showed that PK2 was without effects on Ca²⁺ currents evoked by voltage ramps, suggesting that PK2 induced Ca²⁺ influx was secondary to PK2 induced increases in action potential frequency, an hypothesis supported by data showing that tetrodotoxin abolished effects of PK2 on [Ca²⁺]_i. These observations suggested PK2 modulation of voltage-gated Na⁺ currents, a possibility confirmed by voltage clamp experiments showing that PK2 increased the amplitude of both transient (INaT) and persistent (INaP ) Na⁺ currents in 29% of SFO neurons (by 34% and 38% respectively). These data indicate that PK2 influences SFO neurons through the activation of a MAP kinase cascade which in turn modulates Na⁺ and K⁺ conductances.