Prokineticin 2 influences subfornical organ neurons through regulation of MAP kinase and the modulation of sodium channels

• DOI: 10.1152/ajpregu.00779.2007
• Publication Date: 2008-07-09T21:06:58Z
• Authors: Mark Fry; G. Trevor Cottrell; Alastair V. Ferguson
• Keywords: Male; Neurons; 0301 basic medicine; Patch-Clamp Techniques; Calcium Channels, L-Type; Neuropeptides; Sodium; Autonomic Nervous System; Sodium Channels; Rats; Gastrointestinal Hormones; Rats, Sprague-Dawley; 03 medical and health sciences; Potassium; Animals; Calcium; Calcium Channels; Mitogen-Activated Protein Kinases; Ion Channel Gating; Subfornical Organ

Prokineticin 2 (PK2) is a neuropeptide that acts as a 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 (Cottrell GT, and Ferguson AV. J. Neurosci. 24: 2375–2379, 2004). 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 mitogen-activated protein (MAP) kinase inhibitor PD-98059 prevented PK2-induced depolarization and decreases in delayed rectifier K+ current. PK2 also increased intracellular Ca2+ concentration ([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 and persistent 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.