Prokineticin 2 influences subfornical organ neurons through regulation of MAP kinase and the modulation of sodium channels.
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 Ca(2+) concentration ([Ca(2+)](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 Ca(2+), suggesting that PK2-induced [Ca(2+)](i) transients resulted from Ca(2+) entry through voltage-gated Ca(2+) channels. Voltage-clamp recordings showed that PK2 was without effects on Ca(2+) currents evoked by voltage ramps, suggesting that PK2-induced Ca(2+) influx was secondary to PK2-induced increases in action potential frequency, an hypothesis supported by data showing that tetrodotoxin abolished effects of PK2 on [Ca(2+)](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.
Fry
Mark
M
Dept. of Physiology, Queen's Univ., Botterell Hall, 4floor, Kingston, ON, Canada K7L 3N6.
Cottrell
G Trevor
GT
Ferguson
Alastair V
AV
D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000502:physiology; D005768:Gastrointestinal Hormones / Q000502:physiology*; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology*; D009479:Neuropeptides / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000502:physiology*; D013356:Subfornical Organ / Q000166:cytology / Q000502:physiology*
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; D015222:Sodium Channels; C513686:prokineticin 2, rat; D012964:Sodium; D020928:Mitogen-Activated Protein Kinases; D011188:Potassium; D002118:Calcium