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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

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

¹Department of Physiology, Queen's University, Kingston; and ²Sheridan Institute of Technology and Advanced Learning, Oakville, Ontario, Canada

Submitted 25 October 2007 ; accepted in final form 4 July 2008

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.

circumventricular organs; neuropeptides; potassium current; sodium current; mitogen-activated protein kinase; intracellular Ca²⁺