Inhibition of A-Type K+ Channels by Urotensin-II Induces Sensory Neuronal Hyperexcitability Through the PKC alpha-ERK Pathway

摘要

Previous studies have implicated urotensin-II in the nociception of sensory neurons. However, to date the relevant mechanisms remain unknown. In the current study we determined the role of urotensin-II in the regulation of transient outward A-type potassium currents (I-A) and neuronal excitability in trigeminal ganglion (TG) neurons. We found that application of urotensin-II to small-diameter TG neurons decreased I-A in a dose-dependent manner, whereas the delayed rectifier potassium current was unaffected. The I-A decrease induced by urotensin-II depended on the urotensin-II receptor (UT-R) and was associated with a hyperpolarizing shift in the steady-state inactivation curve. Exposure of TG cells to urotensin-II markedly increased protein kinase C (PKC) activity, and PKC inhibition eliminated the UT-R-mediated I-A decrease. Antagonism of PKC alpha, either pharmacologically or genetically, but not of PKC beta prevented the decrease in I-A induced by urotensin-II. Analysis of phospho-extracellular signal-regulated kinase (p-ERK) revealed that urotensin-II significantly increased the expression level of p-ERK, whereas p-p38 and p-c-Jun N-terminal kinase remained unchanged. Inhibition of mitogen-activated protein kinase/ERK signaling by the kinase antagonist U0126 and PD98059 completely abolished the UT-R-mediated I-A decrease. Moreover, urotensin-II significantly increased the action potential firing rate of small TG neurons; pretreatment with 4-aminopyridine prevented this effect. In summary, our findings suggest that urotensin-II selectively attenuated I-A through stimulation of the PKC alpha-dependent ERK1/2 signaling pathway. This UT-R-dependent mechanism might contribute to neuronal hyperexcitability in TG neurons.