Prostaglandin E 2-induced modification of tetrodotoxin-resistant Na + currents involves activation of both EP 2 and EP 4 receptors in neonatal rat nodose ganglion neurones

Abstract

The aim of the present study was to investigate which EP receptor subtypes (EP 1-EP 4) act predominantly on the modification of the tetrodotoxin-resistant Na + current (I NaR) in acutely isolated neonatal rat nodose ganglion (NG) neurones. Of the four EP receptor agonists ranging from 0.01 to 10 μM;, the EP 2 receptor agonist (ONO-AE1-259, 0.1-10 μM) and the EP 4 receptor agonist (ONO-AE1-329, 1 μM) significantly increased peak I NaR. The responses were associated with a hyperpolarizing shift in the activation curve. Neither the EP 1 receptor agonist ONO-DI-004 nor the EP 3 receptor agonist ONO-AE-248 significantly modified the properties of I NaR. In PGE 2 applications ranging from 0.01 to μM, 1 μM PGE 2 produced a maximal increase in the peak I NaR amplitude. The PGE 2 (1 mu;M)-induced increase in the GV 1/2 baseline (% change in G at baseline V 1/2) was significantly attenuated by either intracellular application of the PKA inhibitor PKI or extracellular application of the protein kinase C inhibitor staurosporine (1 μM). However, the slope factor k was not significantly altered by PGE 2 applications at 0.01-10 μM. In addition, the hyperpolarizing shift of V 1/2 by PGE 2 was not significantly altered by either PKI or staurosporine. In other series of experiments, reverse transcription-polymerase chain reaction (RT-PCR) of mRNA from nodose ganglia indicated that all four EP receptors were present. The NG contained many neuronal cell bodies (diameter < 30 μM) with intense or moderate EP 2, EP 3, and EP 4 receptor-immunoreactivities. These results suggest that the PGE 2-induced modification of I NaR is mainly mediated by activation of both EP 2 and EP 4 receptors. © 2005 Nature Publishing Group. All rights reserved.