Prostaglandin E2-induced modification of tetrodotoxin-resistant Na+ currents involves activation of both EP2 and EP4 receptors in neonatal rat nodose ganglion neurones

1 The aim of the present study was to investigate which EP receptor subtypes (EP1-EP4) act predominantly on the modification of the tetrodotoxin-resistant Na+ current (I-NaR) in acutely isolated neonatal rat nodose ganglion (NG) neurones. 2 Of the four EP receptor agonists ranging from 0.01 to 10 mu M, the EP2 receptor agonist (ONO-AE1-259, 0.1-10 mu M) and the EP4 receptor agonist (ONO-AE1-329, 1 mu M) significantly increased peak INaR. The responses were associated with a hyperpolarizing shift in the activation curve. 3 Neither the EP1 receptor agonist ONO-DI-004 nor the EP3 receptor agonist ONO-AE-248 significantly modified the properties of INaR. 4 In PGE(2) applications ranging from 0.01 to 10 mu M, 1 mu M 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 mu M). However, the slope factor k was not significantly altered by PGE(2) applications at 0.01-10 mu M. In addition, the hyperpolarizing shift of V-1/2 by PGE(2) was not significantly altered by either PKI or staurosporine. 5 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. 6 The NG contained many neuronal cell bodies (diameter < 30 mu m) with intense or moderate EP2, EP3, and EP4 receptor-immunoreactivities. 7 These results suggest that the PGE(2)-induced modification of I-NaR is mainly mediated by activation of both EP2 and EP4 receptors.