Up-regulation of tetrodotoxin-sensitive sodium currents by prostaglandin E2 in type-4 rat dorsal root ganglion cells

Mechanisms were studied by which prostaglandin E2 (PGE2) up-regulates Na+ currents (INa) in medium diameter dorsal root ganglion (DRG) cells that express large T-type Ca2+ currents (type-4 DRG cells). PGE2 or the adenylyl cyclase (AC) activator forskolin (10 μM) up-regulated peak INa evoked by test potentials (TP) to −10 mV by an average of 13.5% and 21.8%, respectively. The PGE2 and forskolin induced up-regulation of INa, evoked with TPs to −10 mV, began approximately 15–20 s after initiation of drug exposure and continued gradually over the course of 2–3 min. Both PGE2 and forskolin significantly increased peak conductance without significantly shifting the voltage at which INa was ½ activated (Va) or ½ steady state inactivated. However, although Va was not significantly shifted, both PGE2 and forskolin induced a proportionally greater percent increase in conductance at weak TPs to around −30 mV compared to stronger TPs to around 10 mV. The PGE2-induced up-regulation of INa was occluded by prior up-regulation with forskolin, and the up-regulation of INa by both PGE2 and forskolin was blocked by Rp-cAMPs and 50 nM tetrodotoxin (TTX). In the presence of Rp-cAMPs, both PGE2 and forskolin induced decreases in INa that peaked around 25 s following initiation of PGE2/forskolin application. The decrease induced by PGE2 averaged 8.5%, which was significantly greater than the average 3.5% decrease induced by forskolin. Estimation of kinetic rate constants by fitting INa with a Markov channel state model, suggested that both PGE2 and forskolin up-regulated INa by changing channel gating rather than by increasing channel number or unitary conductance. The data suggest that application of PGE2 may initially induce a relatively rapid down-regulation of TTX-sensitive INa (signaling pathway uncharacterized), followed by a gradual up-regulation of INa via activation of an AC/PKA-dependent signaling pathway. The up-regulation of INa in sensory neurons with type-4 cell bodies may increase excitability and strengthen signaling, and may play some role in the allodynia and hyperalgesia associated with injury to nerves and peripheral tissues.

▶PGE2 up-regulates tetrodotoxin-sensitive (TTX-s) Na+ current in type-4 DRG cells. ▶The up-regulation is PKA-dependent and is underlain by changes in channel gating. ▶PGE2 also induces down-regulation of TTX-s Na+ current that precedes up-regulation. ▶A non-PKA-dependent signaling pathway mediates the down-regulation. ▶The PGE2 induced up-regulation may play a role in inflammatory or neuropathic pain.