Prostaglandin E2-mediated upregulation of neuroexcitation and persistent tetrodotoxin-resistant Na+ currents in Ah-type trigeminal ganglion neurons isolated from adult female rats

- PGE2 increases excitability of Ah- and C-, not A-type TGNs from adult female rats.
- Effect of PGE2 is cAMP- & 17β-estradiol-dependent in Ah-, rather than C-type TGNs.
- PGE2 modulates the persistent TTX-R Na+ currents uniquely expressed in Ah-types.
- PGE2-mediated neuromodulation in Ah-TGNs contributes to sex difference in migraine.
- Persistent TTX-R Na+ channel is a potential target for pharmacological convention.

Prostaglandin-E2 (PGE2) is a very important inflammatory mediator and PGE2-mediated neuroexcitation in sex-specific distribution of Ah-type trigeminal ganglion neurons (TGNs) isolated from adult female rats is not fully addressed. The whole-cell patch-clamp experiment was performed to verify the effects of PGE2, forskolin, and GPR30-selective agonist (G-1) on action potential (AP) and tetrodotoxin-resistant (TTX-R) Na+ currents in identified Ah-type TGNs. The results showed that the firing frequency was increased in Ah- and C-types by PGE2, which was simulated by forskolin and inhibited by Rp-cyclic adenosine monophosphate (cAMP), while G-1 mimicked this effect only in Ah-types, which was abolished by GPR30-selective antagonist (G-15). Although the amplitude of AP was increased in Ah- and C-types, increased maximal upstroke velocity was confirmed only in Ah-types, suggesting distinct alternations in current density and/or voltage-dependent property of Na+ channels. With 1.0 μM PGE2, TTX-R Na+ currents were upregulated without changing the current-voltage relationship and voltage-dependent activation in C-types, however, the TTX-R Na+ current was augmented in Ah-types, peaked voltage and the voltage-dependent activation were both shifted toward hyperpolarized direction with faster slope. Intriguingly, the low-threshold persistent TTX-R component was activated from −60 mV and increased almost double at −30 mV compared with ∼30-40% increment of TTX-R component being activated at ∼−10 mV. Additionally, the change in TTX-R component of Ah-types was equivalent well with that in C-type TGNs. Taken these data together, we conclude that PGE2 modulates the neuroexcitation via cAMP-mediated upregulation of TTX-R Na+ currents in both cell-types with hormone-dependent feature, especially persistent TTX-R Na+ currents in sex-specific distribution of myelinated Ah-type TGNs.