Involvement of postsynaptic EP₄ and presynaptic EP₃ receptors in actions of prostaglandin E₂ in rat supraoptic neurones

We have reported that supraoptic nucleus (SON) neurones are excited by prostaglandin E₂ (PGE₂) presumably via dual postsynaptic PG receptors, FP receptors and unidentified EP receptors, and that presynaptic EP receptors may also be involved in the excitation. In the present study, to clarify the receptor mechanism of the PGE₂-mediated actions on SON neurones, we studied the pre- and postsynaptic effects of four newly developed EP agonists that are selective for each of the four EP receptors, EP_1-4, on rat SON neurones using extracellular recording and whole-cell patch-clamp techniques. The EP₄ agonist ONO-AE1-329 mimicked the excitatory effects of PGE₂, whereas the EP₁ agonist ONO-DI-004, the EP₂ agonist ONO-AE1-257 and the EP₃ agonist ONO-AE-248 had little or no effect. The effects of ONO-AE1-329 were unaffected by the EP₁/FP/TP antagonist, ONO-NT-012, which potently suppressed the excitation caused by the FP agonist fluprostenol and PGE₂. ONO-AE1-329 caused marked excitation when responses to fluprostenol were desensitized by repeated applications of fluprostenol. Patch-clamp analysis in SON neurones showed that ONO-AE1-329 induced inward currents at a holding potential of -70 mV and the reversal potential of the currents was -35.1 ± 2.3 mV. On the other hand, the frequency of spontaneous inhibitory postsynaptic currents recorded from SON slice preparations was suppressed by ONO-AE-248, but unaffected by the other three EP agonists. These results suggest that SON neurones possess postsynaptic EP₄ receptors and that γ-aminobutyric acid neurones innervating SON neurones possess presynaptic EP₃ receptors in their terminals. Activation of the two EP receptors may be involved in the excitatory regulation of SON neurones by PGE₂.