INHIBITION OF DOPAMINE RELEASE BY PROSTAGLANDIN EP3 RECEPTOR VIA PERTUSSIS-TOXIN-SENSITIVE AND PERTUSSIS-TOXIN-INSENSITIVE PATHWAYS IN PC12CELLS

Prostaglandin EP3 receptor is involved in the inhibition of neurotrans mitter release from presynaptic nerve terminals in various tissues. We have examined the regulation of neurotransmitter release by the EP3 r eceptor using a PC12 cell line that stably expresses the EP3B receptor isolated from bovine adrenal medulla. In the cells, M&B28767, an EP3 agonist, inhibited the 50 mM KCl- or 10 nM bradykinin-induced [H-3]dop amine release in a concentration-dependent manner (10 pM to 0.1 mu M). This inhibition was partially reversed by pretreatment with pertussis toxin, whereas under the same condition, the agonist-induced inhibiti on of forskolin-stimulated cyclic AMP accumulation was suppressed comp letely. In contrast, M&B28767 did not affect the high K+ - or bradykin in-induced increase in intracellular Ca2+ concentration. Moreover, M&B 28767 also inhibited the [H-3]dopamine release induced by the Ca2+ ion ophore ionomycin, and this inhibition was also partially reversed by p retreatment with pertussis toxin. These results indicate that the EP3 receptor is coupled to dual pathways, pertussis toxin-sensitive and -i nsensitive G-protein pathways, to regulate neurotransmitter release wi thout changing Ca2+ influx in neuronal cells.