Presynaptic modulation by eicosanoids in cortical synaptosomes.

In continuing experiments to determine the ionic basis of inhibitory presynaptic modulation, rat cortical synaptosomes were employed and receptor-activated K+ efflux was determined with a K+ sensitive electrode. When synaptosomes were sub-optimally depolarized by veratridine, the addition of agents that activated purinergic, alpha 2-adrenergic, muscarinic and opioid receptors all promoted K+ efflux. With 2-chloroadenosine as a model inhibitory presynaptic modulator, the increased K+ efflux evoked by this agent was blocked by the cyclooxygenase inhibitor indomethacin suggesting that arachidonic acid or its metabolites was an intermediary in opening the channel. When arachidonic acid and PGE2 were tested, both promoted K+ efflux that was inhibited by dendrotoxin and mast cell degranulating peptide, two agents that are known to inhibit a delayed rectifier K+ current. Our results suggest that via eicosanoid second messengers, inhibitory presynaptic modulators open a sub-class of K channels that hyperpolarize nerve terminals, therefore less Ca2+ would enter per nerve impulse and thus the evoked release of neurotransmitters would be decreased.