KAPPA-OPIOID RECEPTOR ACTIVATION OF A DENDROTOXIN-SENSITIVE POTASSIUMCHANNEL MEDIATES PRESYNAPTIC INHIBITION OF MOSSY FIBER NEUROTRANSMITTER RELEASE

Activation of kappa-opioid receptors on messy fiber terminals in the h ippocampus inhibits excitatory amino acid release. The mechanism of pr esynaptic inhibition at the messy fiber synapse was investigated throu gh whole-cell voltage-clamp of CA3 pyramidal cells. The application of a kappa-opioid agonist, U69593, reduced the amplitude of the excitato ry postsynaptic current response, and this effect was reversed with a kappa receptor antagonist. Presynaptic potassium channels were blocked by bath application of channel toxins, and the effect of kappa recept or activation was tested. The inhibition caused by U69593 was blocked by low doses of 4-aminopyridine (30 mu M) and the selective peptide to xins dendrotoxin and mast cell degranulating peptide. The inhibition w as not blocked by tow doses of tetraethylammonium chloride (1 mM), bar ium, or glibenclamide. Thus, we conclude that presynaptic kappa-opioid receptors are coupled to a Shaker-type voltage-dependent potassium ch annel that is sensitive to dendrotoxin and mast cell degranulating pep tide. An increase in presynaptic potassium conductance would enhance t he rate of repolarization after action potential invasion, thereby lim iting calcium influx and neurotransmitter release. This is the first p hysiological demonstration of the involvement of a dendrotoxin-sensiti ve potassium current in presynaptic inhibition mediated by a G protein -coupled receptor.