k-Opioid receptor activation of a dendrotoxin-sensitive potassium channel mediates presynaptic inhibition of mossy fiber neurotransmitter release.
Activation of kappa-opioid receptors on mossy fiber terminals in the hippocampus inhibits excitatory amino acid release. The mechanism of presynaptic inhibition at the mossy fiber synapse was investigated through whole-cell voltage-clamp of CA3 pyramidal cells. The application of a kappa-opioid agonist, U69593, reduced the amplitude of the excitatory postsynaptic current response, and this effect was reversed with a k receptor antagonist. Presynaptic potassium channels were blocked by bath application of channel toxins, and the effect of kappa receptor activation was tested. The inhibition caused by U69593 was blocked by low doses of 4-aminopyridine (30 microM) and the selective peptide toxins dendrotoxin and mast cell degranulating peptide. The inhibition was not blocked by low doses of tetraethylammonium chloride (1 mM), barium, or glibenclamide. Thus, we conclude that presynaptic kappa-opioid receptors are coupled to a Shaker-type voltage-dependent potassium channel that is sensitive to dendrotoxin and mast cell degranulating peptide. An increase in presynaptic potassium conductance would enhance the rate of repolarization after action potential invasion, thereby limiting calcium influx and neurotransmitter release. This is the first physiological demonstration of the involvement of a dendrotoxin-sensitive potassium current in presynaptic inhibition mediated by a G protein-coupled receptor.
Simmons
M L
ML
Department of Pharmacology, University of Washington, Seattle 98195, USA.
Chavkin
C
C
D015761:4-Aminopyridine / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000494:pharmacology; D001514:Bee Venoms / Q000494:pharmacology; D044482:Benzeneacetamides; D004546:Elapid Venoms / Q000494:pharmacology*; D005071:Evoked Potentials / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000502:physiology*; D051637:Shaker Superfamily of Potassium Channels; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D000700:Analgesics; D001514:Bee Venoms; D044482:Benzeneacetamides; D004546:Elapid Venoms; D009498:Neurotoxins; D010455:Peptides; D015221:Potassium Channels; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D051637:Shaker Superfamily of Potassium Channels; D013757:Tetraethylammonium Compounds; D001464:Barium; C008331:mast cell degranulating peptide; D019789:Tetraethylammonium; C020273:dendrotoxin; D015761:4-Aminopyridine; C045444:U 69593; D005905:Glyburide