Anandamide, an endogenous cannabinoid, inhibits Shaker-related voltage-gated K+ channels.
Anandamide has been identified in porcine brain as an endogenous cannabinoid receptor ligand and is believed to be a counterpart to the psychoactive component of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC). Here we report that anandamide directly inhibits (IC50, 2.7 muM) Shaker-related Kv1.2 K+ channels that are found ubiquitously in the mammalian brain. Delta 9-THC also inhibited Kv1.2 channels with comparable potency (IC50, 2.4 muM), as did several N-acyl-ethanolamides with cannabinoid receptor binding activity. Potassium current inhibition occurred through a pertussis toxin-insensitive mechanism and was not prevented by the cannabinoid receptor antagonist SR141716A. Utilizing excised patches of Kv1.2 channel-rich membrane as a rapid and sensitive bioassay, we found that phospholipase D stimulated the release of an endogenous anandamide-like K+ channel blocker from rat brain slices. Structure-activity studies were consistent with the possibility that the released blocker was either anandamide or another N-acyl-ethanolamide.
Poling
J S
JS
Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol and Abuse and Alcoholism, Rockville, MD 20852, USA.
Rogawski
M A
MA
Salem
N
N
Vicini
S
S
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D051663:Kv1.2 Potassium Channel; D018408:Patch-Clamp Techniques; D010739:Phospholipase D / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D051637:Shaker Superfamily of Potassium Channels; D013329:Structure-Activity Relationship; D014162:Transfection
D001095:Arachidonic Acids; D063388:Endocannabinoids; C496972:Kcna2 protein, rat; D051663:Kv1.2 Potassium Channel; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D051637:Shaker Superfamily of Potassium Channels; D013759:Dronabinol; D010739:Phospholipase D; D000077285:Rimonabant; C078814:anandamide