The endocannabinoid anandamide is a direct and selective blocker of the background K(+) channel TASK-1.
TASK-1 encodes an acid- and anaesthetic-sensitive background K(+) current, which sets the resting membrane potential of both cerebellar granule neurons and somatic motoneurons. We demonstrate that TASK-1, unlike the other two pore (2P) domain K(+) channels, is directly blocked by submicromolar concentrations of the endocannabinoid anandamide, independently of the CB1 and CB2 receptors. In cerebellar granule neurons, anandamide also blocks the TASK-1 standing-outward K(+) current, IKso, and induces depolarization. Anandamide-induced neurobehavioural effects are only partly reversed by antagonists of the cannabinoid receptors, suggesting the involvement of alternative pathways. TASK-1 constitutes a novel sensitive molecular target for this endocannabinoid.
Maingret
F
F
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UPR 411, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France.
Patel
A J
AJ
Lazdunski
M
M
Honoré
E
E
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D019556:COS Cells; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000494:pharmacology*; D002531:Cerebellum / Q000502:physiology; D002522:Chlorocebus aethiops; D063388:Endocannabinoids; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009046:Motor Neurons / Q000502:physiology*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024683:Potassium Channels, Tandem Pore Domain; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D000077285:Rimonabant; D014162:Transfection
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D063388:Endocannabinoids; D009419:Nerve Tissue Proteins; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D011994:Recombinant Proteins; C088155:methanandamide; C420132:potassium channel subfamily K member 3; D000077285:Rimonabant; D006221:Halothane; C078814:anandamide