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.