Anandamide, an Endogenous Cannabinoid, Inhibits Shaker-related Voltage-gated K+ Channels

Abstract 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, Δ 9 -tetrahydrocannabinol (Δ 9 -THC). Here we report that anandamide directly inhibits (IC 50 , 2.7 μM) Shaker -related Kv1.2 K + channels that are found ubiquitously in the mammalian brain. Δ 9 -THC also inhibited Kv1.2 channels with comparable potency (IC 50 , 2.4 μM), 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. Copyright © 1996 Elsevier Science Ltd