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.