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, Δ⁹-tetrahydrocannabinol (Δ⁹-THC). Here we report that anandamide directly inhibits (IC₅₀, 2.7 μM) Shaker-related Kv1.2 K⁺ channels that are found ubiquitously in the mammalian brain. Δ⁹-THC also inhibited Kv1.2 channels with comparable potency (IC₅₀, 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.