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      Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons.

      Molecular pharmacology
      Animals, Arachidonic Acids, pharmacology, Benzoxazines, Calcium, metabolism, Calcium Channel Blockers, Calcium Channels, N-Type, Cannabinoids, Dose-Response Relationship, Drug, Endocannabinoids, G Protein-Coupled Inwardly-Rectifying Potassium Channels, GTP-Binding Proteins, Glycerides, Humans, In Vitro Techniques, Male, Morpholines, Naphthalenes, Neurons, drug effects, Polyunsaturated Alkamides, Potassium Channels, Potassium Channels, Inwardly Rectifying, Rats, Rats, Wistar, Receptor, Cannabinoid, CB1, agonists

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          Abstract

          Endocannabinoids may serve as retrograde messengers to inhibit neurotransmitter release during depolarization-induced suppression of inhibition (DSI) or excitation (DSE). We therefore tested whether endocannabinoids inhibit N-type voltage-dependent Ca2+ channels by activating G(i/o)-protein-coupled CB1 cannabinoid receptors (CB1R)--a possible mechanism underlying DSI/DSE. Three putative endocannabinoids [2-arachidonylglycerol (2-AG), 2-arachidonyl glycerol ether (2-AGE), and anandamide (AEA)] and the cannabimimetic aminoalkylindole WIN 55,212-2 (WIN) inhibited whole-cell Ca2+ currents in rat sympathetic neurons previously injected with cDNA encoding a human CB1R. Agonist-mediated Ca2+ current inhibition was blocked by a selective CB1R antagonist [SR141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride] and pertussis toxin (PTX) pretreatment. The rank order of potency was WIN (IC50=2 nM)>2-AGE (350 nM) approximately 2-AG (480 nM)>AEA (approximately 3 microM), with each agonist displaying similar efficacy (approximately 50% maximal inhibition). Increasing CB1R expression level significantly enhanced AEA potency. AEA (10 microM) also inhibited Ca2+ channels in a voltage-independent, CB1R-independent, and PTX-insensitive manner, whereas 2-AG and 2-AGE were devoid of this activity. All three endocannabinoids activated G-protein-coupled inwardly rectifying potassium (GIRK) channels, GIRK1/4, heterologously expressed in sympathetic neurons. These results suggest a mechanism by which endocannibinoids might influence presynaptic function.

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