Differential effects of endogenous and synthetic cannabinoids on voltage-dependent calcium fluxes in rabbit T-tubule membranes: comparison with fatty acids.
The effects of cannabinoid receptor ligands including 2-arachidonoylglycerol, R-methanandamide, Delta9-THC (Delta9-tetrahydrocannabinol), WIN 55,212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], CP 55,940 ([1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol]) and a series of fatty acids on depolarization-induced Ca2+ effluxes mediated by voltage-dependent Ca2+ channels were investigated comparatively in transverse tubule membrane vesicles from rabbit skeletal muscle. Vesicles were loaded with 45Ca2+ and membrane potentials were generated by establishing potassium gradients across the vesicle using the ionophore valinomycin. Endocannabinoids, 2-arachidonoylglycerol and R-methanandamide (all 10 microM), inhibited depolarization-induced Ca2+ effluxes and specific binding of [3H]PN 200-110 (isradipine) to transverse tubule membranes. On the other hand, synthetic cannabinoids, including CP 55,940, WIN 55,212-2, and Delta9-THC (all 10 microM), were ineffective. Additional experiments using endocannabinoid metabolites suggested that whereas ethanolamine and glycerol were ineffective, arachidonic acid inhibited Ca2+ effluxes and specific binding of [3H]PN 200-110. Further studies indicated that only those fatty acids containing two or more double bonds were effective in inhibiting depolarization-induced Ca2+ effluxes and specific binding of [3H]PN 200-110. These results indicate that endocannabinoids, but not synthetic cannabinoids, directly inhibit the function of voltage-dependent calcium channels (VDCCs) and modulate the specific binding of calcium channel ligands of the dihydropyridine (DHP) class.
Oz
Murat
M
National Institute on Drug Abuse, National Institutes of Health, DHHS, Intramural Research Program, Cellular Neurobiology Branch, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. moz@intra.nida.nih.gov
Tchugunova
Yulia
Y
Dinc
Meral
M
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism
D015220:Calcium Channels; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D005227:Fatty Acids