TY - JOUR
T1 - Endogenous cannabinoid anandamide directly inhibits voltage-dependent Ca2+ fluxes in rabbit T-tubule membranes
AU - Oz, Murat
AU - Tchugunova, Yulia B.
AU - Dunn, Susan M.J.
N1 - Funding Information:
This study was in part supported by the Alberta Heritage Foundation for Medical Research and by the Medical Research Council of Canada.
PY - 2000/9/15
Y1 - 2000/9/15
N2 - The effect of the endogenous cannabinoid, anandamide on Ca2+ flux responses mediated by voltage-dependent Ca2+ channels was studied in transverse tubule membrane vesicles from rabbit skeletal muscle. Vesicles were loaded with 45Ca2+ and membrane potentials were generated by establishing K+ gradients across the vesicle using the ionophore, valinomycin. Anandamide, in the range of 1-100 μM, inhibited depolarization- induced efflux responses. Anandamide also functionally modulated the effects of nifedipine (1-10 μM) and Bay K 8644 (1 μM) on Ca2+ flux responses. Pretreatment with the specific cannabinoid receptor antagonist, SR141716A (1 μM), pertussis toxin (5 μg/ml), the amidohydrolase inhibitor, phenylmethylsulfonyl fluoride (0.2 mM) or the cyclooxygenase inhibitor, indomethacin (5 μM) did not alter the inhibition of efflux responses by anandamide. Arachidonic acid (10-100 μM) also effectively inhibited 45Ca2+ efflux from membrane vesicles. In radioligand binding studies, it was found that both anandamide and arachidonic acid inhibited the specific binding of [3H]PN 200-110 to transverse tubule membranes with IC50 values of 4.4 ± 0.7 and 13.4 ± 3.5 μM, respectively. These results indicate that anandamide, independent of cannabinoid receptor activation, directly inhibits the function of voltage-dependent calcium channels and modulates the specific binding of calcium channel ligands of the dihydropyridine class. (C) 2000 Elsevier Science B.V.
AB - The effect of the endogenous cannabinoid, anandamide on Ca2+ flux responses mediated by voltage-dependent Ca2+ channels was studied in transverse tubule membrane vesicles from rabbit skeletal muscle. Vesicles were loaded with 45Ca2+ and membrane potentials were generated by establishing K+ gradients across the vesicle using the ionophore, valinomycin. Anandamide, in the range of 1-100 μM, inhibited depolarization- induced efflux responses. Anandamide also functionally modulated the effects of nifedipine (1-10 μM) and Bay K 8644 (1 μM) on Ca2+ flux responses. Pretreatment with the specific cannabinoid receptor antagonist, SR141716A (1 μM), pertussis toxin (5 μg/ml), the amidohydrolase inhibitor, phenylmethylsulfonyl fluoride (0.2 mM) or the cyclooxygenase inhibitor, indomethacin (5 μM) did not alter the inhibition of efflux responses by anandamide. Arachidonic acid (10-100 μM) also effectively inhibited 45Ca2+ efflux from membrane vesicles. In radioligand binding studies, it was found that both anandamide and arachidonic acid inhibited the specific binding of [3H]PN 200-110 to transverse tubule membranes with IC50 values of 4.4 ± 0.7 and 13.4 ± 3.5 μM, respectively. These results indicate that anandamide, independent of cannabinoid receptor activation, directly inhibits the function of voltage-dependent calcium channels and modulates the specific binding of calcium channel ligands of the dihydropyridine class. (C) 2000 Elsevier Science B.V.
KW - Anandamide
KW - Ca channel
KW - Skeletal muscle
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U2 - 10.1016/S0014-2999(00)00396-4
DO - 10.1016/S0014-2999(00)00396-4
M3 - Article
C2 - 10980258
AN - SCOPUS:0034666671
SN - 0014-2999
VL - 404
SP - 13
EP - 20
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-2
ER -