The first reports of the CBi receptor and Gi/o protein regulation of Ca2+ currents described a cannabinoid agonist-mediated inhibition of N-type voltage-gated Ca2+ channels in differentiated N18 neuroblastoma and NG108-15 neuroblastoma-glioma hybrid cells (Caulfield and Brown 1992; Mackie and Hille 1992; Mackie et al. 1993; Priller et al. 1995; Pan et al. 1996). WIN55212-2 and CP55940 elicited a maximal response, anandamide produced agonist/antagonist actions, and SR141716 antagonized this response (Mackie et al. 1993). In studies using fura-2 fluorescence to measure intracellular Ca2+ levels, 2-AG and anandamide inhibited the depolarization-evoked intracellular Ca2+ increase in differentiated NG108-15 cells (Sugiura et al. 1997b). Further investigations on the mechanism of inhibition of N-type currents have been carried out using neuronal expression systems (Priller et al. 1995; Pan et al. 1996,1998; Vasquez and Lewis 1999; Guo and Ikeda 2004).
Q-type Ca2+ currents were inhibited by WIN55212-2 and anandamide in AtT-20 pituitary cells expressing recombinant CB1, but not CB2 receptors (Mackie et al. 1995). Pertussis toxin-sensitivity indicated that Gi/o proteins mediated the response. P/Q-type Ca2+ fluxes, detected by fura-2 fluorescence in rat cortical and cerebellar preparations, were inhibited by anandamide (Hampson et al. 1998). This response was blocked by SR141716 and pertussis toxin, indicating mediation by CB1 receptors and Gi/o proteins.
L-type Ca2+ currents were inhibited by anandamide and WIN55212-2 in cat brain arterial smooth muscle cells that endogenously express the CB1 receptor (Gebremedhin et al. 1999). This response was blocked by SR141716 and pertussis toxin, indicating a critical role for CBi receptors and Gi/o. Regulation of L-type Ca2+ channels in these smooth muscle cells could be pharmacologically correlated with vascular relaxation in cat cerebral arterial rings (Gebremedhin et al. 1999).
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