The stimulatory effect of cannabinoids on calcium uptake is mediated by G(s) GTP-binding proteins and CAMP formation

Cannabinoids are neurodepressive drugs that convey their cellular action through G(i/o) GTP-binding proteins which reduce CAMP formation and Ca2+ influx. However, a growing body of evidence indicates that the stimulatory effects of cannabinoids include the elevation in CAMP and cytosolic Ca2+ concentration. The present study expands our previous findings and demonstrates that, in N18TG2 neuroblastoma cells, the cannabinoid agonist desacetyllevonantradol (DALN) stimulates both CAMP formation and Ca2+ uptake. The stimulatory effect of DALN on CAMP formation was not eliminated by blocking Ca2+ entry to the cells, while its stimulatory effect on Ca2+ uptake was abolished by blocking CAMP-dependent protein kinase. Furthermore, elevating CAMP by forskolin stimulated calcium uptake, while elevating the intracellular Ca2+ concentration by ionomycin or KCl failed to stimulate CAMP formation. These findings suggest that CAMP production precedes the influx of Ca2+ in the cannabinoid stimulatory cascade. The stimulatory effect of DALN on calcium uptake resisted pertussis toxin treatment, and was completely blocked by introducing anti-G(s) antibodies into the cells, indicating that the stimulatory activity of cannabinoids is mediated by G(s) GTP-binding proteins. The relevance of the cellular stimulatory activity of DALN to the pharmacological profile of cannabinoid drugs is discussed. Copyright (C) 2003 S. Karger AG, Basel.