Fig. 6.

Model of the signaling pathway for membrane glucocorticoid receptor-induced endocannabinoid synthesis. The membrane-associated glucocorticoid receptor (GR) may be either the nuclear glucocorticoid receptor located at the membrane or an as-yet unidentified G protein-coupled receptor. Binding of glucocorticoid (GC) to the membrane GR triggers activation of PKA early in the pathway, upstream from PKC and ERK-MAPK, presumably via a Gαs-dependent mechanism (Malcher-Lopes et al., 2006). PKA then activates a series of signaling molecules, including Src, PLC, PKC, IP3 receptors, and ERK-MAP kinase. Our data suggest that activation of PLC occurs without upstream activation of Gq, and that this leads to IP3 and PKC production. The glucocorticoid-induced endocannabinoid release also requires IP3 receptor activation and store calcium mobilization. The endocannabinoid synthesized by glucocorticoid activation of a membrane receptor is likely to be 2-AG.