Figure 7.

CB₂ signaling network in mixed human primary leukocytes. Binding of HU308 to CB₂ leads to activation of Gα_iβγ and Gα_sβγ heterotrimers. Gα_i inhibits adenylyl cyclase(s) (AC) and activates a cascade leading to phosphorylation of p38 and CREB. βγ from Gα_iβγ activates Akt and initiates a cascade leading to phosphorylation of ERK. Gα_s stimulates AC which leads (likely via protein kinase A, PKA) to p-CREB. βγ from non-Gα_iβγ (likely from Gα_sβγ) also contributes to p-CREB activation. On the basis of inhibitor effects (Figure 5B), Gα_s and non-Gα_iβγ are the major mediators of p-CREB, whereas p-p38 is a minor p-CREB mediator. JNK phosphorylation was not observed. Given that Gα_i-mediated inhibition of AC does not inhibit p-CREB activation it is likely that Gα_i and Gα_s modulations of AC are either segregated in separate compartments within one cell, or occur in different cells (represented by vertical dotted line). p-CREB likely mediates IL-6/IL-10 induction, which might be released from one cell or from different cell types.