Figure 2.

Three waves of responses to cannabinoid binding. The first wave is initiated by cannabinoids binding to the CB₁/CB₂ receptors. The interaction of cannabinoids with one of these receptors activates heterotrimeric G proteins, thus leading to their dissociation into Gα_i and G_β/G_γ subunits and resulting in three major events: a rapid decrease in cAMP levels due to the direct binding and inhibition of adenylate cyclase by a Gα_i subunit, a decrease in Ca²⁺ conductance, and an increase in K⁺ conductance. The second wave consists of the events associated with the receptor phosphorylation followed by receptor desensitization. Arrestin proteins bind to the phosphorylated receptor leading to receptor internalization, thus redirecting all downstream signaling to other receptors and activating the pathways like mitogen-activated protein family of kinases. The third wave is initiated at the receptors in the intracellular compartments such as endosomes and lysosomes and can be initialized through either G proteins or β-arrestins.