*2.3. Cell Signalling Pathways Activated by CB1 and CB2*

Both CB are GPCRs that couple similar transduction systems of heterotrimeric G proteins [59]. Intracellular signalling is complex because it includes both G protein dependent and independent pathways, as well as ceramide signalling [53]. Figure 2 illustrates the main molecular pathways. Activation of CB decreases the intracellular accumulation of cyclic adenosine monophosphate (cAMP). This results in the inhibition of the adenylyl cyclase activity and a reduction in intracellular Ca2<sup>+</sup>, which eventually leads to the inhibition of protein kinase A and the dephosphorylation of K<sup>+</sup> channel type A [60,61], a critical process that modulates the responses to ionotropic neurotransmitters in neurons. Moreover, CB1 negatively binds certain Ca2<sup>+</sup> voltage dependent channels, induces G-protein-coupled modulating K<sup>+</sup> channels (GIRK), and subsequently inhibits neurotransmitter release independently of cAMP [55]. CB also activate mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinase 1 or 2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK), which are important for orchestrating cellular functions such as cell growth, cellular transformation, and apoptosis [56]. It has been proposed that two signal transduction pathways activate MAPK in response to CB activation: one involves the activation of phosphatidylinositide-3-kinase (PI3K), and the second, sphingomyelin, hydrolysis and release of ceramide [57]. PI3K has also been reported to induce AKT-mediated cell survival by inhibiting apoptosis [56]. De novo ceramide synthesis promoted by CB is known to directly trigger apoptosis in a G protein-independent manner [62]. CB is also associated with β-arrestin, a key mediator of GPCR desensitization [32]. β-arrestin binds to the phosphorylated receptor and initiates its internalization process, during which it can mediate different signalling pathways [32].

**Figure 2.** Molecular and cell signalling pathways of cannabinoid receptors.
