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Figure 2: Major signaling pathways associated with cannabinoid receptor activation by agonists. Activation of both cannabinoid CB1 and CB2 receptors and the subsequent stimulation of Gi/o heterotrimeric proteins is well known to be coupled to inhibition of adenylate cyclase with corresponding inactivation of the protein kinase A phosphorylation pathway or to stimulation of mitogen-activated protein kinase. These intracellular events lead to, among other effects, the regulation of expression of several genes. However, more complex protein phosphorylation cascades - specifically, those involving phosphoinositide-3-kinase and protein kinase B - are also proposed to be triggered by CB1 receptors. Furthermore, stimulation, rather than inhibition, of AC by CB1, but not CB2, receptors, through Gs proteins, has also been described occasionally. CB1, but not CB2, receptor stimulation of Gi/o proteins is also directly coupled to inhibition of voltage-activated Ca2+ channels and stimulation of inwardly rectifying K+ channels in neurons, with subsequent inhibition of neurotransmitter release. The choice between which of these pathways is modulated by cannabinoid receptor activation also depends on the type of agonist under study. Reused with permission from Di Marzo et al.[28] Springer Nature. cAMP = Cyclic AMP, CB1 = Cannabinoid receptor 1, CB2 = Cannabinoid receptor 2

Figure 2: Major signaling pathways associated with cannabinoid receptor activation by agonists. Activation of both cannabinoid CB1 and CB2 receptors and the subsequent stimulation of Gi/o heterotrimeric proteins is well known to be coupled to inhibition of adenylate cyclase with corresponding inactivation of the protein kinase A phosphorylation pathway or to stimulation of mitogen-activated protein kinase. These intracellular events lead to, among other effects, the regulation of expression of several genes. However, more complex protein phosphorylation cascades - specifically, those involving phosphoinositide-3-kinase and protein kinase B - are also proposed to be triggered by CB1 receptors. Furthermore, stimulation, rather than inhibition, of AC by CB1, but not CB2, receptors, through Gs proteins, has also been described occasionally. CB1, but not CB2, receptor stimulation of Gi/o proteins is also directly coupled to inhibition of voltage-activated Ca<sup>2+</sup> channels and stimulation of inwardly rectifying K<sup>+</sup> channels in neurons, with subsequent inhibition of neurotransmitter release. The choice between which of these pathways is modulated by cannabinoid receptor activation also depends on the type of agonist under study. Reused with permission from Di Marzo <i>et al</i>.<sup>[28]</sup> Springer Nature. cAMP = Cyclic AMP, CB1 = Cannabinoid receptor 1, CB2 = Cannabinoid receptor 2