Differential modulation of type 1 and type 2 cannabinoid receptors along the neuroimmune axis

Endocannabinoid-signaling chains have been implicated in a variety ofpathophysiological functions, including memory, coordination, vasoregulation,reproduction, neurodegeneration, and inflammation. These activities were thought to be mediated by the activation of two G-protein-coupled receptors (GPCRs), type1 and type 2 cannabinoid receptors (CB(1)R and CB(2)R). These two CBR subtypesshare common agonists and trigger similar signaling pathways, yet they presentseveral important differences in structure and cell distribution. In particular, recent research has shown that the CB(1)R and CB(2)R are differentially linked tolipid rafts, specialized microdomains of the plasma membrane involved in thesignaling of many other GPCRs. We present an overview of the current literatureon the effects that lipid raft perturbation have on CBRs activities, and provide a mechanistic model to interpret these data in terms of structural and functionalaspects. These findings may also have important implications for the development of new therapeutic approaches, including lipid raft perturbing drugs, aimed toselectively modulate CB(1)R signaling in a variety of pathological conditions.[...]