Cannabinoid receptor signalling in neurodegenerative diseases: a potential role for membrane fluidity disturbance.

Type-1 cannabinoid receptor (CB(1)) is the most abundant G-protein-coupled receptor (GPCR) in the brain. CB(1) and its endogenous agonists, the so-called 'endocannabinoids (eCBs)', belong to an ancient neurosignalling system that plays important functions in neurodegenerative and neuroinflammatory disorders like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. For this reason, research on the therapeutic potential of drugs modulating the endogenous tone of eCBs is very intense. Several GPCRs reside within subdomains of the plasma membranes that contain high concentrations of cholesterol: the lipid rafts. Here, the hypothesis that changes in membrane fluidity alter function of the endocannabinoid system, as well as progression of particular neurodegenerative diseases, is described. To this end, the impact of membrane cholesterol on membrane properties and hence on neurodegenerative diseases, as well as on CB(1) signalling in vitro and on CB(1) -dependent neurotransmission within the striatum, is discussed. Overall, present evidence points to the membrane environment as a critical regulator of signal transduction triggered by CB(1) , and calls for further studies aimed at better clarifying the contribution of membrane lipids to eCBs signalling. The results of these investigations might be exploited also for the development of novel therapeutics able to combat disorders associated with abnormal activity of CB(1).