Membrane Environment and Endocannabinoid Signaling

Two main molecular targets of ∆ 9-tetrahydrocannabinol (∆ 9-THC), the psychoactive principle of Cannabis sativa, are type-1 (CB 1) and type-2 (CB 2) cannabi-noid receptors (Howlett et al., 2010). In the past few years many endogenous agonists of CB receptors have been characterized, and are collectively called " endocannabinoids " (Maccarrone et al., 2010). They are mainly amides and esters of long-chain polyunsat-urated fatty acids isolated from brain and peripheral tissues and, although structurally different from plant cannabinoids, share critical pharmacophores with ∆ 9-THC (Pertwee, 2010). Two arachidonate derivatives , N-arachidonoylethanolamine (anan-damide, AEA) and 2-arachidonoylglycerol (2-AG), were shown to mimic ∆ 9-THC by functionally activating CB receptors, and these are the endocannabinoids whose biological activity has been best characterized to date (Di Marzo, 2009; Maccarrone et al., 2010). CB 1 receptor is the most abundant G protein-coupled receptor (GPCR) in the brain (Howlett et al., 2010). Together with its endogenous agonists (AEA, 2-AG, and other congeners), CB 1 belongs to an ancient neurosignaling system that plays important control functions within the central nervous system (Katona and Freund, 2008). Alterations in this so-called " endocan-nabinoid system " have been extensively investigated in a wide range of neurode-generative and neuroinflammatory disorders , spanning from Alzheimer's disease, Parkinson's disease and Huntington's disease , to amyotrophic lateral sclerosis and multiple sclerosis (Bisogno and Di Marzo, 2010). For this reason, research on the therapeutic potential of drugs modulating the endocannabinoid system is very intense (Di Marzo, 2009). More recently, it has become evident the involvement of membrane lipids, especially cholesterol and glycosphingolipids, in regulating the function of GPCRs like β 2-adrenergic and serotonin 1A receptors, as well as of several other membrane-associated proteins like Also a role for membrane cholesterol in the functional regulation of CB 1 has been well-documented (for an updated review see Dainese et al., 2010). Acute cholesterol depletion by methyl-β-cyclodextrin has been shown to double CB 1-dependent signaling via adenylyl cyclase and mitogen-activated protein kinases in neuronal cells (Bari et al., 2005a,b). Conversely, it has been reported that in the same cells CB 1-dependent binding and signaling was significantly reduced by cholesterol enrichment (Bari et al., 2005a,b, 2006). Notably, the CB 2 receptor that is structurally and functionally related to CB 1 is completely insensitive to the modulation of membrane cholesterol content (Bari et al., 2006), and does not reside in cholesterol-rich microdomains like lipid rafts (Bari et al., 2006; Rimmerman …