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

Abstract

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).

Figure 1

Scheme of a biological membrane containing lipid rafts (LRs). The liquid-ordered regions of LRs are thicker than the liquid-disordered bulk of the membrane, and the cholesterol molecules within this region have a slower rate of lateral and interlayer diffusion (flip-flop). See text for details.

Figure 2

Three-dimensional model of type-1 cannabinoid receptor (CB₁), based on sequence alignment with visual rhodopsin in the inactivated state (PDB code: 1F88). The model was obtained using the protein structure homology-modeling server SWISS-MODEL, integrated in the Deep-View program (Dainese et al., 2010). The three residues (V392, Y397, K402) that form the CRAC sequence are represented as yellow spheres, sized to the Van der Waals radii; these residues belong to the transmembrane helix 7 of CB₁. Additionally, the C-terminal component of CB₁, that is, the intracellular juxtamembrane helix 8, contains a cysteine residue (C415, in green) that could be constitutively palmitoylated. The model was kindly provided by Dr. Enrico Dainese (University of Teramo, Italy). See text for further details.

Figure 3

Overall scheme of the interactions between N-arachidonoylethanolamine (AEA), type-1 transient receptor potential vanilloid (TRPV1), 2-arachidonoylglycerol (2-AG) and metabotropic glutamate 5 (mGlu₅) receptors in the striatum. Stimulation of mGlu₅ receptors increases 2-AG synthesis by enhancing glutathione (GSH) production. 2-AG acts as retrograde signal to limit GABA release through the stimulation of presynaptic type-1 cannabinoid receptor (CB₁) receptors. AEA, on the other hand, stimulates TRPV1 channels, presumably located in the somatodendritic region of striatal neurons, and modulates 2-AG metabolism and physiological effects by inhibiting GSH-stimulated diacylglycerol lipase (DAGL) activity (adapted from Maccarrone et al., 2008).

Figure 4

Schematic representation of the interaction between D₂ receptors, brain-derived neurotrophic factor (BDNF) and type-1 cannabinoid receptor (CB₁) in striatal neurons. Stimulation of dopamine D₂ receptors trough chemical (cocaine) and natural rewards (voluntary exercise or sucrose drinking) reduces striatal contents of BDNF, thus reducing cholesterol synthesis and incorporation within CB₁ receptor-containing lipid rafts mediated by the activation of the tyrosine receptor TrkB. This effect results in increased sensitivity of CB₁Rs(GABA), and is limited to striatal GABAergic neuronal elements. The mechanism by which D₂ receptors reduce BDNF concentrations is conversely still unknown (adapted from De Chiara et al. 2010a,;).