Modulation of the Endocannabinoid System by Lipid Rafts
Endocannabinoids like anandamide and 2-arachidonoylglycerol bind and activate type-1 (CB1R) and type-2 (CB2R) cannabinoid receptors, two inhibitory G protein-coupled receptors (GPCRs) that are localized in the central nervous system and in peripheral tissues. The biological actions of these lipids are controlled through not yet fully characterized cellular mechanisms that regulate the release of endocannabinoids from membrane precursors, their uptake by cells, and their intracellular disposal. The transport of anadamide through the plasma membrane is saturable and energy-independent, and might occur through a putative anandamide membrane transporter. Altogether anandamide and 2-arachidonoylglycerol, their congeners and the proteins that bind, transport, synthesize and hydrolyze these lipids, form the “endocannabinoid system”. Accumulating evidence shows that CB1R (but not CB2R) binding and signaling, as well as anandamide transport, are under the control of lipid rafts (LRs), plasma membrane subdomains which modulate the activity of a number of GPCRs. Here we summarize the main features of the endocannabinoid system and LRs, in order to put the functional and structural effects of LRs on CB receptors, AEA transport and endocannabinoid signaling in a better focus. We outline the structural determinants that might explain the differential sensitivity of cannabic receptors towards raft integrity, and propose a general model to explain the dependence of endocannabinoid system on LRs. Finally, we also discuss the possible exploitation of LRs-targeted drugs as novel therapeutics for the treatment of endocannabinoid system-related pathologies.
No Supplementary Data
No Article Media
Document Type: Research Article
Affiliations: Department of Biomedical Sciences,University of Teramo, Piazza A. Moro 45, 64100 Teramo, Italy.
Publication date: 2007-10-01
More about this publication?
- Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.