Metabolic Fate of Endocannabinoids

Endocannabinoids are thought to act as retrograde messengers in the central nervous system. By activating presynaptic cannabinoid CB1 receptors they can reduce neurotransmitter release and modulate synaptic plasticity. To date, anandamide and 2-arachidonoylglycerol (2- AG) are the best studied endocannabinoids. The life span of these lipid molecules in the extracellular space is an important factor in the regulation of their cellular responses. In this review we will discuss the metabolic fate of endocannabinoids, i.e. the mechanisms leading to the termination and / or modification of their actions. It is thought that endocannabinoids can be inactivated via a two-step mechanism. First, endocannabinoids are proposed to be translocated into the cell via selective transporter(s). However, the elusive nature of the putative protein responsible for endocannabinoid uptake has initiated a debate on its existence. Evidence in favor and against will be discussed. Once inside the cell, two major metabolic pathways act upon endocannabinoids: hydrolysis and oxygenation. Hydrolysis of the amide or ester function in anandamide and 2-AG, respectively, terminates their activity on cannabinoid receptors. The proteins responsible for their hydrolysis, fatty acid amide hydrolase and monoacylglycerol lipase, have been cloned and studied in detail. Much less is known about the oxygenation pathways. Lipoxygenase- and cycloxygenase-catalyzed oxygenation of endocannabinoids has been shown to generate a new array of possible biologically active compounds, such as the prostamides and the prostaglandin-glycerols, acting upon novel molecular targets. We will discuss the formation and the possible actions of these novel endocannabinoid derivatives.