Endocannabinoids as Signaling Molecules in the Central Nervous System

Anandamide is synthesized "on demand" (upon stimulation) (22-24), and released from neurons immediately afterward (23-25). Anandamide is inactivated by reuptake via a membranal transport molecule, the "anandamide membrane transporter" (AMT) and subsequent intracellular enzymatic degradation (23,26,27) by fatty acid amide hydroxylase (FAAH)-mediated hydrolysis (9,28,29). 2-Arachidonoylglycerol (2-AG) undergoes similar FAAH-mediated hydrolysis (9,30) and carrier-mediated transmembranal transport (31), probably through the same anandamide membrane transporter (32).

FAAH and AMT are distributed in brain areas in a patterns corresponding to that of the CB1 receptor, that is, high concentrations in hippocampus, cerebellum, and cerebral cortex (29,30,33,34), thus further supporting the position that the endocannabinoids are true neurotransmitters (35).

It has been argued, based on structure-activity relationships, that 2-AG is the natural ligand at the CB1 receptor (14,36). On the other hand, the observation that anandamide, but not 2-AG, was released upon depolarization in the rat striatum (25), suggests that anandamide rather than 2-AG is the primary ligand for the CB1 receptors, at least in the rat striatum controlling motor activity.

The nature of endocannabinoid (anandamide and 2-AG) neurotransmission has greatly been clarified in a recent series of papers (36-38). These new sets of data have been summarized by Christie and Vaughan (39): endocannabinoids are released from a postsynaptic neuron upon stimulation, diffuse back to presynaptic neurons, where they act on CB1 receptors resulting in a reduced probability of neurotransmitters (such as glutamate and GABA) to be released. Removal of the endocannabinoids is accomplished by uptake into neuronal or glial cells which they enter via endocannabinoid transporters. Once inside the presynaptic cells, the endocannnabinoids are broken down by FAAH. It is too early to generalize these principles to noladin ether.

Endocannabinoids in the central nervous system bind Gi/o-coupled CB1 receptors that modulate adenylyl cyclase, ion channels, and extracellular signal-regulated kinases (21,24,35). Recently it was determined that the CB1 receptor is coupled to ceramide, a lipid second messenger, which in turn mediates cannabinoid induced apoptosis. Such a mechanism opens up new avenues of investigation for the ways by which the endocannabinoids control cell function (40).

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