Endocannabinoids regulation

FIGURE 19.3 Schematic representation of endocannabinoid regulation of cell functions. 

Matias I, Di Marzo V (2006) Endocannabinoid synthesis and degradation, and their regulation in the framework of energy balance. J Endocrinol Invest 29(3 Suppl) 15-26... 

In additon to the central role of endocannabinoids in the regulation of feeding behaviour, a peripheral role has also been described. Gomez and coworkers [360] reported that food deprivation produced a 7-fold reduction in (1) levels in the small intestine of rats, but not in the brain or stomach. Intestinal (1) levels returned to normal when feeding resumed. The authors also showed that peripheral, but not central administration of (382) reduced food intake. The endocannabinoid system has also been reported to regulate peripheral lipogenesis [361]. 

Endocannabinoids are endogenous ligands for the CB1 receptor. The best established are anandamide (N-arachidonoylethanolamine) and 2-AG (2-arachidonoyl-glycerol). Others may also exist. Pathways involved in the formation and inactivation of anandamide and 2-AG are shown in Figure 56-6. Some steps in their formation are Ca2+-dependent. This explains the ability of neuronal depolarization, which increases postsynaptic intracellular Ca2+ levels, to stimulate endocannabinoid formation and release. Some neurotransmitter receptors (e.g. the D2 dopamine receptor) also stimulate endocannabinoid formation, probably by modulating postsynaptic Ca2+ levels or signaling pathways (e.g. PLC) that regulate endocannabinoid formation. 

Chevaleyre V, Castillo PE (2003) Heterosynaptic LTD of hippocampal GABAergic synapses a novel role of endocannabinoids in regulating excitability [comment]. Neiuon 38 461-472... 

Physiological studies have identified both post- and presynaptic roles for ionotropic kainate receptors. Kainate receptors contribute to excitatory post-synaptic currents in many regions of the CNS including hippocampus, cortex, spinal cord and retina. In some cases, postsynaptic kainate receptors are codistributed with AMPA and NMDA receptors, but there are also synapses where transmission is mediated exclusively by postsynaptic kainate receptors for example, in the retina at connections made by cones onto off bipolar cells. Extrasynaptically located postsynaptic kainate receptors are most likely activated by spill-over glutamate (Eder et al. 2003). Modulation of transmitter release by presynaptic kainate receptors can occur at both excitatory and inhibitory synapses. The depolarization of nerve terminals by current flow through ionotropic kainate receptors appears sufficient to account for most examples of presynaptic regulation however, a number of studies have provided evidence for metabotropic effects on transmitter release that can be initiated by activation of kainate receptors. The hyperexcitability evoked by locally applied kainate, which is quite effectively reduced by endocannabinoids, is probably mediated preferentially via an activation of postsynaptic kainate receptors (Marsicano et al. 2003). 

Rather, they are both produced within neurons and released to flow backward across the synapse to find their receptors, designated as CBi and CBz. There are probably more of these CB receptors for marijuana in the human brain than for any other known neurotransmitter. The great abundance of these receptors and their widespread location gives an indication of importance of the endocannabinoid system in the regulation of the brain s normal functioning. 

Alger, B.E., Retrograde signaling in the regulation of synaptic transmission focus on endocannabinoids. Prog. Neurobiol., 68, 247-286, 2002. 

A fifth pathway, finally, is the well-established secretion of small membrane-permeable mediators by diffusion. This mechanism is used for the secretion of nitric oxide, endocannabinoids, and other important lipidic or gaseous neurotransmitters. The major point of regulation of release here is the synthesis of the respective compounds, not their actual secretion. 

A, Paul P, Gangadharan U, Hobbs C, Di Marzo V, Doherty P (2003) Cloning of the first sn 1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signalling in the brain. J Cell Biol 163 463-8... 

Ahn, K., McKinney, M., and Cravatt, B. (2008). Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem. Rea. 108, 1687-1707. 

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