Endocannabinoids anandamide, biosynthesis

Figure 10.6. The biosynthesis of endocannabinoids. Biosynthetic pathways for the biosynthesis of the major endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG). Note that the enzymes N-acyltransferase in anandamide biosynthesis. The biosynthesis of 2-AG can proceed via two different routes and is also dependent on an increase in Ca. Figures reprinted from Piomelli (2003) with permission from Nature Publishing Group.

All the foregoing pharmacological effects of anandamide, in conjunction with the well-documented existence of specific systems for its biosynthesis, catabolism, and cellular reuptake to be discussed shortly, suggest that anandamide is indeed the endogenous cannabinoid ligand. The other two less studied A -acylethanolamide endocannabinoids and also 2-AG may serve similar functions. The differential roles of each of these four endocannabinoids are still unclear. 

Extensive studies on the endocannabinoid system have revealed a number of cannabinergic proteins involved in the inactivation and biosynthesis of endocannabinoids. These include fatty acid amide hydrolase (FAAH) (Di Marzo et al. 1994 Gaetani et al. 2003 Piomelli et al. 1999), monoglyceride lipase (MAG) (Dinh et al. 2002), and the anandamide transporter (ANT) (Beltramo et al. 1997 Di Marzo et al. 1994 Fegley et al. 2004 Hillard et al. 1997). The above three proteins and the two cannabinoid receptors have received considerable attention and show great promise as potential targets for the development of novel medications for various conditions, including pain, immunosuppression, peripheral vascular disease, appetite enhancement or suppression, and motor disorders. 

Anandamide and 2-AG are produced by neurons when the need arises, act near their site of biosynthesis, and are rapidly metabolized so that their bioactivities are terminated. These characteristics distinguish endocannabinoids from classical or peptide neurotransmitters and suggest that endocannabinoids play a role as activity-dependent, short-range modulators of synaptic function. Such a role is supported by data obtained from electrophysiological and neurochemical experiments. 

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