Toward an anandamide transporter
- Raphael Mechoulam*,† and
- Dale G. Deutsch‡
- *Department of Medicinal Chemistry and Natural Products, Hebrew University Medical Faculty, Jerusalem 91120, Israel; and ‡Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, NY 11794-5215
Almost every step in the elucidation of the structure and mechanism of action of the endocannabinoid system has been plagued by controversy. Although the psychoactive component of marijuana was identified in the mid-1960s (1), it took another two decades to show that it does not act by an unspecific mechanism, but via receptors, now known as the endocannabinoid receptors CB1 and CB2 (2). The identification of anandamide (AEA) in 1992 (3) as an endogenous cannabinoid ligand was originally challenged, because its level in mouse brain was found to be negligible. Several thousand publications later, it is now a well established transmitter. For more than a decade, a heated controversy, on paper and at meetings, has been going on over the transport of anandamide into the cell, a central process in its metabolism (Fig. 1). Is it a facilitated transport with the help of a transporter, presumably a protein, or does anandamide passively diffuse through the plasma membrane in a process that is not protein-mediated (4)? In this issue of PNAS, Moore et al. (5) report the identification of a high-affinity, saturable, anandamide binding site that is distinct from fatty acid amide hydrolase (FAAH), the enzyme that hydrolyzes anandamide (5). The authors bring forward evidence that this high-affinity binding site is, in fact, an anandamide transporter. The possibility that alternative transport mechanisms, be they diffusional, endocytic, or FAAH-mediated, are working in parallel to the facilitated transport has, however, not yet been excluded.
How anandamide gets into the cell. AEA, anandamide; FAAH, fatty acid amide hydrolase.
Until now, the biosynthesis and breakdown of anandamide were well understood, but its mechanism of uptake leading to termination of signaling was still ambiguous. In 1993, it was shown that anandamide was readily taken up …
