Theendocannabinoid transporters (eCBTs) aretransport proteins for theendocannabinoids. Mostneurotransmitters are water-soluble and requiretransmembrane proteins to transport them across thecell membrane. The endocannabinoids (anandamide, AEA, and2-arachidonoylglycerol, 2-AG) on the other hand, are non-charged lipids that readily cross lipid membranes.[1][2][3][4][5] However, since the endocannabinoids are waterimmiscible,protein transporters have been described that act as carriers tosolubilize and transport the endocannabinoids through the aqueouscytoplasm. These include theheat shock proteins (Hsp70s) andfatty acid-binding proteins for anandamide (FABPs).[6][7] FABPs such as FABP1, FABP3, FABP5, and FABP7 have been shown to bind endocannabinoids.[8][9] FABP inhibitors attenuate the breakdown of anandamide by theenzymefatty acid amide hydrolase (FAAH) in cell culture.[6] One of these inhibitors (SB-FI-26), isolated from a virtual library of a million compounds, belongs to a class of compounds (named the "truxilloids') that act as ananti-nociceptive agent with mildanti-inflammatory activity in mice.[10] Thesetruxillic acids and their derivatives have been known to have anti-inflammatory and anti-nociceptive effects in mice[11] and are active components of a Chinese herbal medicine ((−)-IncarvillateineIncarvillea sinensis) used to treatrheumatism and pain in human. The blockade of anandamide transport may, at least in part, be the mechanism through which these compounds exert their anti-nociceptive effects.
Studies have found the involvement ofcholesterol in membrane uptake and transport of anandamide. Cholesterol stimulates both the insertion of anandamide into synthetic lipid monolayers andbilayers, and its transport across bilayer membranes, suggest that besides putative anandamide protein-transporters, cholesterol could be an important component of the anandamide transport machinery,[12][13] and as cholesterol-dependent modulation ofCB1cannabinoid receptors innerve cells. Thecatalytic efficiency (i.e., the ratio between maximal velocity andMichaelis–Menten constant) of the AEA membrane transporter (AMT) is almost doubled compared with control cells, demonstrate that, among the proteins of the "endocannabinoid system," only CB1 and AMT critically depend on membrane cholesterol content, an observation that may have important implications for the role of CB1 in protecting nerve cells against (endo)cannabinoid-inducedapoptosis.[14] This can be a reason, why the use of drugs tolower cholesterol is tied to a higherdepression risk, and the correlation between levels and increaseddeath rates fromsuicide and otherviolent causes.[15][16]
Activation of CB1 enhances AMT activity through increasednitric oxide synthase (NOS) activity and subsequent increase ofNO production, whereas AMT activity instead is reduced by activation of theCB2 cannabinoid receptor, which inhibits NOS and NO release, also suggesting the distribution of these receptors may drive AEA directional transport through theblood–brain barrier and otherendothelial cells.[17]
As reviewed in 2016; "Many of the AMT (EMT) proposals have fallen by the wayside."[18] To date a transmembrane protein transporter has not been identified.
^Sandberg, A.; Fowler, C.J. (2005). "Measurement of saturable and non-saturable components of anandamide uptake into P19 embryonic carcinoma cells in the presence of fatty acid-free bovine serum albumin".Chemistry and Physics of Lipids.134 (2):131–139.doi:10.1016/j.chemphyslip.2004.12.010.PMID15784231.
^Deutsch DG. A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs). Frontiers in Pharmacology. 2016;7:370. doi:10.3389/fphar.2016.00370.
