The endocannabinoid transporters (eCBTs) are
transport proteins for the
endocannabinoids. Most
neurotransmitters are water-soluble and require
transmembrane proteins to transport them across the
cell membrane. The endocannabinoids (
anandamide, AEA, and
2-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 water
immiscible,
protein transporters have been described that act as carriers to
solubilize and transport the endocannabinoids through the aqueous
cytoplasm. These include the
heat shock proteins (
Hsp70s) and
fatty 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 the
enzymefatty 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 an
anti-nociceptive agent with mild
anti-inflammatory activity in mice.[10] These
truxillic 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 ((−)-Incarvillateine
Incarvillea sinensis) used to treat
rheumatism 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 of
cholesterol in membrane uptake and transport of anandamide. Cholesterol stimulates both the insertion of anandamide into synthetic lipid monolayers and
bilayers, 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 of
CB1cannabinoid receptors in
nerve cells. The
catalytic efficiency (i.e., the ratio between maximal velocity and
Michaelis–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-induced
apoptosis.[14] This can be a reason, why the use of drugs to
lower cholesterol is tied to a higher
depression risk, and the correlation between levels and increased
death rates from
suicide and other
violent causes.[15][16]
Activation of CB1 enhances AMT activity through increased
nitric oxide synthase (NOS) activity and subsequent increase of
NO production, whereas AMT activity instead is reduced by activation of the
CB2 cannabinoid receptor, which inhibits NOS and NO release, also suggesting the distribution of these receptors may drive AEA directional transport through the
blood–brain barrier and other
endothelial 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.