Global InformationEndocannabinoid transporter information
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 enzyme fatty 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 CB1 cannabinoid 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.
- ^ Kaczocha, Martin; Lin, Qingqing; Nelson, Lindsay D.; McKinney, Michelle K.; Cravatt, Benjamin F.; London, Erwin; Deutsch, Deutsch (2012). "Anandamide Externally Added to Lipid Vesicles Containing-Trapped Fatty Acid Amide Hydrolase (FAAH) Is Readily Hydrolyzed in a Sterol-Modulated Fashion". ACS Chemical Neuroscience. 3 (5): 364–368. doi:10.1021/cn300001w. PMC 3382455. PMID 22860204.
- ^ Bojesen, Inge N.; Hansen, Harald S. (2005). "Membrane transport of anandamide through resealed human red blood cell membranes". The Journal of Lipid Research. 46 no. (8): 1652–1659. doi:10.1194/jlr.M400498-JLR200. PMID 15930521.
- ^ Kaczocha, Martin; Hermann, Anita; Glaser, Sherrye T.; Bojesen, Inge N.; Deutsch, Dale G. (2006). "Anandamide Uptake Is Consistent with Rate-limited Diffusion and Is Regulated by the Degree of Its Hydrolysis by Fatty Acid Amide Hydrolase". The Journal of Biological Chemistry. 281 (14): 9066–9075. doi:10.1074/jbc.M509721200. PMID 16461355.
- ^ 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. PMID 15784231.
- ^ Di Pasquale, E.; Chahinian, H.; Sanchez, P.; Fantini, J. (2009). "The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both Cholesterol-Dependent" [Translated title]. PLOS ONE. 4 (3): e4989. Bibcode:2009PLoSO...4.4989D. doi:10.1371/journal.pone.0004989. PMC 2658885. PMID 19330032.
- ^ a b Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009). "Identification of intracellular carriers for the endocannabinoid anandamide". Proceedings of the National Academy of Sciences of the United States of America. 106 (15): 6375–6380. Bibcode:2009PNAS..106.6375K. doi:10.1073/pnas.0901515106. PMC 2669397. PMID 19307565.
- ^ Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; Finazzi-Agro, A.; Maccarrone, M. (2009). "Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins". Chemistry & Biology. 16 (6): 624–632. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477.
- ^ Huang, Huan; McIntosh, Avery L.; Martin, Gregory G.; Landrock, Danilo; Chung, Sarah; Landrock, Kerstin K.; Dangott, Lawrence J.; Li, Shengrong; Kier, Ann B. (2016-09-20). "FABP1: A Novel Hepatic Endocannabinoid and Cannabinoid Binding Protein". Biochemistry. 55 (37): 5243–5255. doi:10.1021/acs.biochem.6b00446. ISSN 0006-2960. PMC 5322802. PMID 27552286.
- ^ Elmes, Matthew W.; Kaczocha, Martin; Berger, William T.; Leung, KwanNok; Ralph, Brian P.; Wang, Liqun; Sweeney, Joseph M.; Miyauchi, Jeremy T.; Tsirka, Stella E. (2015-04-03). "Fatty Acid-binding Proteins (FABPs) Are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)". Journal of Biological Chemistry. 290 (14): 8711–8721. doi:10.1074/jbc.M114.618447. ISSN 0021-9258. PMC 4423662. PMID 25666611.
- ^ Berger, W.T.; Ralph, B.P.; Kaczocha, M.; Sun, J.; Balius, T.E.; Rizzo, R.C.; Haj-Dahmane, S.; Ojima, I.; Deutsch, D.G. (2012). "Targeting Fatty Acid Binding Protein (FABP) Anandamide Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-Nociceptive Drugs". PLOS ONE. 7 (12): e50968. Bibcode:2012PLoSO...750968B. doi:10.1371/journal.pone.0050968. PMC 3517626. PMID 23236415.
- ^ Nakamura, M.; Chi, Y.M.; Yan, W.M.; Nakasugi, Y.; Yoshizawa, T.; Irino, N.; Hashimoto, F.; Kinjo, J.; Nahara, T.; Sakurada, S. (1999). "Strong antinociceptive effect of incarvillateine, a novel monoterpene alkaloid from Incarvillea sinensis". Journal of Natural Products. 62 (9): 1293–1294. doi:10.1021/np990041c. PMID 10514316.
- ^ Di Pasquale, Eric; Chahinian, Henri; Sanchez, Patrick; Fantini, Jacques (2009-03-30). "The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both Cholesterol-Dependent". PLOS ONE. 4 (3): e4989. Bibcode:2009PLoSO...4.4989D. doi:10.1371/journal.pone.0004989. ISSN 1932-6203. PMC 2658885. PMID 19330032.
- ^ Fowler, Christopher J. (2013-05-01). "Transport of endocannabinoids across the plasma membrane and within the cell". FEBS Journal. 280 (9): 1895–1904. doi:10.1111/febs.12212. ISSN 1742-4658. PMID 23441874. S2CID 12649901.
- ^ Bari, Monica; Paradisi, Andrea; Pasquariello, Nicoletta; Maccarrone, Mauro (2005-07-15). "Cholesterol‐dependent modulation of type 1 cannabinoid receptors in nerve cells". Journal of Neuroscience Research. 81 (2): 275–283. doi:10.1002/jnr.20546. ISSN 1097-4547. PMID 15920744. S2CID 23328664.
- ^ Goleman, Daniel (1995-03-01). "Use of Drugs to Lower Cholesterol Is Tied to a Higher Depression Risk". The New York Times. ISSN 0362-4331. Retrieved 2017-10-31.
- ^ Asellus, Peter; Nordström, Peter; Nordström, Anna-Lena; Jokinen, Jussi (2014-03-30). "Cholesterol and the "Cycle of Violence" in attempted suicide". Psychiatry Research. 215 (3): 646–650. doi:10.1016/j.psychres.2014.01.009. ISSN 0165-1781. PMID 24503286.
- ^ Maccarrone, Mauro; Fiori, Anna; Bari, Monica; Granata, Filippo; Gasperi, Valeria; Stefano, M. Egle De; Finazzi-Agrò, Alessandro; Strom, Roberto (2006). "Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells". Thrombosis and Haemostasis. 95 (1): 117–127. doi:10.1160/TH05-06-0413. hdl:11573/434505. ISSN 0340-6245. PMID 16543970.
- ^ 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.