Endocannabinoid transporter

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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.

See also

Related Research Articles

<span class="mw-page-title-main">Anandamide</span> Chemical compound (fatty acid neurotransmitter)

Anandamide (ANA), also known as N-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid receptors, the same receptors that the psychoactive compound THC in cannabis acts on. Anandamide is found in nearly all tissues in a wide range of animals. Anandamide has also been found in plants, including small amounts in chocolate. The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

<span class="mw-page-title-main">Fatty acid amide hydrolase</span>

Fatty acid amide hydrolase or FAAH is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993. In humans, it is encoded by the gene FAAH.

<span class="mw-page-title-main">2-Arachidonoylglycerol</span> Chemical compound

2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994-1995, although it had been discovered some time before that. The activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).

<span class="mw-page-title-main">AM404</span> Chemical compound

AM404, also known as N-arachidonoylaminophenol, is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action and anticonvulsant effects. Chemically, it is the amide formed from 4-aminophenol and arachidonic acid.

<span class="mw-page-title-main">Oleamide</span> Chemical compound

Oleamide is an organic compound with the formula CH3(CH2)7CH=CH(CH2)7CONH2. It is the amide derived from the fatty acid oleic acid. It is a colorless waxy solid and occurs in nature. Sometimes labeled as a fatty acid primary amide (FAPA), it is biosynthesized from N-oleoylglycine.

<span class="mw-page-title-main">Methoxy arachidonyl fluorophosphonate</span> Chemical compound

Methoxy arachidonyl fluorophosphonate, commonly referred as MAFP, is an irreversible active site-directed enzyme inhibitor that inhibits nearly all serine hydrolases and serine proteases. It inhibits phospholipase A2 and fatty acid amide hydrolase with special potency, displaying IC50 values in the low-nanomolar range. In addition, it binds to the CB1 receptor in rat brain membrane preparations (IC50 = 20 nM), but does not appear to agonize or antagonize the receptor, though some related derivatives do show cannabinoid-like properties.

<span class="mw-page-title-main">Fatty acid-binding protein</span>

The fatty-acid-binding proteins (FABPs) are a family of transport proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. These proteins are thought to facilitate the transfer of fatty acids between extra- and intracellular membranes. Some family members are also believed to transport lipophilic molecules from outer cell membrane to certain intracellular receptors such as PPAR. The FABPs are intracellular carriers that “solubilize” the endocannabinoid anandamide (AEA), transporting AEA to the breakdown by FAAH, and compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids are also discovered to bind human FABPs that function as intracellular carriers, as THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. Levels of fatty-acid-binding protein have been shown to decline with ageing in the mouse brain, possibly contributing to age-associated decline in synaptic activity.

<span class="mw-page-title-main">FABP1</span> Protein-coding gene in the species Homo sapiens

FABP1 is a human gene coding for the protein product FABP1. It is also frequently known as liver-type fatty acid-binding protein (LFABP).

N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) is an enzyme that catalyzes the release of N-acylethanolamine (NAE) from N-acyl-phosphatidylethanolamine (NAPE). This is a major part of the process that converts ordinary lipids into chemical signals like anandamide and oleoylethanolamine. In humans, the NAPE-PLD protein is encoded by the NAPEPLD gene.

<i>N</i>-Acylethanolamine Class of chemical compounds

An N-acylethanolamine (NAE) is a type of fatty acid amide where one of several types of acyl groups is linked to the nitrogen atom of ethanolamine, and highly metabolic formed by intake of essential fatty acids through diet by 20:4, n-6 and 22:6, n-3 fatty acids, and when the body is physically and psychologically active, and the endocannabinoid signaling system (ECS) is the major pathway by which NAEs exerts its physiological effects in animal cells with similarities in plants, and the metabolism of NAEs is an integral part of the ECS. These amides conceptually can be formed from a fatty acid and ethanolamine with the release of a molecule of water, but the known biological synthesis uses a specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamines. Another route relies on the transesterification of acyl groups from phosphatidylcholine by an N-acyltransferase (NAT) activity. The suffixes -amine and -amide in these names each refer to the single nitrogen atom of ethanolamine that links the compound together: it is termed "amine" in ethanolamine because it is considered as a free terminal nitrogen in that subunit, while it is termed "amide" when it is considered in association with the adjacent carbonyl group of the acyl subunit. Names for these compounds may be encountered with either "amide" or "amine" varying by author.

Endocannabinoid reuptake inhibitors (eCBRIs), also called cannabinoid reuptake inhibitors (CBRIs), are drugs which limit the reabsorption of endocannabinoid neurotransmitters by the releasing neuron.

<span class="mw-page-title-main">LY-2183240</span> Chemical compound

LY-2183240 is a drug which acts both as a potent inhibitor of the reuptake of the endocannabinoid anandamide and as an inhibitor of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for degrading anandamide. This leads to markedly elevated anandamide levels in the brain, and LY-2183240 has been shown to produce both analgesic and anxiolytic effects in animal models. While LY-2183240 is a potent inhibitor of FAAH, it has relatively poor selectivity and also inhibits several other enzyme side targets. Consequently, it was never developed for clinical use, though it remains widely used in research, and has also been sold as a designer drug.

<i>N</i>-Arachidonylglycine Chemical compound

N-Arachidonylglycine (NAGly) is a carboxylic metabolite of the endocannabinoid anandamide (AEA). Since it was first synthesized in 1996, NAGly has been a primary focus of the relatively contemporary field of lipidomics due to its wide range of signaling targets in the brain, the immune system and throughout various other bodily systems. In combination with 2‐arachidonoyl glycerol (2‐AG), NAGly has enabled the identification of a family of lipids often referred to as endocannabinoids. Recently, NAGly has been found to bind to G-protein coupled receptor 18 (GPR18), the putative abnormal cannabidiol receptor. NaGly is an endogenous inhibitor of fatty acid amide hydrolase (FAAH) and thereby increases the ethanolamide endocannabinoids AEA, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels. NaGly is found throughout the body and research on its explicit functions is ongoing.

IDFP is an organophosphorus compound related to the nerve agent sarin.

<i>N</i>-Acylamides

N-acyl amides are a general class of endogenous fatty acid compounds characterized by a fatty acyl group linked to a primary amine metabolite by an amide bond. Broadly speaking, N-acyl amides fall into several categories: amino acid conjugates, neurotransmitter conjugates, ethanolamine conjugates, and taurine conjugates. N-acyl amides have pleiotropic signaling functions in physiology, including in cardiovascular function, metabolic homeostasis, memory, cognition, pain, motor control and others. Initial attention focused on N-acyl amides present in mammalian organisms, however recently lipid signaling systems consisting of N-acyl amides have also been found to be present in invertebrates, such as Drosophila melanogaster. N-acyl amides play important roles in many biochemical pathways involved in a variety of physiological and pathological processes, as well as the metabolic enzymes, transporters, and receptors that regulate their signaling.

N-acylethanolamine acid amide hydrolase (NAAA) EC 3.5.1.- is a member of the choloylglycine hydrolase family, a subset of the N-terminal nucleophile hydrolase superfamily. NAAA has a molecular weight of 31 kDa. The activation and inhibition of its catalytic site is of medical interest as a potential treatment for obesity and chronic pain. While it was discovered within the last decade, its structural similarity to the more familiar acid ceramidase (AC) and functional similarity to fatty acid amide hydrolase (FAAH) allow it to be studied extensively.

PF-3845 is a selective inhibitor of fatty acid amide hydrolase. It results in increased levels of anandamide and results in cannabinoid receptor-based effects. It has anti-inflammatory action in mice colitis models. Antidiarrheal and antinociceptive effects were also seen in mouse models of pain.

An endocannabinoid enhancer (eCBE) is a type of cannabinoidergic drug that enhances the activity of the endocannabinoid system by increasing extracellular concentrations of endocannabinoids. Examples of different types of eCBEs include fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, and endocannabinoid transporter (eCBT) inhibitors. An example of an actual eCBE is AM404, the active metabolite of the analgesic paracetamol and a dual FAAH inhibitor and eCBRI.

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. 1 2 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
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