Endocannabinoid transporter

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 (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

* Endocannabinoid reuptake inhibitor
* Endocannabinoid enhancer
* Endocannabinoid system

## 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. 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". PLOS ONE 4 (3). doi:10.1371/journal.pone.0004989. PMID 19330032. Bibcode: 2009PLoSO...4.4989D.
6. ↑ 6.0 6.1 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. doi:10.1073/pnas.0901515106. PMID 19307565. Bibcode: 2009PNAS..106.6375K.
7. ↑ Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; Finazzi-Agro, A. et al. (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 et al. (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. PMID 27552286.
9. ↑ Elmes, Matthew W.; Kaczocha, Martin; Berger, William T.; Leung, KwanNok; Ralph, Brian P.; Wang, Liqun; Sweeney, Joseph M.; Miyauchi, Jeremy T. et al. (2015-04-03). "Fatty Acid-binding Proteins (FABPs) Are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)" (in en). Journal of Biological Chemistry 290 (14): 8711–8721. doi:10.1074/jbc.M114.618447. ISSN 0021-9258. PMID 25666611. PMC 4423662. http://www.jbc.org/content/290/14/8711.
10. ↑ Berger, W.T.; Ralph, B.P.; Kaczocha, M.; Sun, J.; Balius, T.E.; Rizzo, R.C.; Haj-Dahmane, S.; Ojima, I. et al. (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). doi:10.1371/journal.pone.0050968. PMID 23236415. Bibcode: 2012PLoSO...750968B.
11. ↑ Nakamura, M.; Chi, Y.M.; Yan, W.M.; Nakasugi, Y.; Yoshizawa, T.; Irino, N.; Hashimoto, F.; Kinjo, J. et al. (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). doi:10.1371/journal.pone.0004989. ISSN 1932-6203. PMID 19330032. Bibcode: 2009PLoSO...4.4989D.
13. ↑ Fowler, Christopher J. (2013-05-01). "Transport of endocannabinoids across the plasma membrane and within the cell" (in en). FEBS Journal 280 (9): 1895–1904. doi:10.1111/febs.12212. ISSN 1742-4658. PMID 23441874.
14. ↑ Bari, Monica; Paradisi, Andrea; Pasquariello, Nicoletta; Maccarrone, Mauro (2005-07-15). "Cholesterol‐dependent modulation of type 1 cannabinoid receptors in nerve cells" (in en). Journal of Neuroscience Research 81 (2): 275–283. doi:10.1002/jnr.20546. ISSN 1097-4547. PMID 15920744.
15. ↑ Goleman, Daniel (1995-03-01). "Use of Drugs to Lower Cholesterol Is Tied to a Higher Depression Risk" (in en-US). The New York Times. ISSN 0362-4331. https://www.nytimes.com/1995/03/01/us/use-of-drugs-to-lower-cholesterol-is-tied-to-a-higher-depression-risk.html.
16. ↑ Asellus, Peter; Nordström, Peter; Nordström, Anna-Lena; Jokinen, Jussi (2014-03-30). "Cholesterol and the "Cycle of Violence" in attempted suicide" (in English). Psychiatry Research 215 (3): 646–650. doi:10.1016/j.psychres.2014.01.009. ISSN 0165-1781. PMID 24503286. http://www.psy-journal.com/article/S0165-1781(14)00045-6/fulltext.
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" (in en). Thrombosis and Haemostasis 95 (1): 117–127. doi:10.1160/TH05-06-0413. ISSN 0340-6245. PMID 16543970. https://th.schattauer.de/en/contents/archive/issue/745/manuscript/5619.html.
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.

* v
* t
* e

Cannabinoid receptor modulators

Receptor
(ligands)</small>|

| CB1|

* Agonists (abridged; see here for more): 2-AG
* 2-AGE (noladin ether)
* 11-Hydroxy-THC
* α-Amyrin · β-Amyrin
* AB-CHMINACA
* AM-1172
* AM-1220
* AM-1221
* AM-1235
* AM-2201
* AM-2232
* Anandamide
* Arvanil
* AZ-11713908
* Cannabinol
* CB-13
* CP 47,497
* CP 55,940
* Dimethylheptylpyran
* DEA
* ECG
* EGCG
* Epicatechin
* Gallocatechol (gallocatechin)
* Honokiol
* HU-210
* JWH-007
* JWH-015
* JWH-018
* JWH-073
* Kavain
* L-759,633
* Levonantradol
* Menabitan
* Nabilone
* Nabitan
* NADA
* O-1812
* Oleamide
* Pravadoline
* Serinolamide A
* THC (dronabinol)
* UR-144
* WIN 55,212-2
* Yangonin

* Antagonists: AM-251
* AM-6545
* Cannabidiol
* Cannabigerol
* Drinabant
* Falcarinol (carotatoxin)
* Hemopressin
* Ibipinabant
* LY-320,135
* MK-9470
* NESS-0327
* O-2050
* Otenabant
* PF-514273
* PipISB
* Rimonabant
* Rosonabant
* Surinabant
* Taranabant
* THCV
* TM-38837
* VCHSR
* Virodhamine

* Antibodies: Brizantin (Бризантин)
* Dietressa (Диетресса)

* Unknown/unsorted: MAFP

|

CB2|

* Agonists: 2-AG
* 2-AGE (noladin ether)
* 3,3'-Diindolylmethane
* 4-O-Methylhonokiol
* α-Amyrin · β-Amyrin
* A-796,260
* A-834,735
* A-836,339
* AM-1172
* AM-1221
* AM-1235
* AM-1241
* AM-2232
* Anandamide
* AZ-11713908
* Cannabinol
* Caryophyllene
* CB-13
* CBS-0550
* CP 55,940
* GW-405,833 (L-768,242)
* GW-842,166X
* HU-308
* JTE 7-31
* JWH-007
* JWH-015
* JWH-018
* JWH-73
* JWH-133
* L-759,633
* L-759,656
* Lenabasum (anabasum)
* Magnolol
* MDA-19
* Nabitan
* NADA
* Olorinab (APD-371)
* PF-03550096
* S-444,823
* SER-601
* Serinolamide A
* UR-144
* Tedalinab
* THC (dronabinol)
* THCV
* Tetrahydromagnolol
* Virodhamine

* Antagonists: 4-O-Methylhonokiol
* AM-630
* BML-190
* Cannabidiol
* Honokiol
* JTE-907
* SR-144,528
* WIN 54,461
* WIN 56,098

NAGly
(GPR18)|

* Agonists: Abnormal cannabidiol
* ACPA
* AM251
* Anandamide
* Cannabidiol
* NADGly
* THC (dronabinol)
* O-1602

* Antagonists: CID-85469571
* O-1918

GPR55|

* Agonists: 2-AGE (noladin ether)
* 2-ALPI
* Abnormal cannabidiol
* AM-251
* CID1011163
* CID1252842
* CID1792579
* CP 55,940
* GSK-494581A
* Lysophosphatidylinositol
* ML-184
* ML-185
* ML-186
* O-1602
* Oleoylethanolamide
* Palmitoylethanolamide
* THC (dronabinol)

* Antagonists: Cannabidiol
* CID-16020046
* ML-191
* ML-192
* ML-193
* O-1918
* PSB-SB-487
* PSB-SB-1202
* PSB-SB-1203
* Tetrahydromagnolol

GPR119|

* Agonists: 2-Oleoylglycerol
* Anandamide
* APD668
* AR-231,453
* AS-1269574
* MBX-2982
* N-Oleoyldopamine
* Oleoylethanolamide
* Olvanil
* PSN-375,963
* PSN-632,408

Unsorted|

* Agonists: Revosimeline

Transporter
(modulators)|

| eCBTs|

* Inhibitors: 5'-DMH-CBD
* AM-404
* AM-1172
* Arachidonoyl serotonin
* Arvanil
* Cannabidiol
* Guineensine
* LY-2183240
* O-2093
* OMDM-2
* Paracetamol (acetaminophen)
* SB-FI-26
* UCM-707
* URB-597
* VDM-11
* WOBE490
* WOBE491
* WOBE492

|

Enzyme
(modulators)|

| FAAH|

* Inhibitors: 4-Nonylphenylboronic acid
* AACOCF3
* AM-404
* Arachidonoyl serotonin
* BIA 10-2474
* Biochanin A
* Genistein
* IDFP
* JNJ-1661010
* JNJ-42165279
* JZL-195
* Kaempferol
* LY-2183240
* MAFP
* Palmitoylisopropylamide
* Paracetamol (acetaminophen)
* PF-3845
* PF-04457845
* PF-750
* SA-47
* SA-57
* TAK 21d
* TC-F 2
* UCM710
* URB-597

* Activators: PDP-EA

|

MAGL|

* Inhibitors: ABX-1431
* IDFP
* JJKK 048
* JW 642
* JZL-184
* JZL-195
* JZP-361
* KML 29
* MAFP
* MJN110
* NAM
* Pristimerin
* URB-602

ABHD6|

* Inhibitors: JZP-169
* JZP-430
* KT182
* KT185
* KT195
* KT203
* LEI-106
* ML294
* ML295
* ML296
* UCM710
* WWL-70

ABHD12|

* Inhibitors: Betulinic acid
* Maslinic acid
* MAFP
* Oleanolic acid
* Orlistat (tetrahydrolipstatin)
* Ursolic acid

Others|

* Precursors: Phosphatidylethanolamine
* NAPE
* Diacylglycerol

* Others: 2-PG (directly potentiates activity of 2-AG at CB1 receptor)
* ARN-272 (FAAH-like anandamide transporter inhibitor)

See also
Receptor/signaling modulators
Cannabinoids (cannabinoids by structure)

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Original source: https://en.wikipedia.org/wiki/Endocannabinoid transporter. Read more

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Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Endocannabinoid_transporter&oldid=4324799"
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[CB1]: Cannabinoid receptor type 1
*[CB2]: Cannabinoid receptor type 2
*[NAGly]: N-Arachidonyl glycine receptor
*[GPR18]: G protein-coupled receptor 18
*[GPR55]: G protein-coupled receptor 55
*[GPR119]: G protein-coupled receptor 119
*[eCBTs]: Endocannabinoid transporter
*[FAAH]: Fatty acid amide hydrolase
*[ABHD6]: alpha/beta-Hydrolase domain containing 6
*[ABHD12]: alpha/beta-Hydrolase domain containing 12