Cocaine and amphetamine regulated transcript explained

CART prepropeptide
Hgncid:24323
Symbol:CARTPT
Entrezgene:9607
Omim:602606
Refseq:NM_004291
Uniprot:Q16568
Chromosome:5
Arm:q
Band:13.2
Symbol:CART
CART
Pfam:PF06373
Interpro:IPR009106
Scop:1hy9

Cocaine- and amphetamine-regulated transcript, also known as CART, is a neuropeptide protein that in humans is encoded by the CARTPT gene.[1] [2] CART appears to have roles in reward, feeding, and stress,[3] and it has the functional properties of an endogenous psychostimulant.[4]

Function

CART is a neuropeptide that produces similar behavior in animals as cocaine and amphetamine, but conversely blocks the effects of cocaine when they are co-administered. The peptide is found in several areas, among them the ventral tegmental area (VTA) of the brain. When CART was injected into rat VTA, increased locomotor activity was seen, which is one of the signs of "central stimulation" caused by psychostimulants, such as cocaine and amphetamine.[5] The same rats also tended to return to the place where they were injected. This is called conditioned place preference and is also seen after injection of cocaine.

CART peptides, in particular, CART(55–102), seem to have an important function in the regulation of energy homeostasis and interact with several hypothalamic appetite circuits. CART expression is regulated by several peripheral peptide hormones involved in appetite regulation, including leptin,[6] cholecystokinin and ghrelin,[7] with CART and cholecystokinin having synergistic effects on appetite regulation.[8]

CART is released in response to repeated dopamine release in the nucleus accumbens, and may regulate the activity of neurons in this area.[9] CART production is upregulated by CREB,[10] a protein thought to be involved with the development of drug addiction, and CART may be an important therapeutic target in the treatment of stimulant abuse.[11] [12] [13]

Tissue distribution

CART is an anorectic peptide and is widely expressed in both the central and peripheral nervous systems, particularly concentrated in the hypothalamus.[14] CART is also expressed outside of the nervous system in pituitary endocrine cells, adrenomedullary cells, islet somatostatin cells, and in rat antral gastrin cells.[15] Other structures and pathways associated with CART expression include the mesolimbic pathway (linking the ventral tegmental area to the nucleus accumbens) and amygdala.

CART is also found in a subset of retinal ganglion cells (RGCs), the primary afferent neurons in the retina. Specifically, it labels ON/OFF Direction Selective Ganglion Cells (ooDSGCs), a subpopulation of RGCs that stratify in both the ON and OFF sublamina of the Inner Plexiform Layer (IPL) of the retina. It is also found in a subset of amacrine cells in the Inner Nuclear Layer.[16] No role as of yet has been proposed for the location of this protein in these cell types.

Clinical significance

Studies of CART(54–102) action in rat lateral ventricle and amygdala suggest that CART plays a role in anxiety-like behavior, induced by ethanol withdrawal in rats.[17] Studies on CART knock-out mice indicates that CART modulates the locomotor, conditioned place preference and cocaine self-administration effects of psychostimulants. This suggests a positive neuromodulatory action of CART on the effects of psychostimulants in rats.[18] CART is altered in the ventral tegmental area of cocaine overdose victims, and a mutation in the CART gene is associated with alcoholism.[19] By inhibiting the rewarding effects of cocaine, CART has a potential use in treating cocaine addiction.[20]

CART peptides are inhibitors of food intake (anorectic) and closely associated with leptin and neuropeptide Y, two important food intake regulators. CART hypoactivity in the hypothalamus of depressed animals is associated with hyperphagia and weight gain.[21] [22] CART is thought to play a key role in the opioid mesolimbic dopamine circuit that modulates natural reward processes.[23] CART also appears to play an important role in higher brain functions like cognition.[24]

History

CART was found by examining changes in the brain following cocaine or amphetamine administration. CART mRNA increased with cocaine administration. One of the goals was to find an endogenous anoretic substance. CART inhibited rat food intake by as much as 30 percent. When naturally occurring CART peptides were blocked by means of injecting antibodies for CART, feeding was increased. This led to suggestions that CART may play a role – though not being the only peptide – in satiety. In the late 1980s, researchers started to synthesize structurally cocaine-like and functionally CART-like substances in order to find medications that could help treat eating disorders as well as cocaine abuse. Chemically, these substances belong to phenyltropanes.[25]

CART receptor

The putative receptor target for CART evaded identification through 2011, however in vitro studies strongly suggested that CART binds to a specific G protein-coupled receptor coupled to Gi/Go, resulting in increased ERK release inside the cell.[26] [27] [28] [29] In 2020, CART was identified as the ligand for GPR160.[30] This finding was later challenged by the finding that GPR160 does not show specific binding to a radiolabeled version of CART either in a human cancer cell line that endogeneously expresses GPR160, or in a cell line that was transfected with PGR160.[31] Furthermore, CART does not induce GPR160 mediated signaling in human cells.[32]

Several fragments of CART have been tested to try and uncover the pharmacophore,[33] [34] but the natural splicing products CART(55–102) and CART(62–102) are still of highest activity, with the reduced activity of smaller fragments thought to indicate that a compact structure retaining all three of CART's disulphide bonds is preferred.[35]

See also

Notes and References

  1. Douglass J, Daoud S . Characterization of the human cDNA and genomic DNA encoding CART: a cocaine- and amphetamine-regulated transcript . Gene . 169 . 2 . 241–5 . March 1996 . 8647455 . 10.1016/0378-1119(96)88651-3 .
  2. Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, Larsen PJ, Hastrup S . Hypothalamic CART is a new anorectic peptide regulated by leptin . Nature . 393 . 6680 . 72–6 . May 1998 . 9590691 . 10.1038/29993 . 1998Natur.393...72K . 4427258 .
  3. 10.1111/j.1440-1681.2011.05642.x . 22077697 . Roles of cocaine- and amphetamine-regulated transcript in the central nervous system . November 2011 . Clin. Exp. Pharmacol. Physiol. . Zhang M, Han L, Xu Y . 39 . 6 . 586–92. 25134612 .
  4. Kuhar MJ, Adams S, Dominguez G, Jaworski J, Balkan B . CART peptides . Neuropeptides . 36 . 1 . 1–8 . February 2002 . 12147208 . 10.1054/npep.2002.0887 . 7079530 .
  5. Kimmel HL, Gong W, Vechia SD, Hunter RG, Kuhar MJ . Intra-ventral tegmental area injection of rat cocaine and amphetamine-regulated transcript peptide 55-102 induces locomotor activity and promotes conditioned place preference . The Journal of Pharmacology and Experimental Therapeutics . 294 . 2 . 784–92 . August 2000 . 10900261 .
  6. Murphy KG . Dissecting the role of cocaine- and amphetamine-regulated transcript (CART) in the control of appetite . Brief Funct Genomic Proteomic . 4 . 2 . 95–111 . July 2005 . 16102267 . 10.1093/bfgp/4.2.95. free .
  7. de Lartigue G, Dimaline R, Varro A, Dockray GJ . Cocaine- and amphetamine-regulated transcript: stimulation of expression in rat vagal afferent neurons by cholecystokinin and suppression by ghrelin . Journal of Neuroscience . 27 . 11 . 2876–82 . March 2007 . 17360909 . 6672594. 10.1523/JNEUROSCI.5508-06.2007 . free .
  8. Maletínská L, Maixnerová J, Matysková R, Haugvicová R, Pirník Z, Kiss A, Zelezná B . Synergistic effect of CART (cocaine- and amphetamine-regulated transcript) peptide and cholecystokinin on food intake regulation in lean mice . BMC Neuroscience . 9. 101 . 2008 . 18939974 . 2587474 . 10.1186/1471-2202-9-101 . free .
  9. Hubert GW, Jones DC, Moffett MC, Rogge G, Kuhar MJ . CART peptides as modulators of dopamine and psychostimulants and interactions with the mesolimbic dopaminergic system . . 75 . 1 . 57–62 . January 2008 . 17854774 . 10.1016/j.bcp.2007.07.028 . 3804336.
  10. Rogge GA, Jones DC, Green T, Nestler E, Kuhar MJ . Regulation of CART peptide expression by CREB in the rat nucleus accumbens in vivo . Brain Research . 1251 . 42–52 . January 2009 . 19046951 . 10.1016/j.brainres.2008.11.011 . 2734444.
  11. Fagergren P, Hurd Y . CART mRNA expression in rat monkey and human brain: relevance to cocaine abuse . Physiology & Behavior . 92 . 1–2 . 218–25 . September 2007 . 17631364 . 10.1016/j.physbeh.2007.05.027 . 11245593 .
  12. Vicentic A, Jones DC . The CART (cocaine- and amphetamine-regulated transcript) system in appetite and drug addiction . The Journal of Pharmacology and Experimental Therapeutics . 320 . 2 . 499–506 . February 2007 . 16840648 . 10.1124/jpet.105.091512 . 14212763 .
  13. Rogge G, Jones D, Hubert GW, Lin Y, Kuhar MJ . CART peptides: regulators of body weight, reward and other functions . Nature Reviews. Neuroscience . 9 . 10 . 747–58 . October 2008 . 18802445 . 10.1038/nrn2493 . 4418456.
  14. Keller PA, Compan V, Bockaert J, Giacobino JP, Charnay Y, Bouras C, Assimacopoulos-Jeannet F . Characterization and localization of cocaine- and amphetamine-regulated transcript (CART) binding sites . Peptides . 27 . 6 . 1328–34 . June 2006 . 16309793 . 10.1016/j.peptides.2005.10.016 . 27440114 .
  15. Wierup N, Kuhar M, Nilsson BO, Mulder H, Ekblad E, Sundler F . Cocaine- and amphetamine-regulated transcript (CART) is expressed in several islet cell types during rat development . J. Histochem. Cytochem. . 52 . 2 . 169–77 . February 2004 . 14729868 . 10.1177/002215540405200204 . free .
  16. Kay JN, De la Huerta I, Kim IJ, Zhang Y, Yamagata M, Chu MW, Meister M, Sanes JR . Retinal ganglion cells with distinct directional preferences differ in molecular identity, structure, and central projections . The Journal of Neuroscience . 31 . 21 . 7753–62 . May 2011 . 21613488 . 3108146 . 10.1523/JNEUROSCI.0907-11.2011 .
  17. Dandekar MP, Singru PS, Kokare DM, Lechan RM, Thim L, Clausen JT, Subhedar NK . Importance of cocaine- and amphetamine-regulated transcript peptide in the central nucleus of amygdala in anxiogenic responses induced by ethanol withdrawal . Neuropsychopharmacology . 33 . 5 . 1127–36 . April 2008 . 17637604 . 10.1038/sj.npp.1301516 . free .
  18. Couceyro PR, Evans C, McKinzie A, Mitchell D, Dube M, Hagshenas L, White FJ, Douglass J, Richards WG, Bannon AW . Cocaine- and amphetamine-regulated transcript (CART) peptides modulate the locomotor and motivational properties of psychostimulants . J. Pharmacol. Exp. Ther. . 315 . 3 . 1091–100 . December 2005 . 16099925 . 10.1124/jpet.105.091678 . 15989891 .
  19. Kuhar MJ, Jaworski JN, Hubert GW, Philpot KB, Dominguez G . Cocaine- and amphetamine-regulated transcript peptides play a role in drug abuse and are potential therapeutic targets . AAPS J . 7 . 1 . E259–65 . 2005 . 16146347 . 10.1208/aapsj070125 . 2751515 .
  20. Yu C, Zhou X, Fu Q, Peng Q, Oh KW, Hu Z . A New Insight into the Role of CART in Cocaine Reward: Involvement of CaMKII and Inhibitory G-Protein Coupled Receptor Signaling . . 11 . 244 . 2017 . 10.3389/fncel.2017.00244 . 5559471 . 28860971 . free .
  21. Nakhate KT, Kokare DM, Singru PS, Subhedar NK . Central regulation of feeding behavior during social isolation of rat: evidence for the role of endogenous CART system . Int J Obes (Lond) . 35 . 6 . 773–84 . June 2011 . 21060312 . 10.1038/ijo.2010.231. 23362880 .
  22. Dandekar MP, Singru PS, Kokare DM, Subhedar NK . Cocaine- and amphetamine-regulated transcript peptide plays a role in the manifestation of depression: social isolation and olfactory bulbectomy models reveal unifying principles . Neuropsychopharmacology . 34 . 5 . 1288–300 . April 2009 . 19005467 . 10.1038/npp.2008.201. free .
  23. 22186082 . 10.1016/j.neuropharm.2011.12.004 . 62 . 4 . CART peptide in the nucleus accumbens shell acts downstream to dopamine and mediates the reward and reinforcement actions of morphine . March 2012 . Neuropharmacology . 1823–33 . Upadhya MA, Nakhate KT, Kokare DM, Singh U, Singru PS, Subhedar NK . 10500678 .
  24. Bharne AP, Borkar CD, Bodakuntla S, Lahiri M, Subhedar NK, Kokare DM . Pro-cognitive action of CART is mediated via ERK in the hippocampus . Hippocampus . 26 . 10 . 1313–27 . 2016 . 27258934 . 10.1002/hipo.22608 . 4876304 .
  25. Web site: Cocaine Studies Reveal New Medications For Addiction; How Brain Regulates Hunger . 27 October 1997 . ScienceDaily LLC . 11 February 2009.
  26. 21855138 . 10.1016/j.npep.2011.07.006 . 45 . 5 . CART peptide stimulation of G protein-mediated signaling in differentiated PC12 cells: identification of PACAP 6-38 as a CART receptor antagonist . October 2011 . Neuropeptides . 351–8 . Lin Y, Hall RA, Kuhar MJ . 3170513.
  27. Lakatos A, Prinster S, Vicentic A, Hall RA, Kuhar MJ . Cocaine- and amphetamine-regulated transcript (CART) peptide activates the extracellular signal-regulated kinase (ERK) pathway in AtT20 cells via putative G-protein coupled receptors . Neuroscience Letters . 384 . 1–2 . 198–202 . 2005 . 15908120 . 10.1016/j.neulet.2005.04.072 . 16175568 .
  28. Vicentic A, Lakatos A, Kuhar MJ . CART (cocaine- and amphetamine-regulated transcript) peptide receptors: specific binding in AtT20 cells . European Journal of Pharmacology . 528 . 1–3 . 188–9 . December 2005 . 16330022 . 10.1016/j.ejphar.2005.11.041 .
  29. Maletínská L, Maixnerová J, Matysková R, Haugvicová R, Sloncová E, Elbert T, Slaninová J, Zelezná B . Cocaine- and amphetamine-regulated transcript (CART) peptide specific binding in pheochromocytoma cells PC12 . European Journal of Pharmacology . 559 . 2–3 . 109–14 . March 2007 . 17292884 . 10.1016/j.ejphar.2006.12.014 .
  30. Yosten GL, Harada CM, Haddock C, Giancotti LA, Kolar GR, Patel R, Guo C, Chen Z, Zhang J, Doyle TM, Dickenson AH, Samson WK, Salvemini D . GPR160 de-orphanization reveals critical roles in neuropathic pain in rodents . The Journal of Clinical Investigation . 130 . 5 . 2587–2592 . May 2020 . 31999650 . 7190928 . 10.1172/JCI133270 .
  31. Freitas-Lima LC, Pačesová A, Staňurová J, Šácha P, Marek A, Hubálek M, Kuneš J, Železná B, Maletínská L . GPR160 is not a receptor of anorexigenic cocaine- and amphetamine-regulated transcript peptide . European Journal of Pharmacology . 949 . 175713 . June 2023 . 37054941 . 10.1016/j.ejphar.2023.175713 . free .
  32. Ye C, Zhou Q, Lin S, Yang W, Cai X, Mai Y, Chen Y, Yang D, Wang MW . High expression of GPR160 in prostate cancer is unrelated to CARTp-mediated signaling pathways . Acta Pharmaceutica Sinica. B . 14 . 3 . 1467–1471 . March 2024 . 38487007 . 10935005 . 10.1016/j.apsb.2023.11.025 .
  33. Bannon AW, Seda J, Carmouche M, Francis JM, Jarosinski MA, Douglass J . Multiple behavioral effects of cocaine- and amphetamine-regulated transcript (CART) peptides in mice: CART 42-89 and CART 49-89 differ in potency and activity . The Journal of Pharmacology and Experimental Therapeutics . 299 . 3 . 1021–6 . December 2001 . 11714891 .
  34. Dylag T, Kotlinska J, Rafalski P, Pachuta A, Silberring J . The activity of CART peptide fragments . Peptides . 27 . 8 . 1926–33 . August 2006 . 16730858 . 10.1016/j.peptides.2005.10.025 . 2659119 .
  35. Maixnerová J, Hlavácek J, Blokesová D, Kowalczyk W, Elbert T, Sanda M, Blechová M, Zelezná B, Slaninová J, Maletínská L . Structure-activity relationship of CART (cocaine- and amphetamine-regulated transcript) peptide fragments . Peptides . 28 . 10 . 1945–53 . October 2007 . 17766010 . 10.1016/j.peptides.2007.07.022 . 40284900 .

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