Cocaine and amphetamine regulated transcript

CART prepropeptide
Identifiers
Symbol CARTPT
Entrez 9607
HUGO 24323
OMIM 602606
RefSeq NM_004291
UniProt Q16568
Other data
Locus Chr. 5 q13.2
CART

cocaine- and amphetamine-regulated transcript
Identifiers
Symbol CART
Pfam PF06373
InterPro IPR009106
SCOP 1hy9
SUPERFAMILY 1hy9

Cocaine- and amphetamine-regulated transcript, also known as CART, is a 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 behaviour in animals to 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 is injected into rat VTA, increased locomotor activity is seen, which is one of the signs of "central stimulation" caused by substances such as cocaine and amphetamine. The rats also tended to return to the place where they had been injected. This is called conditioned place preference and is 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,[5] cholecystokinin and ghrelin,[6] with CART and cholecystokinin having synergistic effects on appetite regulation.[7]

CART is released in response to repeated dopamine release in the nucleus accumbens, and may regulate the activity of neurons in this area.[8] CART production is upregulated by CREB,[9] 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.[10][11][12]

Tissue distribution

CART is an anorectic peptide and is widely expressed in both the central and peripheral nervous systems, particularly concentrated in the hypothalamus.[13] CART is outside of the nervous system also expressed in pituitary endocrine cells, adrenomedullary cells, islet somatostatin cells, and in rat antral gastrin cells.[14] Other structures and pathways associated with CART expression include the mesolimbic pathway (linking the ventral tegmental area to the nucleus accumbens) and amygdala.

Clinical significance

Studies of CART (54–102) action in rat lateral ventricle and amygdala suggest that CART play a role in anxiety-like behavior, induced by ethanol withdrawal in rats.[15] Studies on CART knock-out mice indicates that CART modulates the locomotor, conditioned place preference and cocaine self-administration effect of psychostimulants. This suggests a positive neuromodulatory action of CART on psychostimulants effect on rat.[16] CART is altered in the ventral tegmental area of cocaine overdose victims, and a mutation in the CART gene associates with alcoholism.[17] CART peptides are inhibitors of food intake (anorexigenic) 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.[18][19] CART peptides are also involved in fear and startle behavior.[20] CART is thought to play a key role in the opioid mesolimbic dopamine circuit that modulates natural reward processes.[21]

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 anorexigenic substance. CART inhibited rat food intake by as much as 30 percent. When naturally-occurring CART peptides were blocked by means of injecting antibodies to CART, feeding increased. This led to suggestions CART may play a role - though not being the only peptide - in satiety. In the end of the 1980s, researchers started to synthesize cocaine-like and CART-like-acting substances in order to find medications that could affect eating disorders as well as cocaine abuse. These cocaine-like substances are called phenyltropanes.[22]

CART Receptor

The putative receptor target for CART has not yet been identified as of 2011,[23] however in vitro studies strongly suggest that CART binds to a specific G protein-coupled receptor coupled to Gi/Go, resulting in increased ERK release inside the cell.[23][24][25][26]

Several fragments of CART have been tested to try and uncover the pharmacophore,[27][28] 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.[29]

See also

References

  1. ↑ Douglass J, Daoud S (March 1996). "Characterization of the human cDNA and genomic DNA encoding CART: a cocaine- and amphetamine-regulated transcript". Gene 169 (2): 241–5. doi:10.1016/0378-1119(96)88651-3. PMID 8647455.
  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 (May 1998). "Hypothalamic CART is a new anorectic peptide regulated by leptin". Nature 393 (6680): 72–6. doi:10.1038/29993. PMID 9590691.
  3. ↑ Zhang M, Han L, Xu Y (November 2011). "Roles of cocaine- and amphetamine-regulated transcript in the central nervous system". Clin. Exp. Pharmacol. Physiol. 39 (6): 586–92. doi:10.1111/j.1440-1681.2011.05642.x. PMID 22077697.
  4. ↑ Kuhar MJ, Adams S, Dominguez G, Jaworski J, Balkan B (February 2002). "CART peptides". Neuropeptides 36 (1): 1–8. doi:10.1054/npep.2002.0887. PMID 12147208.
  5. ↑ Murphy KG (July 2005). "Dissecting the role of cocaine- and amphetamine-regulated transcript (CART) in the control of appetite". Brief Funct Genomic Proteomic 4 (2): 95–111. doi:10.1093/bfgp/4.2.95. PMID 16102267.
  6. ↑ de Lartigue G, Dimaline R, Varro A, Dockray GJ (March 2007). "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. doi:10.1523/JNEUROSCI.5508-06.2007. PMID 17360909.
  7. ↑ Maletínská L, Maixnerová J, Matysková R, Haugvicová R, Pirník Z, Kiss A, Zelezná B (2008). "Synergistic effect of CART (cocaine- and amphetamine-regulated transcript) peptide and cholecystokinin on food intake regulation in lean mice". BMC Neuroscience 9: 101. doi:10.1186/1471-2202-9-101. PMC 2587474. PMID 18939974.
  8. ↑ Hubert GW, Jones DC, Moffett MC, Rogge G, Kuhar MJ (January 2008). "CART peptides as modulators of dopamine and psychostimulants and interactions with the mesolimbic dopaminergic system". Biochemical Pharmacology 75 (1): 57–62. doi:10.1016/j.bcp.2007.07.028. PMC 3804336. PMID 17854774.
  9. ↑ Rogge GA, Jones DC, Green T, Nestler E, Kuhar MJ (January 2009). "Regulation of CART peptide expression by CREB in the rat nucleus accumbens in vivo". Brain Research 1251: 42–52. doi:10.1016/j.brainres.2008.11.011. PMC 2734444. PMID 19046951.
  10. ↑ Fagergren P, Hurd Y (September 2007). "CART mRNA expression in rat monkey and human brain: relevance to cocaine abuse". Physiology & Behavior 92 (1–2): 218–25. doi:10.1016/j.physbeh.2007.05.027. PMID 17631364.
  11. ↑ Vicentic A, Jones DC (February 2007). "The CART (cocaine- and amphetamine-regulated transcript) system in appetite and drug addiction". The Journal of Pharmacology and Experimental Therapeutics 320 (2): 499–506. doi:10.1124/jpet.105.091512. PMID 16840648.
  12. ↑ Rogge G, Jones D, Hubert GW, Lin Y, Kuhar MJ (October 2008). "CART peptides: regulators of body weight, reward and other functions". Nature Reviews. Neuroscience 9 (10): 747–58. doi:10.1038/nrn2493. PMC 4418456. PMID 18802445.
  13. ↑ Keller PA, Compan V, Bockaert J, Giacobino JP, Charnay Y, Bouras C, Assimacopoulos-Jeannet F (June 2006). "Characterization and localization of cocaine- and amphetamine-regulated transcript (CART) binding sites". Peptides 27 (6): 1328–34. doi:10.1016/j.peptides.2005.10.016. PMID 16309793.
  14. ↑ Wierup N, Kuhar M, Nilsson BO, Mulder H, Ekblad E, Sundler F (February 2004). "Cocaine- and amphetamine-regulated transcript (CART) is expressed in several islet cell types during rat development". J. Histochem. Cytochem. 52 (2): 169–77. doi:10.1177/002215540405200204. PMID 14729868.
  15. ↑ Dandekar MP, Singru PS, Kokare DM, Lechan RM, Thim L, Clausen JT, Subhedar NK (April 2008). "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. doi:10.1038/sj.npp.1301516. PMID 17637604.
  16. ↑ Couceyro PR, Evans C, McKinzie A, Mitchell D, Dube M, Hagshenas L, White FJ, Douglass J, Richards WG, Bannon AW (December 2005). "Cocaine- and amphetamine-regulated transcript (CART) peptides modulate the locomotor and motivational properties of psychostimulants". J. Pharmacol. Exp. Ther. 315 (3): 1091–100. doi:10.1124/jpet.105.091678. PMID 16099925.
  17. ↑ Kuhar MJ, Jaworski JN, Hubert GW, Philpot KB, Dominguez G (2005). "Cocaine- and amphetamine-regulated transcript peptides play a role in drug abuse and are potential therapeutic targets". AAPS J 7 (1): E259–65. doi:10.1208/aapsj070125. PMC 2751515. PMID 16146347.
  18. ↑ Nakhate KT, Kokare DM, Singru PS, Subhedar NK (June 2011). "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. doi:10.1038/ijo.2010.231. PMID 21060312.
  19. ↑ Dandekar MP, Singru PS, Kokare DM, Subhedar NK (April 2009). "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. doi:10.1038/npp.2008.201. PMID 19005467.
  20. ↑ "CART (Cocaine- and Amphetamine-Regulated Transcript) Peptides". anaspec.com. Retrieved 10 February 2009.
  21. ↑ Upadhya MA, Nakhate KT, Kokare DM, Singh U, Singru PS, Subhedar NK (March 2012). "CART peptide in the nucleus accumbens shell acts downstream to dopamine and mediates the reward and reinforcement actions of morphine". Neuropharmacology 62 (4): 1823–33. doi:10.1016/j.neuropharm.2011.12.004. PMID 22186082.
  22. ↑ "Cocaine Studies Reveal New Medications For Addiction; How Brain Regulates Hunger". ScienceDaily LLC. 27 October 1997. Retrieved 11 February 2009.
  23. 1 2 Lin Y, Hall RA, Kuhar MJ (October 2011). "CART peptide stimulation of G protein-mediated signaling in differentiated PC12 cells: identification of PACAP 6-38 as a CART receptor antagonist". Neuropeptides 45 (5): 351–8. doi:10.1016/j.npep.2011.07.006. PMC 3170513. PMID 21855138.
  24. ↑ Lakatos A, Prinster S, Vicentic A, Hall RA, Kuhar MJ (2005). "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. doi:10.1016/j.neulet.2005.04.072. PMID 15908120.
  25. ↑ Vicentic A, Lakatos A, Kuhar MJ (December 2005). "CART (cocaine- and amphetamine-regulated transcript) peptide receptors: specific binding in AtT20 cells". European Journal of Pharmacology 528 (1–3): 188–9. doi:10.1016/j.ejphar.2005.11.041. PMID 16330022.
  26. ↑ Maletínská L, Maixnerová J, Matysková R, Haugvicová R, Sloncová E, Elbert T, Slaninová J, Zelezná B (March 2007). "Cocaine- and amphetamine-regulated transcript (CART) peptide specific binding in pheochromocytoma cells PC12". European Journal of Pharmacology 559 (2–3): 109–14. doi:10.1016/j.ejphar.2006.12.014. PMID 17292884.
  27. ↑ Bannon AW, Seda J, Carmouche M, Francis JM, Jarosinski MA, Douglass J (December 2001). "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. PMID 11714891.
  28. ↑ Dylag T, Kotlinska J, Rafalski P, Pachuta A, Silberring J (August 2006). "The activity of CART peptide fragments". Peptides 27 (8): 1926–33. doi:10.1016/j.peptides.2005.10.025. PMID 16730858.
  29. ↑ Maixnerová J, Hlavácek J, Blokesová D, Kowalczyk W, Elbert T, Sanda M, Blechová M, Zelezná B, Slaninová J, Maletínská L (October 2007). "Structure-activity relationship of CART (cocaine- and amphetamine-regulated transcript) peptide fragments". Peptides 28 (10): 1945–53. doi:10.1016/j.peptides.2007.07.022. PMID 17766010.

External links

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