Cocaine and amphetamine regulated transcript

Last updated

CART prepropeptide
Identifiers
SymbolCARTPT
NCBI gene 9607
HGNC 24323
OMIM 602606
RefSeq NM_004291
UniProt Q16568
Other data
Locus Chr. 5 q13.2
Search for
Structures Swiss-model
Domains InterPro
CART
PDB 1hy9 EBI.jpg
cocaine- and amphetamine-regulated transcript
Identifiers
SymbolCART
Pfam PF06373
InterPro IPR009106
SCOP2 1hy9 / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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]

Contents

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 peculiar 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, [26] 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 GPCR160. [30]

Several fragments of CART have been tested to try and uncover the pharmacophore, [31] [32] 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. [33]

See also

Related Research Articles

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References

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  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. Bibcode:1998Natur.393...72K. doi:10.1038/29993. PMID   9590691. S2CID   4427258.
  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. S2CID   25134612.
  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. S2CID   7079530.
  5. ↑ Kimmel HL, Gong W, Vechia SD, Hunter RG, Kuhar MJ (August 2000). "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. PMID   10900261.
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  10. ↑ 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.
  11. ↑ 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. S2CID   11245593.
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  13. ↑ 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.
  14. ↑ 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. S2CID   27440114.
  15. ↑ 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.
  16. ↑ Kay JN, De la Huerta I, Kim IJ, Zhang Y, Yamagata M, Chu MW, et al. (May 2011). "Retinal ganglion cells with distinct directional preferences differ in molecular identity, structure, and central projections". The Journal of Neuroscience. 31 (21): 7753–62. doi:10.1523/JNEUROSCI.0907-11.2011. PMC   3108146 . PMID   21613488.
  17. ↑ 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.
  18. ↑ 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. S2CID   15989891.
  19. ↑ 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.
  20. ↑ Yu C, Zhou X, Fu Q, Peng Q, Oh KW, Hu Z (2017). "A New Insight into the Role of CART in Cocaine Reward: Involvement of CaMKII and Inhibitory G-Protein Coupled Receptor Signaling". Frontiers in Cellular Neuroscience . 11: 244. doi: 10.3389/fncel.2017.00244 . PMC   5559471 . PMID   28860971.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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. S2CID   10500678.
  24. ↑ Bharne AP, Borkar CD, Bodakuntla S, Lahiri M, Subhedar NK, Kokare DM (2016). "Pro-cognitive action of CART is mediated via ERK in the hippocampus". Hippocampus. 26 (10): 1313–27. doi:10.1002/hipo.22608. PMID   27258934. S2CID   4876304.
  25. ↑ "Cocaine Studies Reveal New Medications For Addiction; How Brain Regulates Hunger". ScienceDaily LLC. 27 October 1997. Retrieved 11 February 2009.
  26. 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.
  27. ↑ 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. S2CID   16175568.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ Yosten GL, Harada CM, Haddock C, Giancotti LA, Kolar GR, Patel R, et al. (May 2020). "GPR160 de-orphanization reveals critical roles in neuropathic pain in rodents". The Journal of Clinical Investigation. 130 (5): 2587–2592. doi:10.1172/JCI133270. PMC   7190928 . PMID   31999650.
  31. ↑ 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.
  32. ↑ 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. S2CID   2659119.
  33. ↑ 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. S2CID   40284900.
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