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The cholecystokinin B receptor also known as CCKBR or CCK2 is a protein[1] that in humans is encoded by the CCKBR gene.[2]

This gene encodes a G protein-coupled receptor for gastrin and cholecystokinin (CCK),[3][4][5] regulatory peptides of the brain and gastrointestinal tract. This protein is a type B gastrin receptor, which has a high affinity for both sulfated and nonsulfated CCK analogs and is found principally in the central nervous system and the gastrointestinal tract. A misspliced transcript variant including an intron has been observed in cells from colorectal and pancreatic tumors.[6]

CNS effects[edit | edit source]

CCK receptors significantly influence neurotransmission in the brain, regulating anxiety, feeding, and locomotion. CCK-B expression may correlate parallel to anxiety and depression phenotypes in humans. CCK-B receptors possess a complex regulation of dopamine activity in the brain. CCK-B activation appears to possess a general inhibitory action on dopamine activity in the brain, opposing the dopamine-enhancing effects of CCK-A. However, the effects of CCK-B on dopamine activity vary depending on location.[7] CCK-B antagonism enhances dopamine release in rat striatum.[8] Activation enhances GABA release in rat anterior nucleus accumbens.[9] CCK-B receptors modulate dopamine release, and influence the development of tolerance to opioids.[10] CCK-B activation decreases amphetamine-induced DA release, and contributes to individual variability in response to amphetamine.[11]

In rats, CCK-B antagonism prevents the stress-induced reactivation of cocaine-induced conditioned place preference, and prevents the long-term maintenance and reinstatement of morphine-induced CPP.[12] Blockade of CCK-B potentiates cocaine-induced dopamine overflow in rat striatum.[8] CCK-B may pose a modulatory role in parkinson's disease. Blockade of CCK-B in dopamine-depleted squirrel monkeys induces significant enhancement of locomotor response to L-DOPA.[13]

Gastrointestinal Tract[edit | edit source]

The cholecystokinin B receptor is stimulated by CCK and Gastrin in the stomach during digestion.

Selective Ligands[edit | edit source]

The cholecystokinin B receptor responds to a number of ligands.

Agonists[edit | edit source]

Antagonists[edit | edit source]

  • Proglumide
  • CI-988
  • CI-1015
  • L-365,260
  • L-369,293
  • YF-476
  • YM-022
  • RP-69758
  • LY-225,910
  • LY-288,513
  • PD-135,158
  • PD-145,942

Inverse agonists[edit | edit source]

  • L-740,093

See also[edit | edit source]

References[edit | edit source]

  1. Noble F, Roques BP (July 1999). CCK-B receptor: chemistry, molecular biology, biochemistry and pharmacology. Prog. Neurobiol. 58 (4): 349–79.
  2. Pisegna JR, de Weerth A, Huppi K, Wank SA (November 1992). Molecular cloning of the human brain and gastric cholecystokinin receptor: structure, functional expression and chromosomal localization. Biochem. Biophys. Res. Commun. 189 (1): 296–303.
  3. Harikumar KG, Clain J, Pinon DI, Dong M, Miller LJ (January 2005). Distinct molecular mechanisms for agonist peptide binding to types A and B cholecystokinin receptors demonstrated using fluorescence spectroscopy. J. Biol. Chem. 280 (2): 1044–50.
  4. Aloj L, Caracò C, Panico M, Zannetti A, Del Vecchio S, Tesauro D, De Luca S, Arra C, Pedone C, Morelli G, Salvatore M (March 2004). In vitro and in vivo evaluation of 111In-DTPAGlu-G-CCK8 for cholecystokinin-B receptor imaging. J. Nucl. Med. 45 (3): 485–94.
  5. Galés C, Poirot M, Taillefer J, Maigret B, Martinez J, Moroder L, Escrieut C, Pradayrol L, Fourmy D, Silvente-Poirot S (May 2003). Identification of tyrosine 189 and asparagine 358 of the cholecystokinin 2 receptor in direct interaction with the crucial C-terminal amide of cholecystokinin by molecular modeling, site-directed mutagenesis, and structure/affinity studies. Mol. Pharmacol. 63 (5): 973–82.
  6. Entrez Gene: CCKBR cholecystokinin B receptor.
  7. Altar CA, Boyar WC (April 1989). Brain CCK-B receptors mediate the suppression of dopamine release by cholecystokinin. Brain Res. 483 (2): 321–6.
  8. 8.0 8.1 Loonam TM, Noailles PA, Yu J, Zhu JP, Angulo JA (June 2003). Substance P and cholecystokinin regulate neurochemical responses to cocaine and methamphetamine in the striatum. Life Sci. 73 (6): 727–39.
  9. Lanza M, Makovec F (January 2000). Cholecystokinin (CCK) increases GABA release in the rat anterior nucleus accumbens via CCK(B) receptors located on glutamatergic interneurons. Naunyn Schmiedebergs Arch. Pharmacol. 361 (1): 33–8.
  10. Dourish CT, O'Neill MF, Coughlan J, Kitchener SJ, Hawley D, Iversen SD (January 1990). The selective CCK-B receptor antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat. Eur. J. Pharmacol. 176 (1): 35–44.
  11. Higgins GA, Sills TL, Tomkins DM, Sellers EM, Vaccarino FJ (August 1994). Evidence for the contribution of CCKB receptor mechanisms to individual differences in amphetamine-induced locomotion. Pharmacol. Biochem. Behav. 48 (4): 1019–24.
  12. Lu L, Huang M, Ma L, Li J (April 2001). Different role of cholecystokinin (CCK)-A and CCK-B receptors in relapse to morphine dependence in rats. Behav. Brain Res. 120 (1): 105–10.
  13. Boyce S, Rupniak NM, Tye S, Steventon MJ, Iversen SD (August 1990). Modulatory role for CCK-B antagonists in Parkinson's disease. Clin Neuropharmacol 13 (4): 339–47.

Further reading[edit | edit source]

  • Herget T (1994). Cholecystokinin stimulates Ca2+ mobilization and clonal growth in small cell lung cancer through CCKA and CCKB/gastrin receptors. Ann. N. Y. Acad. Sci. 713: 283–97.
  • Lee YM (1993). The human brain cholecystokinin-B/gastrin receptor. Cloning and characterization. J. Biol. Chem. 268 (11): 8164–9.
  • Ito M (1995). Functional characterization of two cholecystokinin-B/gastrin receptor isoforms: a preferential splice donor site in the human receptor gene. Cell Growth Differ. 5 (10): 1127–35.
  • Miyake A (1995). A truncated isoform of human CCK-B/gastrin receptor generated by alternative usage of a novel exon. Biochem. Biophys. Res. Commun. 208 (1): 230–7.
  • Maruyama K, Sugano S (1994). Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 138 (1–2): 171–4.
  • Zimonjic DB (1993). Localization of the human cholecystokinin-B/gastrin receptor gene (CCKBR) to chromosome 11p15.5→p15.4 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 65 (3): 184–5.
  • de Weerth A, Pisegna JR, Huppi K, Wank SA (1993). Molecular cloning, functional expression and chromosomal localization of the human cholecystokinin type A receptor. Biochem. Biophys. Res. Commun. 194 (2): 811–8.
  • Ito M (1993). Functional characterization of a human brain cholecystokinin-B receptor. A trophic effect of cholecystokinin and gastrin. J. Biol. Chem. 268 (24): 18300–5.
  • Song I (1993). The human gastrin/cholecystokinin type B receptor gene: alternative splice donor site in exon 4 generates two variant mRNAs. Proc. Natl. Acad. Sci. U.S.A. 90 (19): 9085–9.
  • Beinborn M (1993). A single amino acid of the cholecystokinin-B/gastrin receptor determines specificity for non-peptide antagonists. Nature 362 (6418): 348–50.
  • Silvente-Poirot S, Wank SA (1996). A segment of five amino acids in the second extracellular loop of the cholecystokinin-B receptor is essential for selectivity of the peptide agonist gastrin. J. Biol. Chem. 271 (25): 14698–706.
  • Tarasova NI (1997). Endocytosis of gastrin in cancer cells expressing gastrin/CCK-B receptor. Cell Tissue Res. 287 (2): 325–33.
  • Suzuki Y (1997). Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. Gene 200 (1–2): 149–56.
  • O'Briant KC, Ali SY, Weier HU, Bepler G (1999). An 84-kilobase physical map and repeat polymorphisms of the gastrin/cholecystokinin brain receptor region at the junction of chromosome segments 11p15.4 and 15.5. Chromosome Res. 6 (5): 415–8.
  • Monstein HJ, Nilsson I, Ellnebo-Svedlund K, Svensson SP (1999). Cloning and characterization of 5'-end alternatively spliced human cholecystokinin-B receptor mRNAs. Recept. Channels 6 (3): 165–77.
  • Daulhac L (1999). Src-family tyrosine kinases in activation of ERK-1 and p85/p110-phosphatidylinositol 3-kinase by G/CCKB receptors. J. Biol. Chem. 274 (29): 20657–63.
  • Silvente-Poirot S (1999). Evidence for a direct interaction between the penultimate aspartic acid of cholecystokinin and histidine 207, located in the second extracellular loop of the cholecystokinin B receptor. J. Biol. Chem. 274 (33): 23191–7.
  • Kulaksiz H (2000). Expression and cell-specific localization of the cholecystokinin B/gastrin receptor in the human stomach. Cell Tissue Res. 299 (2): 289–98.

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