Cholecystokinin B receptor explained

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

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] One study shows that visual hallucinations in Parkinson's disease are associated with cholecystokinin −45C>T polymorphism, and this association is still observed in the presence of the cholecystokinin-A receptor TC/CC genotype, indicating a possible interaction of these two genes in the visual hallucinogenesis in Parkinson's disease.^[14]

Gastrointestinal Tract

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

Selective Ligands

The cholecystokinin B receptor responds to a number of ligands.

Agonists

• Cholecystokinin
• CCK-4
• Gastrin
• BBL-454

Antagonists

• Proglumide
• CI-988
• CI-1015
• L-365,260
• L-369,293
• YF476
• YM-022
• RP-69758
• LY-225,910
• LY-288,513
• PD-135,158
• PD-145,942

Inverse agonists

• L-740,093

See also

• Cholecystokinin receptor
• Cholecystokinin antagonist

Further reading

• Herget T, Sethi T, Wu SV, Walsh JH, Rozengurt E . Cholecystokinin stimulates Ca2+ mobilization and clonal growth in small cell lung cancer through CCKA and CCKB/gastrin receptors . Annals of the New York Academy of Sciences . 713 . 283–97 . Mar 1994 . 1 . 8185170 . 10.1111/j.1749-6632.1994.tb44076.x . 1994NYASA.713..283H . 30088015 .
• Lee YM, Beinborn M, McBride EW, Lu M, Kolakowski LF, Kopin AS . The human brain cholecystokinin-B/gastrin receptor. Cloning and characterization . The Journal of Biological Chemistry . 268 . 11 . 8164–9 . Apr 1993 . 10.1016/S0021-9258(18)53076-3 . 7681836 . free .
• Ito M, Iwata N, Taniguchi T, Murayama T, Chihara K, Matsui T . Functional characterization of two cholecystokinin-B/gastrin receptor isoforms: a preferential splice donor site in the human receptor gene . Cell Growth & Differentiation . 5 . 10 . 1127–35 . Oct 1994 . 7848914 .
• Miyake A . A truncated isoform of human CCK-B/gastrin receptor generated by alternative usage of a novel exon . Biochemical and Biophysical Research Communications . 208 . 1 . 230–7 . Mar 1995 . 7887934 . 10.1006/bbrc.1995.1328 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Zimonjic DB, Popescu NC, Matsui T, Ito M, Chihara K . Localization of the human cholecystokinin-B/gastrin receptor gene (CCKBR) to chromosome 11p15.5→p15.4 by fluorescence in situ hybridization . Cytogenetics and Cell Genetics . 65 . 3 . 184–5 . 1993 . 8222757 . 10.1159/000133628 .
• de Weerth A, Pisegna JR, Huppi K, Wank SA . Molecular cloning, functional expression and chromosomal localization of the human cholecystokinin type A receptor . Biochemical and Biophysical Research Communications . 194 . 2 . 811–8 . Jul 1993 . 8343165 . 10.1006/bbrc.1993.1894 .
• Ito M, Matsui T, Taniguchi T, Tsukamoto T, Murayama T, Arima N, Nakata H, Chiba T, Chihara K . Functional characterization of a human brain cholecystokinin-B receptor. A trophic effect of cholecystokinin and gastrin . The Journal of Biological Chemistry . 268 . 24 . 18300–5 . Aug 1993 . 10.1016/S0021-9258(17)46844-X . 8349705 . free . 20.500.14094/D1001304 . free .
• Song I, Brown DR, Wiltshire RN, Gantz I, Trent JM, Yamada T . The human gastrin/cholecystokinin type B receptor gene: alternative splice donor site in exon 4 generates two variant mRNAs . Proceedings of the National Academy of Sciences of the United States of America . 90 . 19 . 9085–9 . Oct 1993 . 8415658 . 47506 . 10.1073/pnas.90.19.9085 . 1993PNAS...90.9085S . free .
• Beinborn M, Lee YM, McBride EW, Quinn SM, Kopin AS . A single amino acid of the cholecystokinin-B/gastrin receptor determines specificity for non-peptide antagonists . Nature . 362 . 6418 . 348–50 . Mar 1993 . 8455720 . 10.1038/362348a0 . 1993Natur.362..348B . 4344412 .
• Silvente-Poirot S, Wank SA . 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 . The Journal of Biological Chemistry . 271 . 25 . 14698–706 . Jun 1996 . 8663021 . 10.1074/jbc.271.25.14698 . free .
• Tarasova NI, Wank SA, Hudson EA, Romanov VI, Czerwinski G, Resau JH, Michejda CJ . Endocytosis of gastrin in cancer cells expressing gastrin/CCK-B receptor . Cell and Tissue Research . 287 . 2 . 325–33 . Feb 1997 . 8995203 . 10.1007/s004410050757 . 25466418 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• O'Briant KC, Ali SY, Weier HU, Bepler G . 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 Research . 6 . 5 . 415–8 . Aug 1998 . 9872672 . 10.1023/A:1009289625352 . 28496235 .
• Monstein HJ, Nilsson I, Ellnebo-Svedlund K, Svensson SP . Cloning and characterization of 5'-end alternatively spliced human cholecystokinin-B receptor mRNAs . Receptors & Channels . 6 . 3 . 165–77 . 1999 . 10100325 .
• Daulhac L, Kowalski-Chauvel A, Pradayrol L, Vaysse N, Seva C . Src-family tyrosine kinases in activation of ERK-1 and p85/p110-phosphatidylinositol 3-kinase by G/CCKB receptors . The Journal of Biological Chemistry . 274 . 29 . 20657–63 . Jul 1999 . 10400698 . 10.1074/jbc.274.29.20657 . free .
• Silvente-Poirot S, Escrieut C, Galès C, Fehrentz JA, Escherich A, Wank SA, Martinez J, Moroder L, Maigret B, Bouisson M, Vaysse N, Fourmy D . 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 . The Journal of Biological Chemistry . 274 . 33 . 23191–7 . Aug 1999 . 10438490 . 10.1074/jbc.274.33.23191 . free .
• Kulaksiz H, Arnold R, Göke B, Maronde E, Meyer M, Fahrenholz F, Forssmann WG, Eissele R . Expression and cell-specific localization of the cholecystokinin B/gastrin receptor in the human stomach . Cell and Tissue Research . 299 . 2 . 289–98 . Feb 2000 . 10741470 . 10.1007/s004410050027 . 2024-03-26 .

Notes and References

1. Noble F, Roques BP . CCK-B receptor: chemistry, molecular biology, biochemistry and pharmacology . Progress in Neurobiology . 58 . 4 . 349–79 . Jul 1999 . 10368033 . 10.1016/S0301-0082(98)00090-2 . 24402373 .
2. Pisegna JR, de Weerth A, Huppi K, Wank SA . Molecular cloning of the human brain and gastric cholecystokinin receptor: structure, functional expression and chromosomal localization . Biochemical and Biophysical Research Communications . 189 . 1 . 296–303 . Nov 1992 . 1280419 . 6719700 . 10.1016/0006-291X(92)91557-7 .
3. Harikumar KG, Clain J, Pinon DI, Dong M, Miller LJ . Distinct molecular mechanisms for agonist peptide binding to types A and B cholecystokinin receptors demonstrated using fluorescence spectroscopy . The Journal of Biological Chemistry . 280 . 2 . 1044–50 . Jan 2005 . 15520004 . 10.1074/jbc.M409480200 . free .
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 . In vitro and in vivo evaluation of 111In-DTPAGlu-G-CCK8 for cholecystokinin-B receptor imaging . Journal of Nuclear Medicine . 45 . 3 . 485–94 . Mar 2004 . 15001692 .
5. Galés C, Poirot M, Taillefer J, Maigret B, Martinez J, Moroder L, Escrieut C, Pradayrol L, Fourmy D, Silvente-Poirot S . 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 . Molecular Pharmacology . 63 . 5 . 973–82 . May 2003 . 12695525 . 10.1124/mol.63.5.973 . 38395309 .
6. Web site: Entrez Gene: CCKBR cholecystokinin B receptor.
7. Altar CA, Boyar WC . Brain CCK-B receptors mediate the suppression of dopamine release by cholecystokinin . Brain Research . 483 . 2 . 321–6 . Apr 1989 . 2706523 . 10.1016/0006-8993(89)90176-5 . 7306848 .
8. Loonam TM, Noailles PA, Yu J, Zhu JP, Angulo JA . Substance P and cholecystokinin regulate neurochemical responses to cocaine and methamphetamine in the striatum . Life Sciences . 73 . 6 . 727–39 . Jun 2003 . 12801594 . 10.1016/S0024-3205(03)00393-X .
9. Lanza M, Makovec F . Cholecystokinin (CCK) increases GABA release in the rat anterior nucleus accumbens via CCK(B) receptors located on glutamatergic interneurons . Naunyn-Schmiedeberg's Archives of Pharmacology . 361 . 1 . 33–8 . Jan 2000 . 10651144 . 10.1007/s002109900161 . 25668780 .
10. Dourish CT, O'Neill MF, Coughlan J, Kitchener SJ, Hawley D, Iversen SD . The selective CCK-B receptor antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat . European Journal of Pharmacology . 176 . 1 . 35–44 . Jan 1990 . 2311658 . 10.1016/0014-2999(90)90129-T .
11. Higgins GA, Sills TL, Tomkins DM, Sellers EM, Vaccarino FJ . Evidence for the contribution of CCKB receptor mechanisms to individual differences in amphetamine-induced locomotion . Pharmacology Biochemistry and Behavior . 48 . 4 . 1019–24 . Aug 1994 . 7972279 . 10.1016/0091-3057(94)90214-3 . 30502684 .
12. Lu L, Huang M, Ma L, Li J . Different role of cholecystokinin (CCK)-A and CCK-B receptors in relapse to morphine dependence in rats . Behavioural Brain Research . 120 . 1 . 105–10 . Apr 2001 . 11173090 . 10.1016/S0166-4328(00)00361-2 . 23094648 .
13. Boyce S, Rupniak NM, Tye S, Steventon MJ, Iversen SD . Modulatory role for CCK-B antagonists in Parkinson's disease . Clinical Neuropharmacology . 13 . 4 . 339–47 . Aug 1990 . 1976438 . 10.1097/00002826-199008000-00009 .
14. Wang J, Si YM, Liu ZL, Yu L . Cholecystokinin, cholecystokinin-A receptor and cholecystokinin-B receptor gene polymorphisms in Parkinson's disease . Pharmacogenetics . 13 . 6 . 365–9 . Jun 2003 . 12777967 . 10.1097/00008571-200306000-00008 .