Cholecystokinin B receptor

Cholecystokinin B receptor
NMR structure of the third extracellular loop of the human CCK-B receptor. PDB rendering based on 1l4t.
Available structures PDB 1l4t
Identifiers
Symbols	CCKBR; CCK-B; CCK2R; GASR
External IDs	OMIM: 118445 MGI: 99479 HomoloGene: 7258 IUPHAR: CCK2 GeneCards: CCKBR Gene
Gene Ontology Molecular function • phosphatidylinositol phospholipase C activity • receptor activity • G-protein coupled receptor activity • cholecystokinin receptor activity • protein binding • gastrin receptor activity • type B gastrin/cholecystokinin receptor binding • 1-phosphatidylinositol-3-kinase regulator activity Cellular component • membrane fraction • nucleus • cytoplasm • plasma membrane • plasma membrane • integral to plasma membrane Biological process • histamine secretion • behavioral defense response • apoptosis • cell surface receptor linked signaling pathway • activation of phospholipase C activity by G-protein coupled receptor protein signaling pathway coupled to IP3 second messenger • elevation of cytosolic calcium ion concentration • digestion • sensory perception • feeding behavior • cell proliferation • positive regulation of cell proliferation • positive regulation of synaptic transmission, GABAergic • response to insulin stimulus • regulation of sensory perception of pain • positive regulation of synaptic transmission, glutamatergic • estrous cycle phase • ERK1 and ERK2 cascade • positive regulation of somatostatin secretion Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	887	12426
Ensembl	ENSG00000110148	ENSMUSG00000030898
UniProt	P32239	Q3ZB46
RefSeq (mRNA)	NM_176875.2	NM_007627.4
RefSeq (protein)	NP_795344.1	NP_031653.1
Location (UCSC)	Chr 11: 6.28 – 6.29 Mb	Chr 7: 112.57 – 112.62 Mb
PubMed search	[1]	[2]

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]

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
• YF-476
• 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

References

1. ^ Noble F, Roques BP (July 1999). "CCK-B receptor: chemistry, molecular biology, biochemistry and pharmacology". Prog. Neurobiol. 58 (4): 349–79. doi:10.1016/S0301-0082(98)00090-2. PMID 10368033. 
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. doi:10.1016/0006-291X(92)91557-7. PMID 1280419. 
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. doi:10.1074/jbc.M409480200. PMID 15520004. 
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. PMID 15001692. 
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. doi:10.1124/mol.63.5.973. PMID 12695525. 
6. ^ "Entrez Gene: CCKBR cholecystokinin B receptor". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=887. 
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. doi:10.1016/0006-8993(89)90176-5. PMID 2706523. 
8. ^ ^{a b} 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. doi:10.1016/S0024-3205(03)00393-X. PMID 12801594. 
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. doi:10.1007/s002109900161. PMID 10651144. 
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. doi:10.1016/0014-2999(90)90129-T. PMID 2311658. 
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. doi:10.1016/0091-3057(94)90214-3. PMID 7972279. 
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. doi:10.1016/S0166-4328(00)00361-2. PMID 11173090. 
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. doi:10.1097/00002826-199008000-00009. PMID 1976438. http://journals.lww.com/clinicalneuropharm/Abstract/1990/08000/Modulatory_Role_for_CCK_B_Antagonists_in.9.aspx. 

Further reading

• Herget T, Sethi T, Wu SV et al. (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. doi:10.1111/j.1749-6632.1994.tb44076.x. PMID 8185170. 
• Lee YM, Beinborn M, McBride EW et al. (1993). "The human brain cholecystokinin-B/gastrin receptor. Cloning and characterization". J. Biol. Chem. 268 (11): 8164–9. PMID 7681836. 
• Ito M, Iwata N, Taniguchi T et al. (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. PMID 7848914. 
• 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. doi:10.1006/bbrc.1995.1328. PMID 7887934. 
• 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. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
• Zimonjic DB, Popescu NC, Matsui T et al. (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. doi:10.1159/000133628. PMID 8222757. 
• 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. doi:10.1006/bbrc.1993.1894. PMID 8343165. 
• Ito M, Matsui T, Taniguchi T et al. (1993). "Functional characterization of a human brain cholecystokinin-B receptor. A trophic effect of cholecystokinin and gastrin". J. Biol. Chem. 268 (24): 18300–5. PMID 8349705. 
• Song I, Brown DR, Wiltshire RN et al. (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. doi:10.1073/pnas.90.19.9085. PMC 47506. PMID 8415658. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=47506. 
• Beinborn M, Lee YM, McBride EW et al. (1993). "A single amino acid of the cholecystokinin-B/gastrin receptor determines specificity for non-peptide antagonists". Nature 362 (6418): 348–50. doi:10.1038/362348a0. PMID 8455720. 
• 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. doi:10.1074/jbc.271.25.14698. PMID 8663021. 
• Tarasova NI, Wank SA, Hudson EA et al. (1997). "Endocytosis of gastrin in cancer cells expressing gastrin/CCK-B receptor". Cell Tissue Res. 287 (2): 325–33. doi:10.1007/s004410050757. PMID 8995203. 
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
• 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. doi:10.1023/A:1009289625352. PMID 9872672. 
• 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. PMID 10100325. 
• Daulhac L, Kowalski-Chauvel A, Pradayrol L et al. (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. doi:10.1074/jbc.274.29.20657. PMID 10400698. 
• Silvente-Poirot S, Escrieut C, Galès C et al. (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. doi:10.1074/jbc.274.33.23191. PMID 10438490. 
• Kulaksiz H, Arnold R, Göke B et al. (2000). "Expression and cell-specific localization of the cholecystokinin B/gastrin receptor in the human stomach". Cell Tissue Res. 299 (2): 289–98. doi:10.1007/s004410050027. PMID 10741470. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.