Cholecystokinin A receptor explained

Symbol:	CholecysA-Rec_N
Cholecystokinin A receptor, N-terminal domain
Pfam:	PF09193
Interpro:	IPR015276
Scop:	1d6g

The Cholecystokinin A receptor is a human protein, also known as CCKAR or CCK₁, with CCK₁ now being the IUPHAR-recommended name.

Function

This gene encodes a G-protein coupled receptor that binds sulfated members of the cholecystokinin (CCK) family of peptide hormones. This receptor is a major physiologic mediator of pancreatic enzyme secretion and smooth muscle contraction of the gallbladder and stomach. In the central and peripheral nervous system this receptor regulates satiety and the release of beta-endorphin and dopamine.^[1]

The extracellular, N-terminal, domain of this protein adopts a tertiary structure consisting of a few helical turns and a disulfide-cross linked loop. It is required for interaction of the cholecystokinin A receptor with its corresponding hormonal ligand.^[2]

Selective Ligands

Agonists

• Cholecystokinin
• CCK-4
• SR-146,131
• A-71623 - modified tetrapeptide, potent and selective CCK_A agonist, IC₅₀ 3.7nM, 1200x selectivity over CCK_B, CAS# 130408-77-4

Antagonists

• Proglumide
• Lorglumide
• Devazepide
• Dexloxiglumide
• Asperlicin
• SR-27897
• IQM-95333
• JNJ-17156516

See also

• Cholecystokinin receptor
• Cholecystokinin antagonist

External links

• Web site: Cholecystokinin Receptors: CCK₁ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-12-04 . 2012-10-23 . https://web.archive.org/web/20121023083930/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2247 . dead .

Further reading

• Varga G, Bálint A, Burghardt B, D'Amato M . Involvement of endogenous CCK and CCK1 receptors in colonic motor function . British Journal of Pharmacology . 141 . 8 . 1275–84 . Apr 2004 . 15100163 . 1574909 . 10.1038/sj.bjp.0705769 .
• 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 .
• Miller LJ, Holicky EL, Ulrich CD, Wieben ED . Abnormal processing of the human cholecystokinin receptor gene in association with gallstones and obesity . Gastroenterology . 109 . 4 . 1375–80 . Oct 1995 . 7557108 . 10.1016/0016-5085(95)90601-0 .
• Huppi K, Siwarski D, Pisegna JR, Wank S . Chromosomal localization of the gastric and brain receptors for cholecystokinin (CCKAR and CCKBR) in human and mouse . Genomics . 25 . 3 . 727–9 . Feb 1995 . 7759110 . 6736545 . 10.1016/0888-7543(95)80018-H .
• 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 .
• Ulrich CD, Ferber I, Holicky E, Hadac E, Buell G, Miller LJ . Molecular cloning and functional expression of the human gallbladder cholecystokinin A receptor . Biochemical and Biophysical Research Communications . 193 . 1 . 204–11 . May 1993 . 8503909 . 10.1006/bbrc.1993.1610 .
• Kennedy K, Gigoux V, Escrieut C, Maigret B, Martinez J, Moroder L, Fréhel D, Gully D, Vaysse N, Fourmy D . Identification of two amino acids of the human cholecystokinin-A receptor that interact with the N-terminal moiety of cholecystokinin . The Journal of Biological Chemistry . 272 . 5 . 2920–6 . Jan 1997 . 9006937 . 10.1074/jbc.272.5.2920 . free .
• Inoue H, Iannotti CA, Welling CM, Veile R, Donis-Keller H, Permutt MA . Human cholecystokinin type A receptor gene: cytogenetic localization, physical mapping, and identification of two missense variants in patients with obesity and non-insulin-dependent diabetes mellitus (NIDDM) . Genomics . 42 . 2 . 331–5 . Jun 1997 . 9192855 . 10.1006/geno.1997.4749 .
• Gigoux V, Escrieut C, Silvente-Poirot S, Maigret B, Gouilleux L, Fehrentz JA, Gully D, Moroder L, Vaysse N, Fourmy D . Met-195 of the cholecystokinin-A receptor interacts with the sulfated tyrosine of cholecystokinin and is crucial for receptor transition to high affinity state . The Journal of Biological Chemistry . 273 . 23 . 14380–6 . Jun 1998 . 9603948 . 10.1074/jbc.273.23.14380 . free .
• Funakoshi A, Fukamizu Y, Miyasaka K . Mechanism of cholecystokinin-A- receptor antagonist on human pancreatic exocrine secretion. Localization of CCK-A receptor in the human duodenum . Digestion . 60 . 75–80 . 2000 . Suppl 1 . 10026437 . 10.1159/000051459 . 41117645 .
• Gigoux V, Escrieut C, Fehrentz JA, Poirot S, Maigret B, Moroder L, Gully D, Martinez J, Vaysse N, Fourmy D . Arginine 336 and asparagine 333 of the human cholecystokinin-A receptor binding site interact with the penultimate aspartic acid and the C-terminal amide of cholecystokinin . The Journal of Biological Chemistry . 274 . 29 . 20457–64 . Jul 1999 . 10400673 . 10.1074/jbc.274.29.20457 . free .
• Gigoux V, Maigret B, Escrieut C, Silvente-Poirot S, Bouisson M, Fehrentz JA, Moroder L, Gully D, Martinez J, Vaysse N, Fourmy AD . Arginine 197 of the cholecystokinin-A receptor binding site interacts with the sulfate of the peptide agonist cholecystokinin . Protein Science . 8 . 11 . 2347–54 . Nov 1999 . 10595537 . 2144185 . 10.1110/ps.8.11.2347 .
• Funakoshi A, Miyasaka K, Matsumoto H, Yamamori S, Takiguchi S, Kataoka K, Takata Y, Matsusue K, Kono A, Shimokata H . Gene structure of human cholecystokinin (CCK) type-A receptor: body fat content is related to CCK type-A receptor gene promoter polymorphism . FEBS Letters . 466 . 2–3 . 264–6 . Jan 2000 . 10682840 . 10.1016/S0014-5793(00)01080-2 . 11683500 . free .
• Tachikawa H, Harada S, Kawanishi Y, Okubo T, Shiraishi H . Novel polymorphisms of the human cholecystokinin A receptor gene: an association analysis with schizophrenia . American Journal of Medical Genetics . 96 . 2 . 141–5 . Apr 2000 . 10893485 . 10.1002/(SICI)1096-8628(20000403)96:2<141::AID-AJMG3>3.0.CO;2-R .
• Giragossian C, Mierke DF . Intermolecular interactions between cholecystokinin-8 and the third extracellular loop of the cholecystokinin A receptor . Biochemistry . 40 . 13 . 3804–9 . Apr 2001 . 11300760 . 10.1021/bi002659n .
• Schmitz F, Schrader H, Otte J, Schmitz H, Stüber E, Herzig K, Schmidt WE . Identification of CCK-B/gastrin receptor splice variants in human peripheral blood mononuclear cells . Regulatory Peptides . 101 . 1–3 . 25–33 . Sep 2001 . 11495676 . 10.1016/S0167-0115(01)00281-6 . 22693627 .
• Tachikawa H, Harada S, Kawanishi Y, Okubo T, Suzuki T . Linked polymorphisms (-333G>T and -286A>G) in the promoter region of the CCK-A receptor gene may be associated with schizophrenia . Psychiatry Research . 103 . 2–3 . 147–55 . Sep 2001 . 11549403 . 10.1016/S0165-1781(01)00276-1 . 24442175 .
• Schmitz F, Göke MN, Otte JM, Schrader H, Reimann B, Kruse ML, Siegel EG, Peters J, Herzig KH, Fölsch UR, Schmidt WE . Cellular expression of CCK-A and CCK-B/gastrin receptors in human gastric mucosa . Regulatory Peptides . 102 . 2–3 . 101–10 . Dec 2001 . 11730982 . 10.1016/S0167-0115(01)00307-X . 42131386 .
• Okubo T, Harada S, Higuchi S, Matsushita S . Investigation of quantitative trait loci in the CCKAR gene with susceptibility to alcoholism . Alcoholism: Clinical and Experimental Research . 26 . 8 Suppl . 2S–5S . Aug 2002 . 12198366 . 10.1111/j.1530-0277.2002.tb02693.x .
• Takata Y, Takeda S, Kawanami T, Takiguchi S, Yoshida Y, Miyasaka K, Funakoshi A . Promoter analysis of human cholecystokinin type-A receptor gene . Journal of Gastroenterology . 37 . 10 . 815–20 . 2003 . 12424565 . 10.1007/s005350200135 . 35526543 .

Notes and References

1. Web site: Entrez Gene: CCKAR cholecystokinin A receptor.
2. Pellegrini M, Mierke DF . Molecular complex of cholecystokinin-8 and N-terminus of the cholecystokinin A receptor by NMR spectroscopy . Biochemistry . 38 . 45 . 14775–83 . Nov 1999 . 10555959 . 10.1021/bi991272l .