HGNC Approved Gene Symbol: CCKAR
Cytogenetic location: 4p15.2 Genomic coordinates (GRCh38): 4:26,481,396-26,490,484 (from NCBI)
Ulrich et al. (1993) used a combination of hybridization screening of a cDNA library and PCR to clone a 2.1-kb cDNA that encodes the human gallbladder CCK receptor type A (CCKAR). Nucleotide sequence analysis revealed an open reading frame encoding a 428-amino acid protein, with 7 putative transmembrane domains and a high degree of homology with the cholecystokinin A receptor protein of rat and guinea pig.
By PCR testing of DNAs from a panel of human/hamster somatic cell hybrids, de Weerth et al. (1993) assigned the CCKAR gene to chromosome 4. Samuelson et al. (1995) mapped the murine homolog, Cckar, to mouse chromosome 5. Huppi et al. (1995) likewise mapped the CCKAR gene to human chromosome 4 and mouse chromosome 5. The human assignment was made by PCR analysis of human/hamster hybrid DNAs; the mouse gene was mapped by interspecific backcrosses. The region of mouse chromosome 5 shows conserved synteny with human 4p16.2-p15.1, suggesting that as the location of the CCKAR gene. By fluorescence in situ hybridization, Inoue et al. (1997) mapped the CCKAR gene to 4p15.2-p15.1.
The cholecystokinin (CCK) family of peptide hormones (see 118440) have been implicated in numerous important physiologic events. These appear to be mediated through 2 general classes of receptors, A and B, based on their binding affinities for CCK/gastrin family peptides. Boden et al. (1995) compared the biologic and molecular properties of CCKA and CCKB (118445) receptors. Ulrich et al. (1993) noted that, through binding to class A receptors, CCK is a major physiologic mediator of gallbladder contraction and pancreatic enzyme secretion. It appears to play a role in slowing gastric emptying, relaxation of the sphincter of Oddi, and potentiation of insulin secretion. Further, it has been implicated as a mediator of pancreatic growth and tumorigenesis. Class A receptors have also been described in the anterior pituitary, myenteric plexus, and regions of the central nervous system, where they have been implicated in the pathogenesis of feeding disorders, Parkinson disease, schizophrenia, and drug addiction.
Inoue et al. (1997) identified 2 missense variants of the CCKAR gene, the functional significance of which remained to be determined. One was a heterozygous gly21-to-arg (G21R; 118444.0001) mutation in an African American patient with obesity and noninsulin-dependent diabetes mellitus (NIDDM; 125853). The G21 residue is located within the N-terminal extracellular region of the receptor and is conserved in all sequences available. Another obese African American patient had a val365-to-ile (V365I) substitution in a residue conserved among species. Miller et al. (1995) had found aberrant splicing of exon 3 of the CCKAR gene, predicted to result in a nonfunctional receptor, in 1 patient with cholesterol gallstone disease and obesity.
Funakoshi et al. (1995) found a defect in expression of the CCKAR gene in both the fetal and the adult pancreas of a strain of rats (OLETF). They proposed these rats as a useful model for determining CCK receptor function.
Wang et al. (2004) compared wildtype and Cckar (Cck1r)-deficient mice on standard chow or a lithogenic diet. On either diet, the null mice had larger gallbladder volumes, significant retardation of small intestine transit times, and increased biliary cholesterol secretion rates, the combination of which resulted in a significantly higher prevalence of cholesterol gallstones.
Using SSCP-based screening, Inoue et al. (1997) identified 2 missense variants in the coding region of the CCKAR gene: a G-to-C base exchange in exon 1, resulting in a glycine-to-arginine amino acid substitution in codon 21; and a G-to-A base exchange in exon 5 that introduced an isoleucine for valine in codon 365. In African Americans with or without NIDDM, both mutations were very rare, with allele frequencies between 0.004 and 0.027. By RFLP analysis using restriction enzymes with cutting characteristics altered by one or the other of these 2 mutations, Hamann et al. (1999) found a mutated CCKAR allele in none of 298 morbidly obese children and adolescents or 134 underweight subjects. In 10 obese individuals, automated sequencing of exon 1 and exon 5 revealed no difference from the published CCKAR sequence.
See 118444.0001 and Inoue et al. (1997).
Marchal-Victorion et al. (2002) characterized the V365I mutation and demonstrated a decreased level of expression (26%) and efficacy (25%) to stimulate inositol phosphates. They suggested, therefore, that one can expect, in humans bearing the V365I mutation, decreases in CCKAR expression and coupling efficiency influencing cholecystokinin-induced regulation of satiety.
Boden, P., Hall, M. D., Hughes, J. Cholecystokinin receptors. Cell. Molec. Neurobiol. 15: 545-559, 1995. [PubMed: 8719040] [Full Text: https://doi.org/10.1007/BF02071316]
de Weerth, A., Pisegna, J. R., Huppi, K., Wank, S. A. Molecular cloning, functional expression and chromosomal localization of the human cholecystokinin type A receptor. Biochem. Biophys. Res. Commun. 194: 811-818, 1993. [PubMed: 8343165] [Full Text: https://doi.org/10.1006/bbrc.1993.1894]
Funakoshi, A., Miyasaka, K., Shinozaki, H., Masuda, M., Kawanami, T., Takata, Y., Kono, A. An animal model of congenital defect of gene expression of cholecystokinin (CCK)-A receptor. Biochem. Biophys. Res. Commun. 210: 787-796, 1995. [PubMed: 7539259] [Full Text: https://doi.org/10.1006/bbrc.1995.1728]
Hamann, A., Busing, B., Munzberg, H., de Weerth, A., Hinney, A., Mayer, H., Siegfried, W., Hebebrand, J., Greten, H. Missense variants in the human cholecystokinin type A receptor gene: no evidence for association with early-onset obesity. Horm. Metab. Res. 31: 287-288, 1999. [PubMed: 10333087] [Full Text: https://doi.org/10.1055/s-2007-978735]
Huppi, K., Siwarski, D., Pisegna, J. R., Wank, S. Chromosomal localization of the gastric and brain receptors for cholecystokinin (CCKAR and CCKBR) in human and mouse. Genomics 25: 727-729, 1995. [PubMed: 7759110] [Full Text: https://doi.org/10.1016/0888-7543(95)80018-h]
Inoue, H., Iannotti, C. A., Welling, C. M., Veile, R., Donis-Keller, H., Permutt, M. A. 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: 331-335, 1997. [PubMed: 9192855] [Full Text: https://doi.org/10.1006/geno.1997.4749]
Marchal-Victorion, S., Vionnet, N., Escrieut, C., Dematos, F., Dina, C., Dufresne, M., Vaysse, N., Pradayrol, L., Froguel, P., Fourmy, D. Genetic, pharmacological and functional analysis of cholecystokinin-1 and cholecystokinin-2 receptor polymorphism in type 2 diabetes and obese patients. Pharmacogenetics 12: 23-30, 2002. [PubMed: 11773861] [Full Text: https://doi.org/10.1097/00008571-200201000-00004]
Miller, L. J., Holicky, E. L., Ulrich, C. D., Wieben, E. D. Abnormal processing of the human cholecystokinin receptor gene in association with gallstones and obesity. Gastroenterology 109: 1375-1380, 1995. [PubMed: 7557108] [Full Text: https://doi.org/10.1016/0016-5085(95)90601-0]
Samuelson, L. C., Isakoff, M. S., Lacourse, K. A. Localization of the murine cholecystokinin A and B receptor genes. Mammalian Genome 6: 242-246, 1995. [PubMed: 7613026] [Full Text: https://doi.org/10.1007/BF00352408]
Ulrich, C. D., Ferber, I., Holicky, E., Hadac, E., Buell, G., Miller, L. J. Molecular cloning and functional expression of the human gallbladder cholecystokinin A receptor. Biochem. Biophys. Res. Commun. 193: 204-211, 1993. [PubMed: 8503909] [Full Text: https://doi.org/10.1006/bbrc.1993.1610]
Wang, D. Q.-H., Schmitz, F., Kopin, A. S., Carey, M. C. Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis. J. Clin. Invest. 114: 521-528, 2004. [PubMed: 15314689] [Full Text: https://doi.org/10.1172/JCI16801]