HGNC Approved Gene Symbol: CCK
Cytogenetic location: 3p22.1 Genomic coordinates (GRCh38): 3:42,257,826-42,266,185 (from NCBI)
Cholecystokinin is a brain/gut peptide. In the gut, it induces the release of pancreatic enzymes and the contraction of the gallbladder (summary by Takahashi et al., 1986).
CCK peptides exist in multiple molecular forms (e.g., sulfated CCK8, unsulfated CCK8, and CCK4), each resulting from distinct posttranslational processing of the CCK gene product. CCK receptors are divided into 2 types: the CCKA receptor (CCKAR; 118444) and the CCKB receptor (CCKBR; 118445). The CCKA receptor mediates the action of CCK on contraction of the gallbladder, secretion of pancreatic amylase, and gastric emptying. CCKB receptor activity is associated with increased neuronal firing, anxiety, and nociception (summary by Fujii et al., 1999).
The major forms of CCK are CCK58, CCK33, CCK22, and CCK8. To determine their relative abundance in human plasma and intestine, Rehfeld et al. (2001) examined extracts of intestinal biopsies and plasma from 10 human subjects by chromatography, enzyme cleavages, and measurements using a library of sequence-specific RIAs. The abundance of the larger forms varied with the 8 C-terminal assays in the library, as 2 assays overestimated and 3 underestimated the amounts present. One assay showed that the predominant plasma form is CCK33, both in the fasting state (approximately 51%) and postprandially (approximately 57%), whereas CCK22 is the second most abundant (approximately 34% and 30%, respectively). In contrast, CCK58 is less abundant in human intestines (approximately 18%) and plasma (approximately 11%), but was the predominant form in feline intestines.
Takahashi et al. (1986) determined the entire structure of the human CCK gene, which spans 7 kb and contains 3 exons.
By chromosome sorting in combination with velocity sedimentation and Southern hybridization, Takahashi et al. (1986) mapped the CCK gene to chromosome 3pter-p21. S1 endonuclease analysis showed 2 putative transcription initiation sites. By Southern analysis of DNA from human-hamster hybrid cell lines, Lund et al. (1986) mapped CCK to 3pter-q12.
Using 3 separate approaches, Friedman et al. (1989) mapped the mouse Cck gene to distal chromosome 9. They concluded that this mapping excludes cholecystokinin as an etiologic factor in the pathogenesis of any of the known mouse obesity syndromes because these map to other sites.
Friedman et al. (1992) demonstrated that Ewing sarcoma (612219) and neuroepithelioma cells express the CCK gene--an almost unique finding among tumor cells. Most, however, were unable to process the precursor material sufficiently to generate immunoreactive CCK octapeptide-like peptides. The findings supported the view that Ewing sarcoma and neuroepithelioma are derived from the same transformed cell type, which may serve to differentiate them from other types of pediatric tumors.
CCK modulates the release of dopamine and dopamine-related behaviors in the mesolimbic pathway, where CCK and dopamine coexist (Hokfelt et al., 1980; Marshall et al., 1991).
CCK is a gut hormone and a neuropeptide that has the capacity to stimulate insulin secretion. Since insulin secretion is impaired in type 2 diabetes (see 125853), Ahren et al. (2000) studied whether exogenous administration of CCK exerts antidiabetogenic action. The C-terminal octapeptide of CCK (CCK8) was infused intravenously in 6 healthy postmenopausal women and in 6 postmenopausal women with type 2 diabetes. In both healthy subjects and subjects with type 2 diabetes, CCK8 reduced the increase in circulating glucose after meal ingestion and potentiated the increase in circulating insulin. In contrast, the increase in the circulating levels of gastric inhibitory polypeptide (GIP; 137240), glucagon-like peptide-1 (GLP1; see 138030), or glucagon (138030) after meal ingestion was not significantly affected by CCK8. The authors concluded that CCK8 exerts an antidiabetogenic action in both healthy subjects and those with type 2 diabetes through an insulinotropic action that most likely is exerted through a direct islet effect. They suggested administration of CCK as a potential treatment for type 2 diabetes.
Hogenauer et al. (2001) described a patient with autoimmune polyglandular syndrome type I (240300) who had a severe malabsorption syndrome caused by a deficiency of cholecystokinin-producing enteroendocrine cells in the mucosa of his proximal small intestine. Oral bile acid replacement therapy may ameliorate fat malabsorption in patients with steatorrhea due to cholecystokinin deficiency.
CCK immunoreactivity in the substantia nigra is reduced in Parkinson disease (168600) patients (Studler et al., 1982). Fujii et al. (1999) conducted a systematic analysis of genetic variations in both the promoter region and the coding region of the CCK gene, with a comparison between Parkinson disease patients and controls. They also analyzed the relationship between polymorphism of the CCK gene and clinical features of the disease, including age of onset. Four polymorphic sites (-196G-A, -45C-T, 1270C-G, and 6662C-T) were found in Parkinson disease patients and controls. Complete linkage disequilibrium was observed between the -45 locus and the 1270 locus, and a possible linkage disequilibrium was found between the -45 and -196 loci. A significant difference was found in the distributions of 3 identified genotypes at the -45 locus between 116 Parkinson disease patients and 95 age-matched control subjects (p = 0.018). In addition, significant differences were obtained among the 3 genotypic groups at the -45 locus when compared between the 23 Parkinson disease patients who experienced hallucinations and the 93 patients who did not (p = 0.018). Among 44 white PD patients, Goldman et al. (2004) found a higher frequency of the CCK -45T allele in patients with hallucinations, but the difference did not reach statistical significance.
Ahren, B., Holst, J. J., Efendic, S. Antidiabetogenic action of cholecystokinin-8 in type 2 diabetes. J. Clin. Endocr. Metab. 85: 1043-1048, 2000. [PubMed: 10720037] [Full Text: https://doi.org/10.1210/jcem.85.3.6431]
Friedman, J. M., Schneider, B. S., Barton, D. E., Francke, U. Level of expression and chromosome mapping of the mouse cholecystokinin gene: implications for murine models of genetic obesity. Genomics 5: 463-469, 1989. [PubMed: 2575582] [Full Text: https://doi.org/10.1016/0888-7543(89)90010-4]
Friedman, J. M., Vitale, M., Maimon, J., Israel, M. A., Horowitz, M. E., Schneider, B. S. Expression of the cholecystokinin gene in pediatric tumors. Proc. Nat. Acad. Sci. 89: 5819-5823, 1992. [PubMed: 1631063] [Full Text: https://doi.org/10.1073/pnas.89.13.5819]
Fujii, C., Harada, S., Ohkoshi, N., Hayashi, A., Yoshizawa, K., Ishizuka, C., Nakamura, T. Association between polymorphism of the cholecystokinin gene and idiopathic Parkinson's disease. Clin. Genet. 56: 394-399, 1999. [PubMed: 10668930] [Full Text: https://doi.org/10.1034/j.1399-0004.1999.560508.x]
Goldman, J. G., Goetz, C. G., Berry-Kravis, E., Leurgans, S., Zhou, L. Genetic polymorphisms in Parkinson disease subjects with and without hallucinations: an analysis of the cholecystokinin system. Arch. Neurol. 61: 1280-1284, 2004. [PubMed: 15313848] [Full Text: https://doi.org/10.1001/archneur.61.8.1280]
Hogenauer, C., Meyer, R. L., Netto, G. J., Bell, D., Little, K. H., Ferries, L., Santa Ana, C. A., Porter, J. L., Fordtran, J. S. Malabsorption due to cholecystokinin deficiency in a patient with autoimmune polyglandular syndrome type I. New Eng. J. Med. 344: 270-274, 2001. [PubMed: 11172154] [Full Text: https://doi.org/10.1056/NEJM200101253440405]
Hokfelt, T., Rehfeld, J. F., Skirboll, L., Ivemark, B., Goldstein, M., Markey, K. Evidence for coexistence of dopamine and CCK in meso-limbic neurones. Nature 285: 476-478, 1980. [PubMed: 6105617] [Full Text: https://doi.org/10.1038/285476a0]
Lund, T., Geurts van Kessel, A. H. M., Haun, S., Dixon, J. E. The genes for human gastrin and cholecystokinin are located on different chromosomes. Hum. Genet. 73: 77-80, 1986. [PubMed: 3011648] [Full Text: https://doi.org/10.1007/BF00292669]
Marshall, F. H., Barnes, S., Hughes, J., Woodruff, G. N., Hunter, J. C. Cholecystokinin modulates the release of dopamine from the anterior and posterior nucleus accumbens by two different mechanisms. J. Neurochem. 56: 917-922, 1991. [PubMed: 1993898] [Full Text: https://doi.org/10.1111/j.1471-4159.1991.tb02009.x]
Rehfeld, J. F., Sun, G., Christensen, T., Hillingso, J. G. The predominant cholecystokinin in human plasma and intestine is cholecystokinin-33. J. Clin. Endocr. Metab. 86: 251-258, 2001. [PubMed: 11232009] [Full Text: https://doi.org/10.1210/jcem.86.1.7148]
Studler, J. M., Javoy-Agid, F., Cesselin, F., Legrand, J. C., Agid, Y. CCK-8-immunoreactivity distribution in human brain: selective decrease in the substantia nigra from parkinsonian patients. Brain Res. 243: 176-179, 1982. [PubMed: 6288173] [Full Text: https://doi.org/10.1016/0006-8993(82)91135-0]
Takahashi, Y., Fukushige, S., Murotsu, T., Matsubara, K. Structure of human cholecystokinin gene and its chromosomal location. Gene 50: 353-360, 1986. [PubMed: 3582983] [Full Text: https://doi.org/10.1016/0378-1119(86)90339-2]