HGNC Approved Gene Symbol: CORT
Cytogenetic location: 1p36.22 Genomic coordinates (GRCh38) : 1:10,450,031-10,451,998 (from NCBI)
De Lecea et al. (1996) identified cortistatin, a rat neuropeptide that exhibits strong structural similarity to somatostatin (182450). The 14-amino acid neuropeptide is produced by cleavage of a 112-amino acid precursor, preprocortistatin. Administration of cortistatin into brain ventricles specifically enhances slow-wave sleep, presumably by antagonizing the effects of acetylcholine on cortical excitability.
De Lecea et al. (1997) cloned cDNAs encoding mouse and human preprocortistatin. Sequence analysis revealed that the predicted rat and mouse proteins share 82% identity, and the mature neuropeptides are identical. Compared to rat and mouse cortistatin, the putative human neuropeptide has a single amino acid substitution and 3 additional N-terminal amino acids. Independently, Fukusumi et al. (1997) isolated a human preprocortistatin cDNA. They noted that the predicted rat and human proteins are 55% identical. The 105-amino acid human preprocortistatin contains a 21-amino acid putative signal sequence.
By Northern blot analysis, de Lecea et al. (1997) determined that preprocortistatin is expressed as 2 mRNAs in human and mouse brain. Fukusumi et al. (1997) observed a single 1-kb band on Northern blots of spinal cord and caudate nucleus mRNA, and faint bands in cerebral cortex, hippocampus, and testis. Using in situ hybridization, de Lecea et al. (1997) found that mouse preprocortistatin mRNA is present in GABAergic interneurons in the cerebral cortex and hippocampus.
Using chemically synthesized peptide and mammalian cells expressing human somatostatin receptors (SSTRs), Fukusumi et al. (1997) showed that human cortistatin inhibited the cAMP production induced by forskolin through SSTRs, and bound SSTR subtypes in almost the same manner as rat cortistatin. Administration of the human neuropeptide to rat cerebral ventricle caused flattening of cortical and hippocampal electroencephalograms, suggesting that it had sleep-modulating activity similar to that of rat cortistatin.
Ejeskar et al. (2000) determined that the CORT gene contains 2 exons divided by a 1-kb intron.
By analysis of an interspecific backcross, de Lecea et al. (1997) mapped the preprocortistatin gene to the distal portion of mouse chromosome 4 and, by homology of synteny, to chromosome 1p36 in humans. Ejeskar et al. (2000) mapped the CORT gene to 1p36.3-p36.2 by radiation hybrid analysis and BAC physical mapping.
In a murine model of Crohn disease (see IBD1; 266600), Gonzalez-Rey et al. (2006) demonstrated that cortistatin treatment significantly ameliorated the clinical and histopathologic severity of inflammatory colitis. The therapeutic effect was associated with downregulation of inflammatory and Th1-driven autoimmune responses, including regulation of a wide spectrum of inflammatory mediators. Gonzalez-Rey et al. (2006) concluded that cortistatin is an antiinflammatory factor capable of deactivating intestinal inflammatory response and restoring mucosal immune tolerance at multiple levels.
Gonzalez-Rey et al. (2006) found that Cort protected mice with various models of lethal endotoxemia from mortality and reduced related histopathologic manifestations. The protection was further enhanced in a synergistic manner by treatment with vasoactive intestinal peptide (VIP; 192320). Cort-treated macrophages stimulated with LPS produced less Tnf (191160), Il6 (147620), and nitric oxide than controls. Gonzalez-Rey et al. (2006) concluded that CORT represents a potential multistep therapeutic agent for human septic shock.
de Lecea, L., Criado, J. R., Prospero-Garcia, O., Gautvik, K. M., Schweitzer, P., Danielson, P. E., Dunlop, C. L. M., Siggins, G. R., Henriksen, S. J., Sutcliffe, J. G. A cortical neuropeptide with neuronal depressant and sleep-modulating properties. Nature 381: 242-245, 1996. [PubMed: 8622767] [Full Text: https://doi.org/10.1038/381242a0]
de Lecea, L., Ruiz-Lozano, P., Danielson, P. E., Peelle-Kirley, J., Foye, P. E., Frankel, W. N., Sutcliffe, J. G. Cloning, mRNA expression, and chromosomal mapping of mouse and human preprocortistatin. Genomics 42: 499-506, 1997. [PubMed: 9205124] [Full Text: https://doi.org/10.1006/geno.1997.4763]
Ejeskar, K., Abel, F., Sjoberg, R.-M., Backstrom, J., Kogner, P., Martinsson, T. Fine mapping of the human preprocortistatin gene (CORT) to neuroblastoma consensus deletion region 1p36.3-p36.2, but absence of mutations in primary tumors. Cytogenet. Cell Genet. 89: 62-66, 2000. [PubMed: 10894940] [Full Text: https://doi.org/10.1159/000015566]
Fukusumi, S., Kitada, C., Takekawa, S., Kizawa, H., Sakamoto, J., Miyamoto, M., Hinuma, S., Kitano, K., Fujino, M. Identification and characterization of a novel human cortistatin-like peptide. Biochem. Biophys. Res. Commun. 232: 157-163, 1997. [PubMed: 9125122] [Full Text: https://doi.org/10.1006/bbrc.1997.6252]
Gonzalez-Rey, E., Chorny, A., Robledo, G., Delgado, M. Cortistatin, a new antiinflammatory peptide with therapeutic effect on lethal endotoxemia. J. Exp. Med. 203: 563-571, 2006. [PubMed: 16492802] [Full Text: https://doi.org/10.1084/jem.20052017]
Gonzalez-Rey, E., Varela, N., Sheibanie, A. F., Chorny, A., Ganea, D., Delgado, M. Cortistatin, an antiinflammatory peptide with therapeutic action in inflammatory bowel disease. Proc. Nat. Acad. Sci. 103: 4228-4233, 2006. [PubMed: 16537513] [Full Text: https://doi.org/10.1073/pnas.0508997103]