Cortistatin (neuropeptide)

"CORT" redirects here. For other uses, see CORT (disambiguation).

Not to be confused with the steroids also called cortistatins.

CORT
Identifiers
Aliases	CORT, CST-14, CST-17, CST-29, cortistatin, SST2
External IDs	OMIM: 602784; MGI: 109538; HomoloGene: 997; GeneCards: CORT; OMA:CORT - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1p36.22 Start 10,450,031 bp End 10,451,998 bp
Gene location (Mouse) Chr. Chromosome 4 (mouse) Band 4 E2|4 78.89 cM Start 149,209,491 bp End 149,211,220 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in putamen caudate nucleus prefrontal cortex nucleus accumbens superior frontal gyrus anterior cingulate cortex gonad temporal lobe amygdala Brodmann area 9 Top expressed in embryo primary visual cortex embryo dentate gyrus of hippocampal formation granule cell superior frontal gyrus hippocampus proper fetal liver hematopoietic progenitor cell perirhinal cortex tail of embryo olfactory bulb More reference expression data BioGPS n/a
Gene ontology Molecular function neuropeptide hormone activity G protein-coupled receptor binding hormone activity chromatin binding double-stranded DNA binding Cellular component extracellular region Fanconi anaemia nuclear complex FANCM-MHF complex extracellular space Biological process adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway chemical synaptic transmission mitotic recombination resolution of meiotic recombination intermediates interstrand cross-link repair replication fork processing regulation of signaling receptor activity G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1325 12854 Ensembl ENSG00000241563 ENSMUSG00000028971 UniProt O00230 P56469 RefSeq (mRNA) NM_001302 NM_007745 RefSeq (protein) NP_001293 NP_031771 Location (UCSC) Chr 1: 10.45 – 10.45 Mb Chr 4: 149.21 – 149.21 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Precortistatin is a protein that in humans is encoded by the CORT gene. The 105 amino acid residue human precortistatin in turn is cleaved into cortistatin-17 and cortistatin-29. Cortistatin-17 is the only active peptide derived from the precursor. Cortistatin (or more specifically cortistatin-17) is a neuropeptide that is expressed in inhibitory neurons of the cerebral cortex, and which has a strong structural similarity to somatostatin. Unlike somatostatin, when infused into the brain, it enhances slow-wave sleep. It binds to sites in the cortex, hippocampus and the amygdala.

Structure, sequence conservation, and chemical synthesis

Peptide rCST14 shares 11 of its 14 amino acids with SST14, including the two cysteine residues that form the cyclic structure. Circular dichroism and nuclear magnetic resonance spectroscopy indicate that cyclic rCST14 does not adopt a single defined conformation in solution. The principal processing products of the preprocortistatin and preprosomatostatin genes are the 29/28-mer and 14-mer peptides. Within the N-terminal 15/14 residues of the 29/28-mer peptides, cortistatin and somatostatin show notable sequence similarity. However, only one residue is conserved between rCST14 and rCST29 in this region in rat and human peptides, with no clearly identifiable structurally or functionally homologous regions; two residues are conserved in mouse peptides. By contrast, the N-terminal sequence of somatostatin is highly conserved across species, differing by only one amino acid between human and chicken and by two between human and frog. The functional significance of this region in cortistatin signaling remains unclear, although these structural differences may contribute to physiologically relevant distinctions between CST29 and SST28 activity.

Separately, the cortistatins (cortistatins A–L) constitute a class of marine natural products characterized by an unusual steroidal skeleton and distinct from the endogenous neuropeptide cortistatin. Synthetic studies have proposed that cortistatins A and J may arise from cortistatin L, or from a precursor of equivalent oxidation state, with cortistatin L itself potentially generated by C2 oxidation of cortistatin K. Cortistatins A, J, K, and L have been synthesized through parallel routes from closely related intermediates derived from a common precursor. These compounds have been reported to inhibit proliferation of various mammalian cell types in culture through mechanisms that remain unclear.

Biosynthesis and processing

Cortistatin is a 112-amino-acid protein encoded by the preprocortistatin gene, which contains multiple potential endoproteolytic cleavage sites. Preprocortistatin is cleaved at two C-terminal dibasic sites (KK and KR) to generate rCST14 and rCST29, analogous to SST14 and SST28 derived from preprosomatostatin. In tissue culture cells, the ratio of rCST14:rCST29:preprocortistatin was reported as 41:55:4.5, whereas secreted peptides showed an approximate rCST14:rCST29 ratio of 2:1, indicating preferential release of rCST14 despite near-equal production. The enzymes responsible for cortistatin processing remain unknown; however, mouse AtT-20 cells express the proprotein convertases PC1 and PC2, both of which are highly expressed in the cerebral cortex, a major site of cortistatin expression. Because PC1 and PC2 also participate in preprosomatostatin processing, they are considered plausible candidates for in vivo preprocortistatin processing.

Comparison with somatostatin

The 14-mer cortistatin and somatostatin peptides are structurally similar, with rat CST14 and SST14 sharing 11 of 14 residues. Most differences occur outside the cyclic region. In the N-terminal extracyclic region, CST14 contains either a single Pro residue in rat and mouse or an Asp–Arg–Met–Pro sequence in humans, whereas SST14 contains an Ala–Gly sequence. At the C-terminus, SST14 ends with the cysteine residue that participates in the Cys–Cys loop, whereas all known CST14 peptides are predicted to contain an additional lysine residue beyond this cysteine. It remains uncertain whether this C-terminal lysine is retained in the mature peptide, as it represents a likely site for carboxypeptidase-mediated cleavage, although radioimmunoassay and HPLC analysis of brain extracts identified a peptide with an elution profile consistent with CST14.

Within the Cys–Cys loop, rat and mouse CST14 peptides are identical, whereas the human peptide differs by a single substitution in which arginine replaces lysine immediately following the N-terminal cysteine. CST14 also differs from SST14 within the loop by containing a serine residue two positions upstream of the C-terminal cysteine, where SST14 contains threonine. Several of these structural differences have been shown to have physiological and pharmacological significance for cortistatin function.

Function

Cortistatin is a neuropeptide with strong structural similarity to somatostatin (both peptides belong to the same family). It binds to all known somatostatin receptors, and shares many pharmacological and functional properties with somatostatin, including the depression of neuronal activity. However, it also has many properties distinct from somatostatin, such as induction of slow-wave sleep, apparently by antagonism of the excitatory effects of acetylcholine on the cortex, reduction of locomotor activity, and activation of cation selective currents not responsive to somatostatin.

Clinical significance

Diagnostic

Cortistatin is a cyclic neuropeptide related tosomatostatin that has emerged as a potential endogenous antiin-flammatory factor based on its production by, and binding to, immune cell. Studies from say the use of Cortistatin treatment significantly help the clinical and histopathologic severity of the inflammatory colitis, stopping body weight loss, diarrhea, and inflammation. There was also a notable increase in the survival rate of the colitic mice. The use of Cortistatin treatment's therapeutic effect was associated with notable down-regulation of inflammatory and the down-regulation of the Th1-driven autoimmune response. This includes the regulation of a wide spectrum of inflammatory mediators. Also, there was partial involvement of regulatory IL-10-secreting T cells in this therapeutic effect. The most important factor for this Cortistatin Treatment was that it was therapeutically effective in colitis and it avoided the recurrence of the disease. This work in Cortistatin Treatment identifies cortistatin as a potential antiinflammatory factor with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels.

Another study tested Cortistatin to treat Osteoarthritis on mice. Osteoarthritis is a degenerative joint disease caused by the breakdown of cartilage. The tumor necrosis factor (TNF-α) is known to play a critical role in Osteoarthritis. The results showed that Cortistatin competitively bounded to TNFR1 as well as TNFR2. Cortistatin suppressed the proinflammatory function of TNF-α. Notably, both the spontaneous and surgically induced Osteoarthritis models indicated that deficiency of Cortistatin led to an accelerated Osteoarthritis-like phenotype. Analysis of TNFR1- and TNFR2-knockout mice found that TNFRs might be involved in the protective role of Cortistatin in Osteoarthritis. Mice treated with cortistatin for 3 consecutive days starting 6 days after TNBS administration and the onset of disease quickly reversed the lost body weight. Cortistatin treatment completely removed established colitis and reduced the disease recurrence. Mice treated with cortistatin 12 h after TNBS injection survived and did not suffer disease recurrence after a second administration of TNBS.

Another study tested Cortistatin treatments on a preclinical mouse model of Parkinson's disease induced by acute exposure to the neurotoxin 1-methil-4-phenyl1-1,2,3,6-tetrahydropyridine (MPTP). Researchers observed that treatment with cortistatin mitigated the MPTP-induced loss of dopaminergic neurons, which are in the substantia nigra and their connections to the striatum. The study found that cortistatin administration improved the locomotor activity of mice intoxicated with 1-methil-4-phenyl1-1,2,3,6-tetrahydropyridine. The study also found that cortistatin diminished the presence and activation of glial cells in the affected brain regions of 1-methil-4-phenyl1-1,2,3,6-tetrahydropyridine-treated mice. Cortistatin also reduced the production of immune mediators and also promoted the expression of neurotrophic factors in the striatum of mice. In conclusion, these findings again suggest that cortistatin could emerge as a potential antiinflammatory factor and that cortistatin has neuroprotective properties to regulate the progression of Parkinson's disease.

Further reading

• Spier AD, de Lecea L (2001). "Cortistatin: a member of the somatostatin neuropeptide family with distinct physiological functions". Brain Research. Brain Research Reviews. 33 (2–3): 228–241. doi:10.1016/S0165-0173(00)00031-X. PMID 11011067. S2CID 14657640.
• Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Fukusumi S, Kitada C, Takekawa S, Kizawa H, Sakamoto J, Miyamoto M, et al. (March 1997). "Identification and characterization of a novel human cortistatin-like peptide". Biochemical and Biophysical Research Communications. 232 (1): 157–163. doi:10.1006/bbrc.1997.6252. PMID 9125122.
• Puebla L, Mouchantaf R, Sasi R, Khare S, Bennett HP, James S, et al. (September 1999). "Processing of rat preprocortistatin in mouse AtT-20 cells". Journal of Neurochemistry. 73 (3): 1273–1277. doi:10.1046/j.1471-4159.1999.0731273.x. PMID 10461921. S2CID 11290164.
• Ejeskär K, Abel F, Sjöberg R, Bäckström J, Kogner P, Martinsson T (2000). "Fine mapping of the human preprocortistatin gene (CORT) to neuroblastoma consensus deletion region 1p36.3-->p36.2, but absence of mutations in primary tumors". Cytogenetics and Cell Genetics. 89 (1–2): 62–66. doi:10.1159/000015566. PMID 10894940. S2CID 13005311.
• Deghenghi R, Papotti M, Ghigo E, Muccioli G (2001). "Cortistatin, but not somatostatin, binds to growth hormone secretagogue (GHS) receptors of human pituitary gland". Journal of Endocrinological Investigation. 24 (1): RC1–3. doi:10.1007/bf03343800. PMID 11227737. S2CID 30072435.
• Harrington JJ, Sherf B, Rundlett S, Jackson PD, Perry R, Cain S, et al. (May 2001). "Creation of genome-wide protein expression libraries using random activation of gene expression". Nature Biotechnology. 19 (5): 440–445. doi:10.1038/88107. PMID 11329013. S2CID 25064683.
• Broglio F, Arvat E, Benso A, Gottero C, Prodam F, Grottoli S, et al. (August 2002). "Endocrine activities of cortistatin-14 and its interaction with GHRH and ghrelin in humans". The Journal of Clinical Endocrinology and Metabolism. 87 (8): 3783–3790. doi:10.1210/jc.87.8.3783. PMID 12161511.
• Dalm VA, van Hagen PM, van Koetsveld PM, Langerak AW, van der Lely AJ, Lamberts SW, et al. (January 2003). "Cortistatin rather than somatostatin as a potential endogenous ligand for somatostatin receptors in the human immune system". The Journal of Clinical Endocrinology and Metabolism. 88 (1): 270–276. doi:10.1210/jc.2002-020950. hdl:1765/10051. PMID 12519865.
• Dalm VA, van Hagen PM, van Koetsveld PM, Achilefu S, Houtsmuller AB, Pols DH, et al. (August 2003). "Expression of somatostatin, cortistatin, and somatostatin receptors in human monocytes, macrophages, and dendritic cells". American Journal of Physiology. Endocrinology and Metabolism. 285 (2): E344–53. doi:10.1152/ajpendo.00048.2003. PMID 12684217. S2CID 7954897.
• Robas N, Mead E, Fidock M (2004). "MrgX2 is a high potency cortistatin receptor expressed in dorsal root ganglion". The Journal of Biological Chemistry. 278 (45): 44400–44404. doi:10.1074/jbc.M302456200. PMID 12915402.
• Papotti M, Tarabra E, Allia E, Bozzalla-Cassione F, Broglio F, Deghenghi R, et al. (August 2003). "Presence of cortistatin in the human pancreas". Journal of Endocrinological Investigation. 26 (8): RC15–8. doi:10.1007/bf03347348. PMID 14669820. S2CID 32817369.
• Hernández C, Carrasco E, Casamitjana R, Deulofeu R, García-Arumí J, Simó R (August 2005). "Somatostatin molecular variants in the vitreous fluid: a comparative study between diabetic patients with proliferative diabetic retinopathy and nondiabetic control subjects". Diabetes Care. 28 (8): 1941–1947. doi:10.2337/diacare.28.8.1941. PMID 16043736.