Affinage

CORT

Cortistatin · UniProt O00230

Round 2 corrected
Length
105 aa
Mass
11.5 kDa
Annotated
2026-04-28
130 papers in source corpus 20 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Cortistatin is a neuropeptide derived from preprocortistatin (primarily processed to CST-14 via the regulated secretory pathway) that functions as a pleiotropic anti-inflammatory and neuromodulatory signaling molecule, acting through somatostatin receptors (sst1–sst5), the ghrelin/GHS receptor, MRGPRX2, and TNF-α receptors (TNFR1/TNFR2) (PMID:9125122, PMID:12915402, PMID:30826358). In the nervous system, cortistatin is expressed in cortical GABAergic interneurons, enhances slow-wave sleep by antagonizing cholinergic cortical excitation, and exerts anticonvulsant effects mediated specifically through sst2 and sst3 (PMID:9205124, PMID:24685142). In the immune system, cortistatin—rather than somatostatin—serves as the predominant endogenous sst2 ligand in monocytes, macrophages, and dendritic cells, and additionally suppresses NF-κB-dependent inflammation by competing with TNF-α for TNFR1/TNFR2 binding and by inhibiting NLRP3 inflammasome activation through blockade of mitochondrial ROS (PMID:12684217, PMID:30826358, PMID:32550919). Cortistatin also inhibits vascular smooth muscle cell proliferation and migration via sst2/sst5 and ghrelin receptor signaling, with cortistatin-deficient mice developing exaggerated neointimal hyperplasia (PMID:23595952).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1997 High

    Cloning of human preprocortistatin revealed a new neuropeptide that shares all five somatostatin receptors yet produces distinct neurophysiological effects (cortical EEG flattening), establishing cortistatin as a somatostatin-related but functionally distinct signaling molecule.

    Evidence cDNA cloning from human fetal brain, radioligand binding at five SSTRs, cAMP inhibition assays, and in vivo rat EEG recording; parallel mouse/human gene cloning with in situ hybridization localizing expression to cortical/hippocampal GABAergic interneurons

    PMID:9125122 PMID:9205124

    Open questions at the time
    • No cortistatin-specific receptor identified at this stage
    • Mature peptide form(s) generated in vivo not yet resolved
    • Peripheral expression and function unexplored
  2. 1999 High

    Reconstitution of preprocortistatin processing in neuroendocrine cells demonstrated that CST-14 is the predominant mature cleavage product released via the regulated secretory pathway, resolving the identity of the bioactive peptide.

    Evidence Stable transfection of AtT-20 cells with rat preprocortistatin, HPLC separation and RIA quantification of secreted products

    PMID:10461921

    Open questions at the time
    • Processing in non-neuroendocrine tissues unknown
    • Convertase(s) responsible for cleavage not identified
  3. 2001 Medium

    Identification of cortistatin—but not somatostatin—as a ligand for the growth hormone secretagogue receptor (GHS-R) established the first receptor pharmacology distinguishing cortistatin from somatostatin.

    Evidence Radioligand competition binding on human pituitary membranes; confirmed in vivo by clinical crossover study showing CST-14 blunts ghrelin-induced GH release

    PMID:11227737 PMID:12161511

    Open questions at the time
    • Physiological relevance of GHS-R engagement in non-pituitary tissues not determined
    • Small clinical cohort (n=6)
  4. 2003 High

    Discovery that immune cells express cortistatin (but not somatostatin) alongside sst2 redefined cortistatin as the endogenous sst2 ligand in the immune system, while identification of MRGPRX2 as a cortistatin-specific Gq-coupled receptor in sensory neurons revealed a second non-somatostatin receptor.

    Evidence RT-PCR, radioligand displacement, and confocal microscopy in human monocytes/macrophages/DCs; reverse pharmacology with Ca²⁺ mobilization and cAMP assays in MRGPRX2-expressing cells; expression profiling in DRG neurons

    PMID:12519865 PMID:12684217 PMID:12915402

    Open questions at the time
    • Downstream signaling cascades in immune cells not characterized
    • MRGPRX2 function in mast cells not yet addressed
    • Relative contributions of sst2 vs. MRGPRX2 signaling unclear
  5. 2003 Medium

    Localization of cortistatin mRNA and protein in human pancreatic islets and retinal tissue expanded the known sites of cortistatin action beyond the CNS, with subsequent clinical data revealing reduced CST expression in diabetic retinopathy.

    Evidence RT-PCR, in situ hybridization, and immunohistochemistry in human pancreatic islets; RIA/HPLC of vitreous fluid; immunofluorescence and TUNEL assays in postmortem diabetic vs. nondiabetic retinal tissue

    PMID:14669820 PMID:16043736 PMID:18709137

    Open questions at the time
    • Functional role of cortistatin in islet hormone regulation not demonstrated by intervention
    • Whether CST reduction is causal in diabetic retinopathy or a consequence of disease
    • Retinal receptor mediating CST effects unidentified
  6. 2013 High

    Mechanistic dissection in vascular smooth muscle cells showed that cortistatin inhibits PDGF-driven proliferation and migration through sst2, sst5, and ghrelin receptor signaling (via cAMP/p38 induction, Akt inhibition, and Rac1 suppression), with cortistatin-knockout mice validating the vascular protective role in vivo.

    Evidence Receptor-selective pharmacology, proliferation/migration assays, Rac1/Akt/p38 biochemistry, calcium imaging, and carotid artery ligation model in CST-knockout mice

    PMID:23595952

    Open questions at the time
    • Whether CST acts in an autocrine or paracrine fashion in vasculature unknown
    • Contribution of each receptor subtype to in vivo neointima prevention not individually resolved
  7. 2014 High

    Pharmacological and genetic epistasis experiments established that cortistatin's anticonvulsant activity is mediated by sst2 and sst3 (each independently necessary) and is independent of the ghrelin receptor, refining the receptor logic underlying cortistatin's neuronal functions.

    Evidence In vivo pilocarpine-induced seizure model with selective sst2 and sst3 antagonists, ghrelin receptor knockout mice, EEG telemetry

    PMID:24685142

    Open questions at the time
    • Downstream intracellular pathways mediating anticonvulsant effect unexplored
    • Whether cortistatin affects seizure circuits via inhibitory interneurons or direct postsynaptic action unresolved
  8. 2019 High

    Identification of direct cortistatin binding to TNFR1 and TNFR2 revealed a receptor interaction independent of the somatostatin/ghrelin receptor families, providing a mechanism for cortistatin's anti-inflammatory effects through competitive suppression of TNF-α/NF-κB signaling.

    Evidence Co-immunoprecipitation and biotin-based solid-phase binding assay, NF-κB pathway analysis, surgically-induced OA in CST-knockout and TNFR-knockout mice

    PMID:30826358

    Open questions at the time
    • Structural basis of CST–TNFR interaction unresolved
    • Whether CST–TNFR binding occurs in all TNF-responsive tissues or is context-restricted
  9. 2020 High

    Studies in CST-knockout mice and human disc tissue demonstrated that cortistatin suppresses NLRP3 inflammasome activation via inhibition of mitochondrial ROS, establishing a new effector arm of cortistatin's anti-inflammatory mechanism distinct from NF-κB blockade.

    Evidence CST-knockout mouse intervertebral disc degeneration model, TNF-α stimulation of nucleus pulposus cells, mitochondrial ROS measurement, NLRP3 inflammasome activity assays

    PMID:32550919

    Open questions at the time
    • Receptor(s) mediating mitochondrial ROS inhibition in NP cells not identified
    • Whether NLRP3 suppression is a general cortistatin function or tissue-specific
  10. 2021 High

    Cryo-EM resolution of the MRGPRX2–Gi1 complex bound to cortistatin-14 provided the first atomic-level view of cortistatin receptor engagement, revealing a shallow binding pocket and an unconventional activation mechanism involving Gly6.48 replacement of the canonical toggle switch.

    Evidence Cryo-electron microscopy structure determination with functional Gi/Gq coupling validation

    PMID:34789874 PMID:34789875

    Open questions at the time
    • No structure of cortistatin bound to any somatostatin receptor or TNFR
    • MRGPRX2 signaling downstream of Gq/Gi in mast cell degranulation not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of cortistatin engagement with somatostatin receptors and TNFRs, the identity of receptor(s) mediating cortistatin's metabolic effects in pancreatic islets, whether cortistatin reduction in Alzheimer's disease and diabetic retinopathy is causally pathogenic, and the relative signaling contributions of each receptor in different tissue contexts.
  • No structural data for CST at any somatostatin receptor
  • Causal role of CST loss in neurodegeneration unproven
  • Tissue-specific receptor hierarchy for CST signaling unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 1
Partners
GHSRMRGPRX2SSTR1SSTR2SSTR3SSTR5TNFRSF1ATNFRSF1B

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Human preprocortistatin cDNA was cloned and mapped to chromosome 1p36 (mouse chromosome 4); the encoded peptide cortistatin-17 (hCS-17) binds all five human somatostatin receptor (SSTR) subtypes and inhibits forskolin-stimulated cAMP production through SSTRs; intracerebroventricular administration flattened cortical and hippocampal EEGs in rats. cDNA cloning from human fetal brain EST library, radioligand binding assay on cells expressing each SSTR subtype, cAMP inhibition assay, in vivo EEG recording Biochemical and biophysical research communications High 9125122
1997 Mouse and human preprocortistatin genes were cloned; mouse cortistatin mRNA is expressed in cortical and hippocampal GABAergic interneurons; the gene maps to mouse chromosome 4 / human 1p36; only cortistatin-14 is predicted as the sole mature cleavage product based on conservation of dibasic cleavage sites. cDNA cloning, Northern blot, in situ hybridization, chromosomal mapping (conserved synteny analysis) Genomics High 9205124
1999 Rat preprocortistatin (PPCST) stably expressed in AtT-20 pituitary cells is processed to both CST-14 and CST-29 via cleavage at C-terminal dibasic sites; CST-14 is preferentially released (63–70%) via the regulated secretory pathway under basal and forskolin-stimulated conditions. Stable transfection of AtT-20 cells, HPLC separation, radioimmunoassay of secreted products, forskolin stimulation Journal of neurochemistry High 10461921
2000 Cortistatin-14 shares binding to all five cloned somatostatin receptors but has distinct physiological properties including induction of slow-wave sleep (by antagonizing acetylcholine excitatory effects on cortex), reduction of locomotor activity, and activation of cation-selective currents not responsive to somatostatin; cortistatin mRNA follows a circadian rhythm and is upregulated by sleep deprivation. Review synthesizing electrophysiology, behavioral pharmacology, receptor binding, and expression studies Brain research. Brain research reviews Medium 11011067
2000 Fine mapping placed the human CORT gene to chromosome 1p36.3→p36.2 near marker D1S244; the gene consists of two exons divided by a ~1 kb intron; two synonymous polymorphisms were detected in the coding region but no mutations were found in 49 primary neuroblastomas. Radiation hybrid mapping, BAC physical mapping, BAC sequencing, genomic sequencing of 49 tumor samples Cytogenetics and cell genetics High 10894940
2001 Cortistatin (but not somatostatin) binds to growth hormone secretagogue receptors (GHS-R) in human pituitary membranes, competing with 125I-Tyr-Ala-hexarelin and ghrelin; CST-14 and ghrelin showed similar affinity (~5×10⁻⁷ mol/L) for GHS-R, whereas somatostatin fragments did not displace binding. Radioligand competition binding assay on human pituitary membranes using 125I-Tyr-Ala-hexarelin Journal of endocrinological investigation Medium 11227737
2002 In humans, intravenous cortistatin-14 inhibits basal and GHRH-stimulated GH secretion and insulin secretion to the same extent as somatostatin-14; unlike somatostatin, CST-14 also binds GHS-R and partially blunts ghrelin-induced GH release; neither CST-14 nor SST-14 modified PRL or ACTH responses to ghrelin. Randomized crossover clinical study in 6 normal adults; hormone measurements by RIA/IRMA during iv infusion of CST-14, SS-14, GHRH, and ghrelin The Journal of clinical endocrinology and metabolism Medium 12161511
2003 MrgX2 (MRGPRX2), an orphan G-protein-coupled receptor expressed in dorsal root ganglion, was identified as a high-potency receptor for cortistatin-14; cortistatin stimulated intracellular Ca²⁺ increases (Gq-coupled) but had no effect on cAMP in MrgX2-expressing cells; MrgX2 has a pharmacological profile distinct from other Mrg family members. Reverse pharmacology/expression cloning, calcium mobilization assay, cAMP assay, immunohistochemistry, quantitative PCR The Journal of biological chemistry High 12915402
2003 Human monocytes, macrophages, and dendritic cells selectively express sst2 mRNA and cortistatin (CST) mRNA but not somatostatin mRNA; CST mRNA is upregulated during monocyte-to-macrophage/DC differentiation and by LPS stimulation; sst2 protein is present on macrophages but not dendritic cells; CST displaces [125I-Tyr3]octreotide from sst2-expressing cells, indicating CST acts as the endogenous sst2 ligand in immune cells rather than somatostatin. RT-PCR, quantitative RT-PCR, ELISA, confocal microscopy, autoradiography, radioligand binding competition American journal of physiology. Endocrinology and metabolism High 12684217
2003 Human lymphoid tissues and immune cells express CST mRNA (but not SS mRNA, except thymus); CST mRNA expression levels differ across tissues and immune cell types; CST is proposed as the endogenous ligand for sst2 in the human immune system; two differently sized CST cDNA fragments were detected, with T-cell lines expressing both and most B-cell lines expressing only the short fragment. RT-PCR, quantitative RT-PCR, autoradiography on thymic tissue, radioligand displacement assay The Journal of clinical endocrinology and metabolism Medium 12519865
2003 Cortistatin mRNA and protein are present in human pancreatic islet cells (but not exocrine pancreas); islet cells expressing CST also express somatostatin receptors sst2, sst3, and sst5, as well as ghrelin and GHS receptors, suggesting local autocrine/paracrine cortistatin circuits in the endocrine pancreas. RT-PCR, in situ hybridization, immunohistochemistry with anti-CST-17 antibody Journal of endocrinological investigation Medium 14669820
2005 Cortistatin is abundant in human vitreous fluid and significantly contributes to somatostatin-like immunoreactivity (SLI) in vitreous; intravitreous cortistatin levels were higher than plasma levels in both nondiabetic controls and diabetic patients with PDR. Radioimmunoassay with HPLC separation of vitreous and plasma samples from 22 diabetic PDR patients and 22 controls Diabetes care Medium 16043736
2008 Cortistatin is produced by the human retina (both neuroretina and RPE); CST mRNA levels are significantly lower in diabetic retinas compared to nondiabetic donors in both RPE and neuroretina; reduced CST expression is associated with increased GFAP (glial activation) and higher apoptosis (TUNEL-positive cells), establishing CST reduction as an early event in diabetic retinopathy. RT-PCR, confocal laser microscopy immunofluorescence, TUNEL assay in postmortem human eye tissue from 5 diabetic and 5 nondiabetic donors Molecular vision Medium 18709137
2010 Expression of cortistatin (CST) mRNA is reduced in multiple regions of the temporal lobe in Alzheimer's disease patients compared to controls, alongside reduction of somatostatin, somatostatin receptors (sst1-5), and dopamine receptors; neprilysin expression was not altered, suggesting that Aβ accumulation results from lack of SST/CST activation of neprilysin rather than reduced neprilysin expression. Quantitative real-time PCR on postmortem temporal lobe tissue from AD patients and age-matched controls Journal of Alzheimer's disease : JAD Medium 20164562
2013 Cortistatin inhibits platelet-derived growth factor (PDGF)-stimulated proliferation of human vascular smooth muscle cells (SMCs) via binding to somatostatin receptors (sst2 and sst5) and ghrelin receptor, with downstream induction of cAMP and p38-MAPK and inhibition of Akt; cortistatin also impairs lamellipodia formation and migration of SMCs toward PDGF by inhibiting Rac1 activation and cytosolic calcium increases in a ghrelin-receptor-dependent manner; cortistatin-deficient mice develop greater neointimal hyperplasia after carotid artery ligation. Cell proliferation assays, receptor binding (sst2/sst5/ghrelin-R), cAMP measurement, p38/Akt Western blot, Rac1 activity assay, calcium imaging, in vivo carotid ligation model in cortistatin-knockout mice Circulation research High 23595952
2014 Cortistatin-14 exerts anticonvulsant effects in a pilocarpine-induced seizure model in rats and mice; these anticonvulsant actions are mediated by sst2 and sst3 receptors (selective antagonists for each independently reverse the effect), but not by ghrelin receptors (ghrelin receptor knockout mice show comparable CST-14 anticonvulsant effect to wild-type). In vivo microdialysis, telemetry-based EEG recording, pharmacological antagonism with selective sst2 antagonist (cyanamid15486) and sst3 antagonist (SST3-ODN-8), ghrelin receptor knockout mice CNS neuroscience & therapeutics High 24685142
2019 Cortistatin competitively binds to TNF-α receptors TNFR1 and TNFR2 (demonstrated by co-immunoprecipitation and biotin-based solid-phase binding assay), suppresses pro-inflammatory TNF-α function, inhibits NF-κB signaling in chondrocytes, and attenuates osteoarthritis development in vivo; CST-deficient mice show accelerated OA-like phenotype and TNFR1/TNFR2 knockout mice show reduced protective effect of CST. Co-immunoprecipitation, biotin-based solid-phase binding assay, Western blot, RT-PCR, ELISA, immunofluorescence, NF-κB pathway analysis, surgically-induced and spontaneous OA mouse models, TNFR knockout mice, flow cytometry EBioMedicine High 30826358
2020 Cortistatin expression in nucleus pulposus (NP) cells is reduced during aging and TNF-α-induced intervertebral disc degeneration; CST-knockout mice show accelerated metabolic imbalance, enhanced apoptosis, and disorganized NP tissue; exogenous CST inhibits mitochondrial dysfunction and suppresses NLRP3 inflammasome activation through mitochondrial ROS-dependent mechanisms; increased NF-κB pathway activity was associated with IVD degeneration in CST-/- mice. NP tissue/cell isolation from patients and mice, CST-knockout mouse model, TNF-α stimulation, mitochondrial ROS measurement, NLRP3 inflammasome activity assay, NF-κB pathway analysis, Western blot, immunohistochemistry, in vitro and ex vivo experiments Theranostics High 32550919
2021 Cryo-EM structures of MRGPRX2-Gi1 complex bound to cortistatin-14 were resolved; cortistatin-14 occupies a shallow, solvent-exposed ligand-binding pocket; MRGPRX2 shows an unusual kink at TM6 and replacement of the general toggle switch Trp6.48 with Gly6.48, suggesting a distinct activation mechanism; the receptor couples to both Gi and Gq in mast cells. Cryo-electron microscopy structure determination, functional validation (Gi/Gq coupling), antagonist probe development Nature High 34789874 34789875

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2003 The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome research 285 12975309
2003 MrgX2 is a high potency cortistatin receptor expressed in dorsal root ganglion. The Journal of biological chemistry 204 12915402
1987 Pheromonal regulation and sequence of the Saccharomyces cerevisiae SST2 gene: a model for desensitization to pheromone. Molecular and cellular biology 192 2830483
2021 Structure, function and pharmacology of human itch GPCRs. Nature 179 34789874
2000 Cortistatin: a member of the somatostatin neuropeptide family with distinct physiological functions. Brain research. Brain research reviews 166 11011067
2006 Internalization of sst2, sst3, and sst5 receptors: effects of somatostatin agonists and antagonists. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 157 16513620
2003 Expression of somatostatin, cortistatin, and somatostatin receptors in human monocytes, macrophages, and dendritic cells. American journal of physiology. Endocrinology and metabolism 151 12684217
2015 ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease. Science translational medicine 138 26446957
1997 Identification and characterization of a novel human cortistatin-like peptide. Biochemical and biophysical research communications 136 9125122
1997 Immunohistochemical localization of the somatostatin SST2(A) receptor in the rat brain and spinal cord. Neuroscience 134 8971774
2021 Structure, function and pharmacology of human itch receptor complexes. Nature 128 34789875
2020 Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation. Theranostics 124 32550919
2016 TSLP, IL-31, IL-33 and sST2 are new biomarkers in endophenotypic profiling of adult and childhood atopic dermatitis. Journal of the European Academy of Dermatology and Venereology : JEADV 121 27152943
2010 Primary sources and immunological prerequisites for sST2 secretion in humans. Cardiovascular research 118 20363761
2001 Cortistatin, but not somatostatin, binds to growth hormone secretagogue (GHS) receptors of human pituitary gland. Journal of endocrinological investigation 111 11227737
2018 Conflicting vascular and metabolic impact of the IL-33/sST2 axis. Cardiovascular research 109 29982301
2011 Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis. Journal of Korean medical science 99 21935266
1998 sst2 somatostatin receptor mediates negative regulation of insulin receptor signaling through the tyrosine phosphatase SHP-1. The Journal of biological chemistry 98 9507021
1997 Cloning, mRNA expression, and chromosomal mapping of mouse and human preprocortistatin. Genomics 97 9205124
1997 sst2 somatostatin receptor expression reverses tumorigenicity of human pancreatic cancer cells. Cancer research 95 9041201
2000 Involvement of sst2 somatostatin receptor in locomotor, exploratory activity and emotional reactivity in mice. The European journal of neuroscience 89 11029646
2016 Soluble IL-33 receptor sST2 inhibits colorectal cancer malignant growth by modifying the tumour microenvironment. Nature communications 87 27882929
2009 Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 81 19086053
2006 Direct binding of p85 to sst2 somatostatin receptor reveals a novel mechanism for inhibiting PI3K pathway. The EMBO journal 77 16917505
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 75 12519865
2008 Lowered cortistatin expression is an early event in the human diabetic retina and is associated with apoptosis and glial activation. Molecular vision 71 18709137
2002 Endocrine activities of cortistatin-14 and its interaction with GHRH and ghrelin in humans. The Journal of clinical endocrinology and metabolism 67 12161511
2008 Preparation and biological evaluation of 64Cu-CB-TE2A-sst2-ANT, a somatostatin antagonist for PET imaging of somatostatin receptor-positive tumors. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 66 18927338
2009 Anxiolytic and antidepressant actions of somatostatin: the role of sst2 and sst3 receptors. Psychopharmacology 64 19609508
2001 Somatostatin sst(2) receptor-mediated inhibition of mesenteric afferent nerves of the jejunum in the anesthetized rat. Gastroenterology 62 11487545
1998 Chronic treatment with estrogen up-regulates expression of sst2 messenger ribonucleic acid (mRNA) but down-regulates expression of sst5 mRNA in rat pituitaries. Endocrinology 61 9528936
1998 Fates of endocytosed somatostatin sst2 receptors and associated agonists. The Biochemical journal 61 9820803
2020 IL-33 and its decoy sST2 in patients with Alzheimer's disease and mild cognitive impairment. Journal of neuroinflammation 60 32505187
2019 Cortistatin binds to TNF-α receptors and protects against osteoarthritis. EBioMedicine 60 30826358
2010 Comprehensive copy number variant (CNV) analysis of neuronal pathways genes in psychiatric disorders identifies rare variants within patients. Journal of psychiatric research 59 20398908
2001 Creation of genome-wide protein expression libraries using random activation of gene expression. Nature biotechnology 59 11329013
2010 Expression of Somatostatin, cortistatin, and their receptors, as well as dopamine receptors, but not of neprilysin, are reduced in the temporal lobe of Alzheimer's disease patients. Journal of Alzheimer's disease : JAD 58 20164562
1999 Immunohistochemical localization of somatostatin receptor subtypes sst1 and sst2 in the rat retina. Investigative ophthalmology & visual science 58 10476805
2020 The obesity-induced adipokine sST2 exacerbates adipose Treg and ILC2 depletion and promotes insulin resistance. Science advances 57 32426492
2013 Cortistatin inhibits migration and proliferation of human vascular smooth muscle cells and decreases neointimal formation on carotid artery ligation. Circulation research 57 23595952
2017 Association of sST2 and hs-CRP levels with new-onset atrial fibrillation in coronary artery disease. International journal of cardiology 53 28942872
2006 Genome-scale analysis reveals Sst2 as the principal regulator of mating pheromone signaling in the yeast Saccharomyces cerevisiae. Eukaryotic cell 53 16467474
2015 The Association of Serum IL-33 and sST2 with Breast Cancer. Disease markers 52 26456994
2014 Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures. Endocrine-related cancer 52 25012983
2014 The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test. Hormones and behavior 51 24530653
1998 Growth hormone-releasing hormone neurons in the arcuate nucleus express both Sst1 and Sst2 somatostatin receptor genes. Endocrinology 50 9492082
2005 Somatostatin molecular variants in the vitreous fluid: a comparative study between diabetic patients with proliferative diabetic retinopathy and nondiabetic control subjects. Diabetes care 49 16043736
1998 [125I][Tyr3]octreotide labels human somatostatin sst2 and sst5 receptors. European journal of pharmacology 47 9652348
1998 Identification of somatostatin sst2(a) receptor expressing neurones in central regions involved in nociception. Brain research 47 9666064
1996 Induction of a negative autocrine loop by expression of sst2 somatostatin receptor in NIH 3T3 cells. The Journal of clinical investigation 46 8621771
2015 Does corticosterone regulate the onset of breeding in free-living birds?: The CORT-Flexibility Hypothesis and six potential mechanisms for priming corticosteroid function. Hormones and behavior 42 26524719
2013 Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic factors in preeclampsia. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 42 23488689
2006 Novel synergistic mechanism for sst2 somatostatin and TNFalpha receptors to induce apoptosis: crosstalk between NF-kappaB and JNK pathways. Cell death and differentiation 42 16645635
1998 Molecular cloning and functional characterization of a rat somatostatin sst2(b) receptor splice variant. British journal of pharmacology 42 9776362
2021 Anti-depressive effects of Jiao-Tai-Wan on CORT-induced depression in mice by inhibiting inflammation and microglia activation. Journal of ethnopharmacology 41 34627986
2018 Differential and Predictive Value of Galectin-3 and Soluble Suppression of Tumorigenicity-2 (sST2) in Heart Failure with Preserved Ejection Fraction. Medical science monitor : international medical journal of experimental and clinical research 40 30039808
2001 Influence of the somatostatin receptor sst2 on growth factor signal cascades in human glioma cells. Brain research. Molecular brain research 39 11223155
2017 Somatostatin binds to the human amyloid β peptide and favors the formation of distinct oligomers. eLife 37 28650319
2021 Soluble suppression of tumorigenicity 2 (sST2) for predicting disease severity or mortality outcomes in cardiovascular diseases: A systematic review and meta-analysis. International journal of cardiology. Heart & vasculature 34 34712771
2020 New insights into the effects of caffeine on adult hippocampal neurogenesis in stressed mice: Inhibition of CORT-induced microglia activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 32619083
1999 Evidence that somatostatin sst2 receptors mediate striatal dopamine release. British journal of pharmacology 34 10578151
2021 Alarmins (IL-33, sST2, HMGB1, and S100B) as potential biomarkers for schizophrenia. Journal of psychiatric research 33 33957300
2005 Characterization of the bystander effect of somatostatin receptor sst2 after in vivo gene transfer into human pancreatic cancer cells. Human gene therapy 33 16218779
1996 Role of Sst2 in modulating G protein-coupled receptor signaling. Biochemical and biophysical research communications 33 8806621
2002 Functional characterisation of the putative somatostatin sst2 receptor antagonist CYN 154806. Naunyn-Schmiedeberg's archives of pharmacology 32 12616335
2018 cAMP/PKA-induced filamin A (FLNA) phosphorylation inhibits SST2 signal transduction in GH-secreting pituitary tumor cells. Cancer letters 31 30098401
2022 Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers. Pituitary 30 35000098
2013 Elevated serum level of IL-33 and sST2 in patients with ankylosing spondylitis: associated with disease activity and vascular endothelial growth factor. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 30 23552178
2010 Yttrium-90 DOTATOC therapy in GEP-NET and other SST2 expressing tumors: a selected review. Annals of nuclear medicine 30 21107762
2009 Thrombospondin-1 is a critical effector of oncosuppressive activity of sst2 somatostatin receptor on pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America 30 19805200
2003 Native somatostatin sst2 and sst5 receptors functionally coupled to Gi/o-protein, but not to the serum response element in AtT-20 mouse tumour corticotrophs. Naunyn-Schmiedeberg's archives of pharmacology 30 12750875
2002 Early cerebral activities of the environmental estrogen bisphenol A appear to act via the somatostatin receptor subtype sst(2). Environmental health perspectives 30 12060835
2001 Transcriptional activation of mouse sst2 somatostatin receptor promoter by transforming growth factor-beta. Involvement of Smad4. The Journal of biological chemistry 30 11278805
2006 SST2, a regulator of G-protein signaling for the Candida albicans mating response pathway. Eukaryotic cell 29 16400182
2020 Angiotensin Converting Enzyme Inhibitors (ACEIs) Decrease the Progression of Cardiac Fibrosis in Rheumatic Heart Disease Through the Inhibition of IL-33/sST2. Frontiers in cardiovascular medicine 28 32850979
2008 The role of cortistatin in the human immune system. Molecular and cellular endocrinology 28 18450367
2006 Porcine somatostatin receptor 2 displays typical pharmacological sst2 features but unique dynamics of homodimerization and internalization. Endocrinology 28 17053026
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 28 10894940
1996 Somatostatin sst2 receptor-mediated inhibition of parietal cell function in rat isolated gastric mucosa. British journal of pharmacology 28 8922739
2023 Rosmarinic acid alleviate CORT-induced depressive-like behavior by promoting neurogenesis and regulating BDNF/TrkB/PI3K signaling axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 27 38070249
2014 Cellular noise suppression by the regulator of G protein signaling Sst2. Molecular cell 27 24954905
2016 High plasma sST2 levels in gastric cancer and their association with metastatic disease. Cancer biomarkers : section A of Disease markers 26 26835712
1996 Differences in the operational characteristics of the human recombinant somatostatin receptor types, sst1 and sst2, in mouse fibroblast (Ltk-) cells. British journal of pharmacology 25 8646408
2017 Serum levels of interleukin-33 and its soluble form receptor (sST2) are associated with cognitive performance in patients with schizophrenia. Comprehensive psychiatry 24 28126482
2021 The miRNA199a/SIRT1/P300/Yy1/sST2 signaling axis regulates adverse cardiac remodeling following MI. Scientific reports 23 33594087
2020 Expression of the Novel Cardiac Biomarkers sST2, GDF-15, suPAR, and H-FABP in HFpEF Patients Compared to ICM, DCM, and Controls. Journal of clinical medicine 23 32326570
2018 Eplerenone Modulates Interleukin-33/sST2 Signaling and IL-1β in Left Ventricular Systolic Dysfunction After Acute Myocardial Infarction. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 23 29565745
2004 Subtype selective interactions of somatostatin and somatostatin analogs with sst1, sst2, and sst5 in BON-1 cells. Medical oncology (Northwood, London, England) 23 15456957
2003 Inhibitory role of the somatostatin receptor SST2 on the intracrine-regulated cell proliferation induced by the 210-amino acid fibroblast growth factor-2 isoform: implication of JAK2. The Journal of biological chemistry 23 12665520
1999 Processing of rat preprocortistatin in mouse AtT-20 cells. Journal of neurochemistry 23 10461921
2018 The Selective Glucocorticoid Receptor Modulator Cort 113176 Reduces Neurodegeneration and Neuroinflammation in Wobbler Mice Spinal Cord. Neuroscience 22 29890290
2008 Identification of transcriptional regulatory elements in the human somatostatin receptor sst2 promoter and regions including estrogen response element half-site for estrogen activation. Journal of molecular endocrinology 22 18234910
2003 Somatostatin receptors (sst2) are coupled to Go and modulate GTPase activity in the rabbit retina. Journal of neurochemistry 22 12562507
2003 Presence of cortistatin in the human pancreas. Journal of endocrinological investigation 22 14669820
2001 Transcription of SST2 somatostatin receptor gene in human pancreatic cancer cells is altered by single nucleotide promoter polymorphism. Gastroenterology 22 11208729
2000 Characterisation of somatostatin sst2 receptor splice variants. Journal of physiology, Paris 22 11088000
2020 Circulating sST2 and catestatin levels in patients with acute worsening of heart failure: a report from the CATSTAT-HF study. ESC heart failure 21 32681700
2015 Elevations of inflammatory markers PTX3 and sST2 after resuscitation from cardiac arrest are associated with multiple organ dysfunction syndrome and early death. Clinical chemistry and laboratory medicine 21 25993733
2023 Synergistic neuroprotective effects of two natural medicinal plants against CORT-induced nerve cell injury by correcting neurotransmitter deficits and inflammation imbalance. Phytomedicine : international journal of phytotherapy and phytopharmacology 20 37748389
2013 The role of the serum IL-33/sST2 axis and inflammatory cytokines in chronic obstructive pulmonary disease. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20 24102578
2014 Cholesterol deregulation induced by chronic corticosterone (CORT) stress in pectoralis major of broiler chickens. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 19 25038300
2016 Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours. Endocrine-related cancer 18 26733502
2001 Topology of the signal transduction of the G protein-coupled somatostatin receptor sst2 in human glioma cells. Cell and tissue research 18 11236002
2012 Phosphorylation of sst2 receptors in neuroendocrine tumors after octreotide treatment of patients. The American journal of pathology 17 22538189
2019 Cytoskeleton Protein Filamin A Is Required for Efficient Somatostatin Receptor Type 2 Internalization and Recycling through Rab5 and Rab4 Sorting Endosomes in Tumor Somatotroph Cells. Neuroendocrinology 16 31574507
1999 Differential distribution of somatostatin sst2 receptor splice variants in rat gastric mucosa. Cell and tissue research 16 10398894
2023 GLP-1 plays a protective role in hippocampal neuronal cells by activating cAMP-CREB-BDNF signaling pathway against CORT+HG-induced toxicity. Heliyon 15 37576283
2018 Adenovirus-mediated overexpression of sST2 attenuates cardiac injury in the rat with severe acute pancreatitis. Life sciences 15 29653119
2022 Higher serum sST2 is associated with increased left atrial low-voltage areas and atrial fibrillation recurrence in patients undergoing radiofrequency ablation. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing 14 35175491
2020 Cancer cell-derived interleukin-33 decoy receptor sST2 enhances orthotopic tumor growth in a murine pancreatic cancer model. PloS one 14 32340025
2019 MiR-128/SOX7 alleviates myocardial ischemia injury by regulating IL-33/sST2 in acute myocardial infarction. Biological chemistry 14 30265647
2017 The integrated value of sST2 and global longitudinal strain in the early stratification of patients with severe aortic valve stenosis: a translational imaging approach. The international journal of cardiovascular imaging 14 28664478
2014 Carboxyl-terminal multi-site phosphorylation regulates internalization and desensitization of the human sst2 somatostatin receptor. Molecular and cellular endocrinology 14 24565897
2014 Cortistatin-14 mediates its anticonvulsant effects via sst2 and sst3 but not ghrelin receptors. CNS neuroscience & therapeutics 14 24685142
2012 Different molecular targets of Icariin on bMSCs in CORT and OVX -rats. Frontiers in bioscience (Elite edition) 14 22201948
2008 Somatostatin increases rat locomotor activity by activating sst(2) and sst (4) receptors in the striatum and via glutamatergic involvement. Naunyn-Schmiedeberg's archives of pharmacology 14 18766327
2020 Development of a Novel Homogeneous Nanoparticle-Based Assay for Rapid and High-Throughput Quantitation of the sST2 Protein in Human Serum. International journal of nanomedicine 13 33408473
2019 Alteration of the IL-33-sST2 pathway in hypertensive patients and a mouse model. Hypertension research : official journal of the Japanese Society of Hypertension 13 31235844
2014 Single sST2 protein measurement predicts adverse outcomes at 1-year follow-up in patients with chronic heart failure. Polskie Archiwum Medycyny Wewnetrznej 13 25041760
2012 Role of SST, CORT and ghrelin and its receptors at the endocrine pancreas. Frontiers in endocrinology 13 23162532
2003 Autocrine activation of the pheromone response pathway in matalpha2- cells is attenuated by SST2- and ASG7-dependent mechanisms. Molecular genetics and genomics : MGG 13 13680367
1995 Localization and pharmacological characterization of somatostatin sst2 sites in the rat cerebellum. Naunyn-Schmiedeberg's archives of pharmacology 13 9053731
2022 Effects of liraglutide vs. lifestyle changes on soluble suppression of tumorigenesis-2 (sST2) and galectin-3 in obese subjects with prediabetes or type 2 diabetes after comparable weight loss. Cardiovascular diabetology 12 35277168
2021 Predictive values of sST2 and IL-33 for heart failure in patients with acute myocardial infarction. Experimental biology and medicine (Maywood, N.J.) 12 34342552
2017 A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis. Scientific reports 12 28860510