Affinage

SSTR1

Somatostatin receptor type 1 · UniProt P30872

Round 2 corrected
Length
391 aa
Mass
42.7 kDa
Annotated
2026-04-28
76 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SSTR1 is a Gi-coupled somatostatin receptor that transduces antiproliferative, secretory-inhibitory, and metabolic signals through multiple effector pathways. Upon somatostatin binding, SSTR1 inhibits adenylyl cyclase via pertussis toxin-sensitive Giα3 and stimulates phosphotyrosine phosphatase (SHP-2) activity, which feeds into a Gβγ→Ras→PI3K→c-Src→Raf-1→ERK cascade culminating in p21(cip1/WAF1) upregulation and cell-cycle arrest (PMID:9892010, PMID:7524497, PMID:7854346). Uniquely among somatostatin receptors, SSTR1 inhibits Na⁺/H⁺ exchange through a pertussis toxin-insensitive mechanism structurally mapped to transmembrane domains 2–6, forms selective ligand-dependent heterodimers with SSTR5 that alter signaling efficiency, and coordinates with SSTR5 to regulate pancreatic insulin secretion and glucose homeostasis as demonstrated by single- and double-knockout mouse models (PMID:8144617, PMID:10713101, PMID:15349106, PMID:16406265). Cryo-EM structures of Gi-coupled SSTR1 bound to pasireotide and the SSTR1-selective agonist L-797591 reveal an extended orthosteric pocket with subtype-specific residues including Asp137 (TM3) and Leu107 (TM2) governing selective agonist accommodation (PMID:39361640, PMID:10329447).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1992 High

    Molecular cloning of SSTR1 established it as a 391-amino-acid seven-transmembrane receptor with high-affinity somatostatin binding, resolving the molecular identity of somatostatin receptor subtypes.

    Evidence cDNA cloning with stable expression in CHO cells and radioligand binding assays

    PMID:1346068

    Open questions at the time
    • No effector coupling or signaling pathway identified
    • Tissue-specific function unknown
  2. 1994 High

    Functional coupling studies revealed that SSTR1 inhibits adenylyl cyclase via Giα3, stimulates phosphotyrosine phosphatase activity, and—uniquely among SSTRs—inhibits Na⁺/H⁺ exchange through a pertussis toxin-insensitive mechanism, establishing SSTR1 as a multi-effector receptor with subtype-specific signaling.

    Evidence Heterologous expression in CHO-K1 and Ltk⁻ cells with cAMP, PTP, and NHE assays; Giα-specific antiserum blockade; chimeric receptor analysis localizing NHE coupling to TM2-TM6 domains

    PMID:7524497 PMID:7854346 PMID:7907795 PMID:8144617

    Open questions at the time
    • Identity of the specific phosphotyrosine phosphatase was not determined
    • Molecular mechanism of PTx-insensitive NHE coupling unresolved
    • Downstream consequences of PTP activation for cell fate unknown
  3. 1999 High

    The antiproliferative signaling cascade downstream of SSTR1 was delineated as a Gβγ→Ras→PI3K→c-Src→Raf-1→ERK pathway dependent on SHP-2, culminating in p21(cip1/WAF1) upregulation and cell-cycle arrest, resolving the paradox of growth-inhibitory ERK activation.

    Evidence Dominant-negative constructs for Ras, Raf, PI3K, c-Src, and SHP-2 in stably transfected CHO-K1 cells with ERK activity and p21 immunoblotting

    PMID:11088001 PMID:9892010

    Open questions at the time
    • Pathway validated only in CHO-K1 cells; relevance to endogenous SSTR1-expressing tissues not confirmed
    • Mechanism by which SHP-2 activates c-Src not fully defined
  4. 1999 High

    Mutagenesis identified Asp137 in TM3 and Leu107 in TM2 as critical determinants of SSTR1-selective agonist recognition, providing the first structural basis for receptor subtype selectivity.

    Evidence Chimeric SSTR1/SSTR2 receptors and site-directed mutagenesis with radioligand binding and microphysiometry in transfected cells

    PMID:10329447

    Open questions at the time
    • No high-resolution structural data at this time
    • Additional residues contributing to full selectivity profile unexplored
  5. 2000 High

    Discovery that SSTR1 forms ligand-induced homodimers and selective heterodimers with SSTR5 (but not SSTR4), with heterodimerization altering binding affinity and co-internalization, established receptor oligomerization as a regulatory mechanism for SSTR signaling.

    Evidence FRET, co-immunoprecipitation, and confocal microscopy in CHO-K1 cells co-expressing tagged receptors

    PMID:10713101 PMID:15247250

    Open questions at the time
    • Physiological relevance of heterodimerization in native tissues not demonstrated
    • Downstream signaling consequences of dimers vs. monomers incompletely characterized
  6. 2004 High

    Single and double knockout of SSTR1 and SSTR5 in mice revealed non-redundant, coordinate regulation of insulin secretion and glucose homeostasis, establishing an essential physiological role for SSTR1 in pancreatic endocrine function.

    Evidence SSTR1⁻/⁻ and SSTR1/5⁻/⁻ mice with glucose tolerance tests, perfused pancreas, islet culture, and immunohistochemistry

    PMID:15349106 PMID:16406265

    Open questions at the time
    • Mechanism by which SSTR1 loss alters SSTR5 expression unknown
    • Human relevance of knockout phenotypes not established
  7. 2009 Medium

    In vivo anti-tumor activity of SSTR1 was demonstrated in glioma xenografts, where selective SSTR1 activation suppressed tumor growth, neovascularization, and ERK phosphorylation while upregulating p27(Kip1), confirming cytostatic rather than apoptotic mechanisms.

    Evidence Nude mouse C6 glioma xenograft with SSTR1-selective agonist BIM-23745, immunohistochemistry for Ki-67, p-ERK, p27, and caspase-3

    PMID:19706788

    Open questions at the time
    • Single tumor model and single lab
    • Antiangiogenic mechanism not molecularly defined
    • Switch from ERK-dependent p21 (CHO cells) to p27 (glioma) upregulation unexplained
  8. 2024 High

    Cryo-EM structures of Gi-coupled SSTR1 bound to pasireotide and L-797591 revealed the atomic basis of the orthosteric binding pocket, confirming mutagenesis-predicted selectivity determinants and providing a structural framework for subtype-selective drug design.

    Evidence Cryo-EM structure determination with site-directed mutagenesis validation and functional assays

    PMID:39361640

    Open questions at the time
    • No structure of SSTR1 in apo or antagonist-bound state
    • Structural basis of SSTR1/SSTR5 heterodimerization unknown
    • Mechanism of PTx-insensitive NHE coupling not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for SSTR1's unique pertussis toxin-insensitive coupling to Na⁺/H⁺ exchange, the physiological significance of SSTR1/SSTR5 heterodimerization in native human tissues, and the molecular mechanism by which SSTR1 loss alters SSTR5 expression in pancreatic islets.
  • No structural model for PTx-insensitive NHE pathway coupling
  • SSTR1/SSTR5 heterodimer not demonstrated in native tissue
  • Human genetic studies linking SSTR1 variants to metabolic disease absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 2 R-HSA-392499 Metabolism of proteins 2
Partners
GNAI3PTPN11SRCSSTR5

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 SSTR1 was cloned and functionally characterized as a seven-transmembrane G protein-coupled receptor with 391 amino acids. Stably transfected CHO cells expressing SSTR1 exhibited specific, high-affinity somatostatin binding (higher affinity for somatostatin-14 than somatostatin-28), establishing SSTR1 as a bona fide somatostatin receptor. cDNA cloning, stable transfection in CHO cells, radioligand binding assays, RNA blotting Proceedings of the National Academy of Sciences of the United States of America High 1346068
1993 SSTR1 gene was chromosomally mapped to human chromosome 14q13, and a simple tandem repeat polymorphism was identified within the SSTR1 gene. Somatic cell hybrid panel segregation analysis, fluorescence in situ hybridization (FISH) Genomics High 8449518
1993 Human SSTR1 stably expressed in HEK 293 cells couples to inhibition of forskolin-induced cAMP production, demonstrating functional coupling to adenylyl cyclase inhibition. Stable transfection in HEK293 cells, cAMP measurement assay FEBS letters High 8405411
1994 SSTR1 stably expressed in CHO-K1 cells couples to inhibition of adenylyl cyclase via pertussis toxin-sensitive G proteins (Gi), and this coupling requires GTP. Specifically, antiserum against Giα3 (but not Giα1/Giα2) blocked SSTR1-mediated inhibition of adenylyl cyclase, identifying Giα3 as the dominant G protein coupling partner. SSTR1 additionally couples to stimulation of inositol 1,4,5-trisphosphate (IP3) formation, also through a pertussis toxin-sensitive mechanism. Stable transfection in CHO cells, cAMP and IP3 measurement assays, pertussis toxin pretreatment, specific Giα antiserum blockade Biochemical and biophysical research communications High 7524497
1994 SSTR1 and SSTR2 stably expressed in CHO-K1 cells both inhibit adenylyl cyclase by approximately 35% via pertussis toxin-sensitive G proteins (Gi). Both SS14 and SS28 activate SSTR1 with high affinity (nanomolar ED50), whereas the synthetic analog MK678 does not activate SSTR1, establishing a pharmacological distinction between the two receptor subtypes. Stable transfection in CHO-K1 cells, adenylyl cyclase assay, pertussis toxin pretreatment, radioligand binding Endocrinology High 7907016
1994 Somatostatin activation of SSTR1 stimulates phosphotyrosine phosphatase (PTP) activity in CHO-K1 cells with an EC50 of ~70 nM. This activation is sensitive to pertussis toxin. PTP stimulation in pituitary cell lines correlates with endogenous SSTR1 expression, suggesting SSTR1 couples to PTP stimulation as an effector pathway distinct from adenylyl cyclase inhibition. Stable transfection in CHO-K1 cells, phosphotyrosine phosphatase activity assay, pertussis toxin treatment, comparison with endogenous pituitary cell expression Molecular endocrinology High 7854346
1994 SSTR1 and SSTR2 display distinct signaling properties when stably expressed in mouse fibroblast Ltk- or transiently in HEK293 cells. Both subtypes mediate somatostatin inhibition of cAMP via pertussis toxin-sensitive G proteins. However, only SSTR1 mediates somatostatin inhibition of Na+/H+ exchange activity, and this effect is pertussis toxin-insensitive. Chimeric receptor analysis localized the structural determinant for SSTR1-specific Na+/H+ exchanger coupling to sequences spanning the second through sixth hydrophobic domains (including second and third cytoplasmic loops), outside the third cytoplasmic loop alone. Stable and transient transfection, cAMP assay, Na+/H+ exchange activity assay, pertussis toxin treatment, chimeric receptor construction and functional analysis The Journal of biological chemistry High 8144617
1994 In cells expressing SSTR1 or SSTR2, somatostatin analogues RC-160 and SMS-201-995 stimulate tyrosine phosphatase activity and inhibit serum-stimulated cell proliferation. In SSTR1-expressing cells, RC-160 (but not SMS-201-995) induced tyrosine phosphatase stimulation, consistent with RC-160's higher affinity for SSTR1. The correlation between receptor-binding affinity, tyrosine phosphatase stimulation, and antiproliferative potency implicates tyrosine phosphatase as a transducer of the SSTR1-mediated growth inhibition signal. Transfection in COS-7 and NIH 3T3 cells, radioligand competition binding assays, tyrosine phosphatase activity assay, cell proliferation assay (serum-stimulated), adenylyl cyclase assay Proceedings of the National Academy of Sciences of the United States of America High 7907795
1996 The first selective SSTR1 agonist, des-AA1,2,5-[DTrp8, IAmp9]SRIF (and its radiolabeled analog), was developed. This ligand binds human SSTR1 with an affinity of 1.8 nM (Kd ~0.5 nM) but does not bind other SSTR subtypes. GTPγS reduced binding of the selective analog to SSTR1 (an effect prevented by pertussis toxin), but did not affect SRIF binding to SSTR1, indicating the selective agonist binds SSTR1 in a functionally distinct, G protein-coupled conformation. Radioligand competition binding assays in COS-7 cells expressing human SSTR1, saturation binding, GTPγS and pertussis toxin modulation of binding The Journal of pharmacology and experimental therapeutics High 8786539
1997 When SSTR1 and SSTR2 are individually expressed in rat pituitary GH12C1 and F4C1 cells lacking endogenous SSTRs: both couple to inhibition of Ca2+ influx and membrane hyperpolarization via pertussis toxin-sensitive G proteins; both mediate adenylyl cyclase inhibition via PTx-sensitive pathways; but only SSTR2 (not SSTR1) stimulates phospholipase C and increases intracellular Ca2+ from intracellular stores. Chimeric receptor analysis showed that sequences beyond the three intracellular loops (i.e., transmembrane domains) are required for SSTR2's unique PLC coupling. Stable transfection in pituitary GH12C1 and F4C1 cells lacking endogenous SSTRs, Ca2+ imaging, membrane potential measurements, cAMP assay, IP3/PLC assay, pertussis toxin treatment, chimeric receptor construction The Journal of biological chemistry High 9228036
1999 SSTR1 stably expressed in CHO-K1 cells activates ERK (MAP kinase) in response to somatostatin, paradoxically augmenting fibroblast growth factor-stimulated ERK activity while antagonizing proliferation. SSTR1-mediated ERK activation requires: (1) pertussis toxin-sensitive Gβγ subunits, (2) Ras, (3) phosphatidylinositol 3-kinase, (4) Raf-1 kinase, and (5) the protein tyrosine phosphatase SHP-2. This ERK activation results in upregulation of the CDK inhibitor p21(cip1/WAF1), linking the SSTR1→SHP-2→ERK axis to the antiproliferative mechanism. Stable transfection in CHO-K1 cells, ERK activity assay (MAP kinase assay), pertussis toxin treatment, dominant-negative Ras and PI3K constructs, Raf-1 inhibition, SHP-2 manipulation, p21 immunoblotting Molecular endocrinology High 9892010
1999 Structural determinants of SSTR1-selective ligand binding were mapped using chimeric SSTR1/SSTR2 receptors and site-directed mutagenesis. Asp137 in transmembrane domain 3 (TM3) of SSTR1 forms an ion pair with the IAmp9 moiety of selective agonist CH275; mutation Asp137→Asn caused loss of binding and reduced potency. Leu107 in TM2 of SSTR1 provides a hydrophobic interaction with the isopropyl group of IAmp; Leu107→Phe substitution reduced CH275 affinity 20-fold without affecting SS affinity. Reciprocal Phe→Leu in a chimeric receptor restored CH275 affinity. These findings define Asp137 (TM3) and Leu107 (TM2) as key determinants of SSTR1 ligand selectivity. Chimeric SSTR1/SSTR2 receptor construction, site-directed mutagenesis (Asp137Asn, Leu107Phe), radioligand binding assays, microphysiometry (extracellular acidification rate) Biochemical and biophysical research communications High 10329447
1999 Using the silicon-based Cytosensor microphysiometer to measure extracellular acidification rate (ECAR) in pituitary F4C1 cells (lacking endogenous SSTRs), SSTR1 activation by somatostatin uniquely causes a decrease in ECAR (not previously observed for any receptor), while SSTR2 causes a biphasic ECAR response (increase then decrease). Both SSTR1- and SSTR2-mediated ECAR decreases are abolished by pertussis toxin. The ECAR responses involve both amiloride-sensitive and amiloride-insensitive Na+-dependent acid transport mechanisms, and removal of extracellular Na+ abolishes responses. Stable transfection in F4C1 pituitary cells, Cytosensor microphysiometry (ECAR measurement), pertussis toxin pretreatment, pharmacological inhibitors (methylisobutylamiloride), Na+-free conditions, receptor-selective agonists (MK678, CH275) Cellular signalling High 10405760
2000 SSTR subtypes form homo- and heterodimers. Ligand activation induces SSTR1 homodimerization and SSTR1/SSTR5 heterodimerization as demonstrated by FRET analysis, pharmacological binding studies, and biochemical approaches. Dimerization alters functional properties including ligand binding affinity and agonist-induced receptor internalization. When SSTR1 and SSTR5 are coexpressed in CHO-K1 cells and treated with agonist, they internalize together into cytoplasmic vesicles. SSTR5 forms heterodimers with SSTR1 but not SSTR4, indicating selectivity of the heterodimerization process. Fluorescence resonance energy transfer (FRET), double-label confocal fluorescence microscopy, co-immunoprecipitation, pharmacological binding assays, transfected mutant and wild-type receptors in CHO-K1 cells The Journal of biological chemistry High 10713101
2000 SSTR1-mediated inhibition of cell proliferation in CHO-K1 cells correlates with activation of the MAP kinase cascade. The antiproliferative signal of SSTR1 requires Gβγ subunits from a pertussis toxin-sensitive G protein, Ras, Raf-1, PI3K, c-Src (a cytosolic tyrosine kinase), and SHP-2 (protein tyrosine phosphatase) to activate ERK. SHP-2 activates upstream kinases requiring tyrosine dephosphorylation (such as c-Src). Somatostatin and bFGF synergistically activate ERK via SSTR1, resulting in upregulation of p21cip/WAF1 as the molecular effector of antiproliferative activity. Stable transfection in CHO-K1 cells, ERK/MAP kinase activity assays, pertussis toxin, dominant-negative constructs for Ras/Raf/PI3K/c-Src/SHP-2, p21 expression analysis, proliferation assays Journal of physiology, Paris Medium 11088001
2003 SSTR1 selective activation by BIM-23926 in primary cultures from GH- and PRL-secreting human pituitary adenomas (expressing SSTR1 mRNA) inhibits GH secretion (~32%), PRL secretion (~20%), and reduces cell viability (~20%). The degree of inhibition correlates with SSTR1 mRNA levels, establishing a functional role for SSTR1 in suppressing hormone secretion and cell viability in pituitary adenoma cells. Primary culture of human pituitary adenoma cells, SSTR1-selective agonist (BIM-23926) treatment, RIA/hormone secretion assays, cell viability assay, quantitative RT-PCR for SSTR1 mRNA The Journal of clinical endocrinology and metabolism Medium 12788890
2004 Activation of hSSTR5 but not hSSTR1 is required for SSTR1/SSTR5 heterodimer formation. In cells co-expressing hSSTR1 and hSSTR5, treatment with SSTR5-selective agonist (but not SSTR1-selective agonist) induced heterodimerization, accompanied by increased adenylyl cyclase coupling efficiency. The C-terminal tail of hSSTR5 was identified as a structural determinant of heterodimer formation via chimeric receptor analysis. In contrast, hSSTR1 alone remains monomeric regardless of agonist treatment. Photobleaching FRET microscopy, Western blot, stable co-expression of hSSTR1 and hSSTR5 in live cells, C-tail chimeric receptors, adenylyl cyclase assay, subtype-selective agonist treatment The Journal of biological chemistry High 15247250
2006 SSTR1 knockout mice display altered glucose homeostasis: at 3 months, SSTR1-/- mice have reduced body weight with growth retardation; isolated perfused pancreata show increased basal insulin secretion in vitro, but systemic insulin levels are decreased due to significantly higher insulin clearance rate; SSTR1-/- mice are glucose intolerant at 3 months but show increased glucose tolerance with exaggerated insulin response at 12 months. Immunohistochemistry showed decreased somatostatin staining and decreased SSTR5 expression in SSTR1-/- islets, suggesting SSTR1 regulates SSTR5 expression and coordinates insulin secretion and glucose homeostasis. SSTR1 knockout mouse model, intraperitoneal glucose tolerance test, isolated perfused pancreas model, islet culture, immunohistochemistry, insulin RIA Molecular and cellular endocrinology High 16406265
2004 Double-gene ablation of SSTR1 and SSTR5 in mice results in islet hyperplasia, hyperinsulinemia, and improved glucose tolerance—a phenotype distinct from single-gene ablation of either receptor alone (which causes diabetes). SSTR1/5-/- islets show no response to somatostatin peptides in vitro, confirming ablation. Double-KO mice show increased basal and glucose-stimulated insulin secretion in vitro and exaggerated late-phase insulin secretion in vivo. This demonstrates that SSTR1 and SSTR5 act coordinately and non-redundantly to regulate insulin secretion and glucose homeostasis. SSTR1/SSTR5 double-knockout mouse generation, intraperitoneal glucose tolerance test, isolated perfused mouse pancreas, islet culture with somatostatin treatment, immunohistochemistry Surgery High 15349106
2009 In C6 rat glioma cells in vivo (nude mouse xenograft model), selective SSTR1 agonist BIM-23745 inhibits tumor growth, reduces intratumoral neovascularization, suppresses Ki-67 expression, decreases ERK1/2 phosphorylation, and upregulates p27(Kip1). Combined activation of SSTR1 and SSTR2 (BIM-23704) shows synergistic antiproliferative and antiangiogenic activity exceeding SSTR5 agonist effects. Only modest caspase-3 activation is observed, indicating the mechanism is primarily cytostatic rather than apoptotic. Nude mouse C6 glioma xenograft model, selective SSTR1 agonist (BIM-23745) and bi-selective compounds, tumor growth measurement, immunohistochemistry for Ki-67, phospho-ERK1/2, p27Kip1, and caspase-3 American journal of physiology. Endocrinology and metabolism Medium 19706788
2014 Following intracerebral hemorrhage (ICH) in adult rats, SSTR1 expression is markedly upregulated in neurons surrounding the hematoma. SSTR1 co-localizes with active caspase-3 (pro-apoptotic) and inversely with Bcl-2 (anti-apoptotic) in a time-dependent manner. Knockdown of SSTR1 in PC12 cells specifically reduces neuronal apoptosis. These data identify SSTR1 as a contributor to post-ICH neuronal apoptosis, coupled to caspase-3 activation and reduction of Bcl-2. Rat ICH model (caudate putamen), Western blot, immunohistochemistry, double-labeled immunofluorescence, SSTR1 siRNA knockdown in PC12 cells, behavioral testing Cellular and molecular neurobiology Medium 25035058
2016 In colorectal cancer (CRC), SSTR1-expressing neuroendocrine cells regulate cancer stem cell (ALDH+) quiescence via paracrine signaling. When SSTR1+ cells are co-cultured with ALDH+ cancer stem cells in transwell assays, sphere formation and proliferation of ALDH+ cells are inhibited. ALDH+ cells themselves lack SST and SSTR1 expression, confirming the paracrine mechanism. Inhibition of SSTR1 signaling by cycloSST (a somatostatin antagonist) decreases ALDH+ cell population size and sphere formation, and the ALDH+/SSTR1+ ratio inversely correlates with growth dynamics. Flow cytometry (ALDH, SSTR1 quantification), transwell co-culture assays, sphere formation assay, proliferation assay (doubling time), exogenous SST and cycloSST treatment, primary normal/tumor tissue analysis, CRC cell lines BMC cancer Medium 27927191
2020 In a MPTP-induced Parkinson's disease mouse model and MPP+-treated MN9D dopaminergic cells, the lncRNA HOTAIR is upregulated while SSTR1 is downregulated. HOTAIR binds to the SSTR1 promoter and recruits DNA methyltransferases to increase SSTR1 promoter methylation, thereby suppressing SSTR1 expression. Overexpression of HOTAIR or silencing of SSTR1 enhances dopaminergic neuron apoptosis and exacerbates dyskinesia; conversely, reduced HOTAIR/restored SSTR1 is neuroprotective. The downstream effect of SSTR1 suppression operates through activation of the ERK1/2 signaling axis. MPTP mouse model and MPP+ cell model of PD, HOTAIR overexpression/knockdown, SSTR1 knockdown/overexpression, chromatin immunoprecipitation (ChIP) for HOTAIR binding to SSTR1 promoter, bisulfite sequencing for methylation, Western blot (ERK1/2), cell viability and apoptosis assays, behavioral testing Molecular therapy. Nucleic acids Medium 32927363
2024 Cryo-EM structures of Gi-coupled SSTR1 were determined bound to the FDA-approved panagonist pasireotide and the SSTR1-selective small molecule agonist L-797591. The structures reveal that pasireotide occupies an extended binding pocket conserved across SSTRs, distinct from the binding mode of SST14, octreotide, and lanreotide. The SSTR1 orthosteric pocket accommodates divergent agonists through dynamic conformational changes. Key residues determining SSTR1 vs. SSTR3 ligand selectivity were identified across the orthosteric pocket, and mutagenesis analyses validated these structural determinants. The structures also reveal the molecular mechanism of receptor activation and G protein coupling. Cryo-electron microscopy (cryo-EM) structure determination of Gi-coupled SSTR1 and SSTR3, site-directed mutagenesis, functional assays validating binding and activation Proceedings of the National Academy of Sciences of the United States of America High 39361640

Source papers

Stage 0 corpus · 76 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
1992 Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Proceedings of the National Academy of Sciences of the United States of America 756 1346068
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
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2000 Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. The Journal of biological chemistry 425 10713101
1994 Stimulation of tyrosine phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by human somatostatin receptor subtypes SSTR1 and SSTR2. Proceedings of the National Academy of Sciences of the United States of America 322 7907795
1994 Expression and localization of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger RNAs in primary human tumors using in situ hybridization. Cancer research 294 8012966
2002 Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Archiv : an international journal of pathology 263 12021920
1999 Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis. Diabetes 254 9892225
1997 Identification and characterization of a novel human cortistatin-like peptide. Biochemical and biophysical research communications 136 9125122
1994 Differential expression of five somatostatin receptor subtypes, SSTR1-5, in the CNS and peripheral tissue. Digestion 124 7698537
1999 Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1). Molecular endocrinology (Baltimore, Md.) 112 9892010
1993 Distribution and second messenger coupling of four somatostatin receptor subtypes expressed in brain. FEBS letters 110 8405411
1994 Localization of somatostatin (SRIF) SSTR-1, SSTR-2 and SSTR-3 receptor mRNA in rat brain by in situ hybridization. Naunyn-Schmiedeberg's archives of pharmacology 108 8170498
2010 A large-scale candidate gene association study of age at menarche and age at natural menopause. Human genetics 106 20734064
1997 Expression of the five somatostatin receptor (SSTR1-5) subtypes in rat pituitary somatotrophes: quantitative analysis by double-layer immunofluorescence confocal microscopy. Endocrinology 105 9322965
1994 Differential expression of messenger RNAs for somatostatin receptor subtypes SSTR1, SSTR2 and SSTR3 in adult rat brain: analysis by RNA blotting and in situ hybridization histochemistry. Neuroscience 103 8190266
1997 Cloning, mRNA expression, and chromosomal mapping of mouse and human preprocortistatin. Genomics 97 9205124
2008 Reviews in molecular biology and biotechnology: transmembrane signaling by G protein-coupled receptors. Molecular biotechnology 92 18240029
1999 In vitro characterization of somatostatin receptors in the human thymus and effects of somatostatin and octreotide on cultured thymic epithelial cells. Endocrinology 86 9886848
2005 Expression of somatostatin receptor subtypes (SSTR1-5) in Alzheimer's disease brain: an immunohistochemical analysis. Neuroscience 85 15961235
2003 Somatostatin receptor subtype 1 selective activation in human growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas: effects on cell viability, GH, and PRL secretion. The Journal of clinical endocrinology and metabolism 84 12788890
1994 The somatostatin receptor SSTR1 is coupled to phosphotyrosine phosphatase activity in CHO-K1 cells. Molecular endocrinology (Baltimore, Md.) 83 7854346
2001 Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line tt. The Journal of clinical endocrinology and metabolism 82 11344221
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
2012 Expression of Somatostatin Receptor (SSTR) Subtypes (SSTR-1, 2A, 3, 4 and 5) in Neuroendocrine Tumors Using Real-time RT-PCR Method and Immunohistochemistry. Acta histochemica et cytochemica 78 22829710
1996 Development of a selective agonist at the somatostatin receptor subtype sstr1. The Journal of pharmacology and experimental therapeutics 76 8786539
2004 An improved method for the synthesis of cellulose membrane-bound peptides with free C termini is useful for PDZ domain binding studies. Chemistry & biology 75 15123239
2015 Expression of somatostatin receptors (SSTR1-SSTR5) in meningiomas and its clinicopathological significance. International journal of clinical and experimental pathology 72 26722517
2008 Dissociation of heterotrimeric g proteins in cells. Science signaling 69 18577758
2001 Somatostatin receptor gene expression in human ocular tissues: RT-PCR and immunohistochemical study. Investigative ophthalmology & visual science 69 11527930
1994 Subtype-specific signaling mechanisms of somatostatin receptors SSTR1 and SSTR2. The Journal of biological chemistry 67 8144617
2009 Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment. Pituitary 63 19330452
1995 Patterns of expression of SSTR1 and SSTR2 somatostatin receptor subtypes in the hypothalamus of the adult rat: relationship to neuroendocrine function. Neuroscience 63 7777168
2004 The role of subtype-specific ligand binding and the C-tail domain in dimer formation of human somatostatin receptors. The Journal of biological chemistry 61 15247250
1994 Gene expression of somatostatin receptor subtypes, SSTR1 and SSTR2, in human lung cancer cell lines. Life sciences 61 7968260
2010 Eighteen insulin-like growth factor pathway genes, circulating levels of IGF-I and its binding protein, and risk of prostate and breast cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 59 20810604
2000 Somatostatin receptor 1 (SSTR1)-mediated inhibition of cell proliferation correlates with the activation of the MAP kinase cascade: role of the phosphotyrosine phosphatase SHP-2. Journal of physiology, Paris 59 11088001
2002 Quantitative and functional expression of somatostatin receptor subtypes in human thymocytes. American journal of physiology. Endocrinology and metabolism 58 12376335
2009 Differential expression of somatostatin and dopamine receptor subtype genes in adrenocorticotropin (ACTH)-secreting pituitary tumors and silent corticotroph adenomas. Endocrine journal 56 19318729
1997 Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours. European journal of clinical investigation 56 9279525
2002 Localization and mRNA expression of somatostatin receptor subtypes in human prostatic tissue and prostate cancer cell lines. Urologic oncology 54 12474541
1993 Human somatostatin receptor genes: localization to human chromosomes 14, 17, and 22 and identification of simple tandem repeat polymorphisms. Genomics 52 8449518
2008 Identification of prognostic biomarkers for prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 51 18347174
1994 The somatostatin receptors SSTR1 and SSTR2 are coupled to inhibition of adenylyl cyclase in Chinese hamster ovary cells via pertussis toxin-sensitive pathways. Endocrinology 46 7907016
1995 Pharmacological identity between somatostatin SS-2 binding sites and SSTR-1 receptors. European journal of pharmacology 42 7781706
1997 Both overlapping and distinct signaling pathways for somatostatin receptor subtypes SSTR1 and SSTR2 in pituitary cells. The Journal of biological chemistry 35 9228036
1994 Multiple effector coupling of somatostatin receptor subtype SSTR1. Biochemical and biophysical research communications 33 7524497
2016 Somatostatin signaling via SSTR1 contributes to the quiescence of colon cancer stem cells. BMC cancer 29 27927191
2004 Double-gene ablation of SSTR1 and SSTR5 results in hyperinsulinemia and improved glucose tolerance in mice. Surgery 28 15349106
2007 Colocalization of somatostatin receptor subtypes (SSTR1-5) with somatostatin, NADPH-diaphorase (NADPH-d), and tyrosine hydroxylase in the rat hypothalamus. The Journal of comparative neurology 26 17626271
2009 Differential efficacy of SSTR1, -2, and -5 agonists in the inhibition of C6 glioma growth in nude mice. American journal of physiology. Endocrinology and metabolism 24 19706788
2019 Somatostatin receptors (SSTR1-5) on inhibitory interneurons in the barrel cortex. Brain structure & function 18 31873798
2010 Molecular characterization and polymorphisms of the caprine Somatostatin (SST) and SST Receptor 1 (SSTR1) genes that are linked with growth traits. Molecular biology reports 18 20140708
2010 SSTR1 and SSTR5 subtypes are the dominant forms of somatostatin receptor in neuroendocrine tumors. Folia histochemica et cytobiologica 17 20529830
2006 Alterations in glucose homeostasis in SSTR1 gene-ablated mice. Molecular and cellular endocrinology 17 16406265
2021 Differences in the expression of SSTR1-5 in meningiomas and its therapeutic potential. Neurosurgical review 16 33899156
1999 Structural basis for the binding specificity of a SSTR1-selective analog of somatostatin. Biochemical and biophysical research communications 16 10329447
1999 Identification of distinct signalling pathways for somatostatin receptors SSTR1 and SSTR2 as revealed by microphysiometry. Cellular signalling 14 10405760
2014 Upregulated expression of SSTR1 is involved in neuronal apoptosis and is coupled to the reduction of bcl-2 following intracerebral hemorrhage in adult rats. Cellular and molecular neurobiology 13 25035058
2005 Transfection of SSTR-1 and SSTR-2 inhibits Panc-1 cell proliferation and renders Panc-1 cells responsive to somatostatin analogue. Journal of the American College of Surgeons 13 16183496
2003 Localization of messenger ribonucleic acids for somatostatin receptor subtypes (sstr1-5) in the rat adrenal gland. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 12 12502754
2014 Expressions of Somatostatin Receptor Subtypes (SSTR-1, 2, 3, 4 and 5) in Neuroblastic Tumors; Special Reference to Clinicopathological Correlations with International Neuroblastoma Pathology Classification and Outcomes. Acta histochemica et cytochemica 10 25861128
2020 Molecular-Level Understanding of the Somatostatin Receptor 1 (SSTR1)-Ligand Binding: A Structural Biology Study Based on Computational Methods. ACS omega 9 32875251
2013 Somatostatin receptor 1 (SSTR1) and somatostatin receptor 5 (SSTR5)expression in hepatocellular carcinoma. Hepato-gastroenterology 9 24634938
2012 Immunohistochemical distribution of somatostatin and somatostatin receptor subtypes (SSTR1-5) in hypothalamus of ApoD knockout mice brain. Journal of molecular neuroscience : MN 9 22581439
2021 Identification of Somatostatin Receptor Subtype 1 (SSTR1) Gene Polymorphism and Their Association with Growth Traits in Hulun Buir Sheep. Genes 8 35052417
2020 HOTAIR Accelerates Dyskinesia in a MPTP-Lesioned Mouse Model of PD via SSTR1 Methylation-Mediated ERK1/2 Axis. Molecular therapy. Nucleic acids 5 32927363
2014 Expression and localization of somatostatin receptor types 3, 4 and 5 in the wild-type, SSTR1 and SSTR1/SSTR2 knockout mouse cochlea. Cell and tissue research 5 25149275
2001 Association analysis of somatostatin receptor (SSTR1 and SSTR2) polymorphisms in breast cancer and solar keratosis. Cancer letters 5 11311492
2024 Selective ligand recognition and activation of somatostatin receptors SSTR1 and SSTR3. Proceedings of the National Academy of Sciences of the United States of America 4 39361640
2018 Neuroanatomical connections between kisspeptin neurones and somatostatin neurones in female and male rat hypothalamus: a possible involvement of SSTR1 in kisspeptin release. Journal of neuroendocrinology 4 29543369
2008 [Somatostatin receptors expression (SSTR1-SSTR5) in pheochromocytomas]. Przeglad lekarski 4 19140390
1995 Expression of sstr1 and sstr2 in rat hypothalamus: correlation with receptor binding and distribution of growth hormone regulatory peptides. Ciba Foundation symposium 4 7587644
2000 Mapping of the CYP1A1, SSTR1 and TTF1 genes to pig chromosome 7q refines the porcine-human comparative map. Animal genetics 2 11105212