Sstr5 encodes somatostatin receptor type 5, a class A (rhodopsin-like) Gi/o-coupled GPCR that preferentially binds somatostatin-28 with approximately 30-fold higher affinity than somatostatin-14. The receptor is prominently expressed in the rat anterior pituitary and small intestine, with lower levels in pancreatic islets. Upon somatostatin binding, SSTR5 activates pertussis toxin-sensitive Gi/o proteins to inhibit adenylyl cyclase, reducing intracellular cAMP and suppressing PKA-dependent signaling. Through this mechanism, SSTR5 is a primary negative regulator of insulin secretion from pancreatic beta cells and contributes to glucose homeostasis, as demonstrated by knockout mouse studies showing decreased blood glucose, hyperinsulinemia, and resistance to diet-induced insulin resistance. SSTR5 expression in pituitary is upregulated by glucocorticoids (dexamethasone), linking the hypothalamic-pituitary-adrenal axis to somatostatinergic tone. The receptor can heterodimerize with SSTR2, enhancing SSTR2-mediated growth inhibition. SSTR5 is palmitoylated at Cys-320 by the palmitoyltransferase ZDHHC5, which may regulate membrane localization and G-protein coupling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004994 somatostatin receptor activity | IDA PMID:1362243 Molecular cloning and expression of a pituitary somatostatin... | ACCEPT | Summary: Directly demonstrated by radioligand binding in COS-7 cells transfected with the cloned rat SSTR5 cDNA. The receptor binds somatostatin-28 with ~30-fold preference over somatostatin-14. This is a core molecular function. Reason: IDA from the original cloning paper. Specific binding of 125I-Tyr11-SRIF was demonstrated in membranes from transfected COS-7 cells. Supporting Evidence: PMID:1362243 Membranes prepared from COS-7 cells transfected with the rAP6-26 cDNA showed specific binding of 125I-Tyr11-SRIF, thus identifying the cDNA clone as a novel SRIF receptor file:rat/Sstr5/Sstr5-deep-research-bioreason-sft.md [BioReason correctly identifies] somatostatin receptor activity (GO:0004994) by binding somatostatin peptides at the extracellular N-terminus and transmembrane pocket file:rat/Sstr5/Sstr5-deep-research-falcon.md SSTR5 has been reported to bind both SST forms, with **~10-fold higher affinity for SST-28 than SST-14**, a property often invoked to explain subtype-selective physiological regulation. |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IDA PMID:1362243 Molecular cloning and expression of a pituitary somatostatin... | ACCEPT | Summary: Directly demonstrated in COS-7 cells expressing cloned SSTR5. Somatostatin inhibited forskolin-induced cAMP accumulation, and GTP sensitivity indicated Gi coupling. This is a core signaling pathway for this receptor. Reason: IDA showing functional coupling to adenylyl cyclase inhibition via Gi proteins, confirmed by pertussis toxin sensitivity in human ortholog studies. Supporting Evidence: PMID:1362243 forskolin-induced cAMP accumulation was inhibited by SRIF and SRIF-28, thus confirming that the rAP6-26 cDNA encodes a functional receptor protein...binding of 125I-Tyr11-SRIF was markedly reduced in the presence of Na+ ions and GTP, indicating coupling of rAP6-26 receptors to inhibitory G proteins file:rat/Sstr5/Sstr5-deep-research-falcon.md Across subtypes, SSTR activation is canonically **Gi/Go-coupled** (pertussis-toxin-sensitive), producing **inhibition of adenylyl cyclase** and decreased intracellular **cAMP**, often accompanied by reduced Ca2+ signaling and suppression of secretion. file:rat/Sstr5/Sstr5-deep-research-falcon.md A major 2024 advance is the **cryo-EM solution of SSTR5–Gi complexes** bound to cyclic peptide agonists **cortistatin-17** and **octreotide** at **2.7–2.9 Å resolution**, enabling residue-level mapping of agonist recognition and activation. |
| GO:0004994 somatostatin receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred somatostatin receptor activity, consistent with the IDA evidence from PMID:1362243. Redundant with the direct experimental evidence. Reason: Correct annotation supported by both phylogenetic inference and direct experimental data. RGD:3765 in WITH/FROM is rat Sstr5's own experimental annotation serving as descendant evidence for the PAINT node, which is expected. Supporting Evidence: PMID:1362243 Membranes prepared from COS-7 cells transfected with the rAP6-26 cDNA showed specific binding of 125I-Tyr11-SRIF, thus identifying the cDNA clone as a novel SRIF receptor UniProtKB:P30938 Receptor for somatostatin-28. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. |
| GO:0004994 somatostatin receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from IPR000586 and IPR001184 (somatostatin receptor family/type 5). Correct and consistent with experimental evidence. Reason: Automated annotation from domain signatures that is accurate for this well-characterized somatostatin receptor. Supporting Evidence: PMID:1362243 Membranes prepared from COS-7 cells transfected with the rAP6-26 cDNA showed specific binding of 125I-Tyr11-SRIF, thus identifying the cDNA clone as a novel SRIF receptor UniProtKB:P30938 Receptor for somatostatin-28. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping from IPR000276 (rhodopsin-like GPCR family). Correct but less specific than GO:0004994 (somatostatin receptor activity). Reason: Accurate but redundant with the more specific somatostatin receptor activity annotation. The parent GPCR activity term is implied by the child term. Supporting Evidence: UniProtKB:P30938 Receptor for somatostatin-28. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred plasma membrane localization, consistent with this being a cell-surface GPCR. Supported by UniProt subcellular location annotation. Reason: Correct localization for a seven-transmembrane receptor that binds extracellular somatostatin ligands. Supporting Evidence: PMID:1362243 Membranes prepared from COS-7 cells transfected with the rAP6-26 cDNA showed specific binding of 125I-Tyr11-SRIF |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping to plasma membrane. Correct and redundant with IBA evidence. Reason: Consistent with GPCR biology; the receptor must be at the plasma membrane to bind extracellular somatostatin. Supporting Evidence: UniProtKB:P30938 SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: RGD ISO annotation transferred from the mouse Sstr5 ortholog (MGI:894282). Correct and consistent with direct evidence for this 7TM receptor. Reason: Accurate localization supported by multiple independent evidence lines; the mouse ortholog donor is a one-to-one ortholog with conserved 7TM topology. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:894282 SUPPORTS TRANSFER Mouse Sstr5 ortholog; plasma membrane localization of a 7TM somatostatin receptor transfers without caveat. Supporting Evidence: UniProtKB:P30938 SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. PMID:1362243 Membranes prepared from COS-7 cells transfected with the rAP6-26 cDNA showed specific binding of 125I-Tyr11-SRIF, thus identifying the cDNA clone as a novel SRIF receptor |
| GO:0043005 neuron projection | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred localization to neuron projections. The original rat cloning study reported absence of SSTR5 mRNA from most brain regions by Northern blot and ISH, with expression concentrated in pituitary anterior lobe. However, the falcon deep research notes that later synthesis describes SSTR5 as moderately expressed throughout the brain with brain expression higher in rats than humans, so low-level neural expression cannot be excluded. Regardless, neuron projection is a subcellular-localization (CC) claim that has not been directly demonstrated for rat SSTR5; the annotation is most plausibly a phylogenetic transfer and is not a core localization. Reason: Neuron projection localization is not directly demonstrated for rat SSTR5. The original studies emphasized pituitary/peripheral expression, while later reviews suggest some rat brain expression. Even if SSTR5 is expressed in some neurons, the specific sub-compartmental neuron-projection localization is an IBA transfer, not a core, directly supported localization. Supporting Evidence: PMID:1362243 a approximately 2.6 kilobase mRNA encoding the receptor was present in the pituitary but not in the liver, small intestine, kidney, pancreas, cerebellum, or cortex. Lack of receptor mRNA expression in the brain was confirmed by in situ hybridization histochemical studies file:rat/Sstr5/Sstr5-deep-research-falcon.md SSTR5 is described as **moderately expressed throughout the brain**, and brain SSTR5 expression is stated to be **higher in rats than humans**, supporting biological relevance for rat neuroendocrine regulation. |
| GO:0042923 neuropeptide binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SSTR5 binds the neuropeptide somatostatin. This is correct but less specific than somatostatin receptor activity (GO:0004994). Reason: Accurate as somatostatin is a neuropeptide, but the more specific term GO:0004994 (somatostatin receptor activity) better represents the core function. Supporting Evidence: PMID:1362243 Membranes prepared from COS-7 cells transfected with the rAP6-26 cDNA showed specific binding of 125I-Tyr11-SRIF, thus identifying the cDNA clone as a novel SRIF receptor |
| GO:0007218 neuropeptide signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SSTR5 participates in somatostatin (neuropeptide) signaling. Correct but less specific than GO:0038170 (somatostatin signaling pathway) and GO:0007193 (adenylate cyclase-inhibiting GPCR signaling pathway). Reason: True at a general level -- somatostatin is a neuropeptide -- but the more specific somatostatin signaling pathway term is more informative for this receptor. Supporting Evidence: UniProtKB:P30938 Receptor for somatostatin-28. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO annotation for general GPCR signaling. Correct but less informative than the specific adenylate cyclase-inhibiting pathway annotation. Reason: Subsumed by the more specific GO:0007193 annotation that is supported by IDA evidence. Supporting Evidence: UniProtKB:P30938 Receptor for somatostatin-28. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. |
| GO:0016020 membrane | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Generic membrane localization from InterPro. Correct but uninformative given the more specific plasma membrane annotation. Reason: Too general; plasma membrane (GO:0005886) is more appropriate and already annotated. Supporting Evidence: UniProtKB:P30938 SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. |
| GO:0038170 somatostatin signaling pathway | IEA GO_REF:0000108 | ACCEPT | Summary: Logically inferred from GO:0004994 (somatostatin receptor activity). This is a correct and informative annotation for this receptor. Reason: SSTR5 is a somatostatin receptor, so involvement in the somatostatin signaling pathway is directly entailed. Supported by functional data from PMID:1362243. Supporting Evidence: PMID:1362243 forskolin-induced cAMP accumulation was inhibited by SRIF and SRIF-28 file:rat/Sstr5/Sstr5-deep-research-falcon.md Somatostatin receptors (SSTR1–5) are **class A/rhodopsin-like GPCRs** with a **canonical 7TM topology**. They mediate the inhibitory endocrine and neuromodulatory actions of the peptide hormone **somatostatin** (SST). |
| GO:0071385 cellular response to glucocorticoid stimulus | IEP PMID:14512709 Role of glucocorticoids in the regulation of pituitary somat... | ACCEPT | Summary: SSTR5 mRNA is upregulated by dexamethasone in rat pituitary, both in vivo and in vitro. This is an expression pattern (IEP) annotation indicating that sst5 expression changes in response to glucocorticoids. The response is distinctive -- sst5 is the only subtype increased by DEX while all others decrease. Reason: Well-supported IEP annotation. DEX treatment increases sst5 mRNA in rat pituitary cells at both in vivo and in vitro levels, demonstrating a cellular response. Supporting Evidence: PMID:14512709 High-dose DEX resulted in a decrease in sst1-sst4 mRNA and an increase in sst5 mRNA, independent of adrenal status |
| GO:0071385 cellular response to glucocorticoid stimulus | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred, consistent with the IEP evidence from PMID:14512709. Reason: Redundant with the directly supported IEP annotation but consistent. RGD:3765 in WITH/FROM is rat Sstr5's own IEP annotation acting as descendant evidence for the PAINT node, which is expected. Supporting Evidence: PMID:14512709 High-dose DEX resulted in a decrease in sst1-sst4 mRNA and an increase in sst5 mRNA, independent of adrenal status |
| GO:0071385 cellular response to glucocorticoid stimulus | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine learning annotation, consistent with IEP evidence. Reason: Consistent with experimental IEP evidence from PMID:14512709. Supporting Evidence: PMID:14512709 High-dose DEX resulted in a decrease in sst1-sst4 mRNA and an increase in sst5 mRNA, independent of adrenal status |
| GO:0050796 regulation of insulin secretion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred role in regulation of insulin secretion. Strongly supported by knockout mouse data showing SSTR5 mediates somatostatin inhibition of insulin secretion. Reason: Core physiological function of SSTR5 demonstrated by knockout studies in mouse, with conservation expected in rat given high sequence identity. Supporting Evidence: PMID:12511609 sst(5) mediates SRIF inhibition of pancreatic insulin secretion and contributes to the regulation of glucose homeostasis and insulin sensitivity file:rat/Sstr5/Sstr5-deep-research-falcon.md Sstr5 acts as an inhibitory GPCR node in paracrine/endocrine circuits where SST restrains secretion (e.g., pancreatic islet hormone release, pituitary hormone output) and can modulate growth-related signaling via phosphatases and MAPK branches. |
| GO:0050796 regulation of insulin secretion | ISO GO_REF:0000121 | ACCEPT | Summary: RGD ISO annotation from mouse ortholog data. Well-supported by SSTR5 KO studies. Reason: Consistent with multiple knockout studies demonstrating SSTR5 role in insulin secretion regulation. Supporting Evidence: PMID:12511609 sst(5) mediates SRIF inhibition of pancreatic insulin secretion and contributes to the regulation of glucose homeostasis and insulin sensitivity |
| GO:0042593 glucose homeostasis | ISO GO_REF:0000121 | ACCEPT | Summary: RGD ISO from mouse data. SSTR5 KO mice show altered blood glucose levels and resistance to diet-induced insulin resistance, supporting a role in glucose homeostasis. Reason: Supported by SSTR5 KO studies showing decreased blood glucose and improved insulin sensitivity. Supporting Evidence: PMID:12511609 sst(5) KO mice exhibited decreased blood glucose and plasma insulin levels...sst(5) KO mice displayed decreased susceptibility to high fat diet-induced insulin resistance file:rat/Sstr5/Sstr5-deep-research-falcon.md genetic SSTR5 deletion and an orally delivered selective antagonist (compound-1) lowered glycemic markers and improved insulin sensitivity indices. |
| GO:0060124 positive regulation of growth hormone secretion | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: RGD ISO annotation transferred from pig SSTR5 (RGD:14121952), whose IMP annotation rests on PMID:16543371. In porcine somatotropes an sst5-selective agonist stimulated basal GH release, and the authors attribute the paradoxical stimulatory action of low-dose somatostatin on pig GH secretion to sst5 or an sst5-related mechanism. The donor annotation is therefore a genuine experimental observation, but one the authors frame as a pig-specific, somatotrope-subpopulation phenomenon that contrasts with the generally inhibitory action of somatostatin on GH release. There is no rat evidence that Sstr5 stimulates GH secretion. Reason: The source annotation is sound for pig, but transferring a species- and cell-subpopulation-specific stimulatory effect to rat overshoots the evidence; in rat, Sstr5 is characterised as a Gi-coupled receptor that inhibits adenylyl cyclase, the mechanism by which somatostatin suppresses pituitary hormone release. (Earlier versions of this review described the donor as human SSTR5 and the problem as a sign inversion; the donor is the pig gene and its evidence is experimental.) Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: RGD:14121952 · pig SSTR5 SUPPORTS SOURCE BUT NOT TARGET RGD:14121952 is the pig (Sus scrofa) SSTR5 gene record (RGD speciesTypeKey 9), annotated by IMP from PMID:16543371. The stimulatory GH effect is described by the authors as pig- and somatotrope-subpopulation-specific, so it does not transfer to rat. Supporting Evidence: PMID:16543371 These results indicate that in the pig, sst1 and sst2 are the primary mediators of the inhibitory effects of somatostatin, whereas sst5 or an sst5-related mechanism mediates the stimulatory action of somatostatin on GH release. PMID:16543371 However in pigs somatostatin can stimulate or inhibit in vitro GH secretion in a dose- and somatotrope subpopulation-dependent manner. file:rat/Sstr5/Sstr5-deep-research-falcon.md Sstr5 acts as an inhibitory GPCR node in paracrine/endocrine circuits where SST restrains secretion (e.g., pancreatic islet hormone release, pituitary hormone output) and can modulate growth-related signaling via phosphatases and MAPK branches. |
| GO:0032467 positive regulation of cytokinesis | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: RGD ISO annotation transferred from human SSTR5 (P35346), whose IMP annotation comes from a genome-scale siRNA screen of 516 GPCRs and related proteins in HeLa cells (PMID:22888021). SSTR5 was one of 12 GPCR hits whose knockdown increased binucleated cells, with failure at the abscission stage. The direction of the term matches the screen phenotype; the issue is the weight of the evidence. SSTR5 was detected only at low transcript levels in HeLa, knockdown was partial, no ligand or mechanism was tested for SSTR5, and the authors caution that for dopamine receptor D3 agonists/antagonists did not reproduce the RNAi phenotype. Reason: A single screen hit in a human cancer cell line, without SSTR5-specific follow-up, does not establish a cytokinesis role for rat Sstr5, whose characterised biology is somatostatin-receptor signalling in pituitary and endocrine cells. (Earlier versions of this review called this a sign inversion; the donor phenotype is in the direction the term asserts, so the objection is evidential weight and context, not sign.) Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P35346 · human SSTR5 SOURCE WEAK OR INFERRED Human SSTR5 IMP from a high-throughput siRNA screen in HeLa cells (PMID:22888021); screen-level evidence without receptor-specific mechanism is too weak to propagate to rat as a biological process. Supporting Evidence: PMID:22888021 RNAi knockdown of these GPCRs caused increased binucleated cell formation, and live cell imaging showed that most formed midbodies but failed at the abscission stage. PMID:22888021 All of the GPCRs showed knockdown, but were only partially depleted. PMID:22888021 We showed recently that small molecule agonists/antagonists of dopamine receptor D3 do not induce cytokinesis failure while RNAi depletion of this GPCR does, suggesting that some of the signaling may be non-traditional |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: RGD ISO annotation transferred from human SSTR5 (P35346). Donor-split sibling of the mouse-derived ISO plasma membrane row. Human SSTR5 carries plasma membrane annotations from HPA immunolocalisation and from its own cloning paper (PMID:7908405), and rat Sstr5 is a cell-surface 7TM receptor that binds extracellular somatostatin. Reason: Correct localization for rat Sstr5; the human ortholog donor is one-to-one and shares the 7TM topology. Consistent with the IBA, IEA and mouse-derived ISO plasma membrane rows. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P35346 · human SSTR5 SUPPORTS TRANSFER Human SSTR5 ortholog; plasma membrane localization of a 7TM somatostatin receptor transfers without caveat. Supporting Evidence: UniProtKB:P30938 SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. PMID:1362243 Membranes prepared from COS-7 cells transfected with the rAP6-26 cDNA showed specific binding of 125I-Tyr11-SRIF, thus identifying the cDNA clone as a novel SRIF receptor |
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Download this section (compressed HTML)Q: What is the relative contribution of SSTR5 versus SSTR2 to somatostatin-mediated inhibition of insulin secretion in rat pancreatic islets specifically?
Suggested experts: Strowski MZ, Brunicardi FC
Q: Does SSTR5 have significant expression in rat brain regions beyond the anterior pituitary, given improved detection methods since the original Northern blot studies?
Suggested experts: O'Carroll AM, Patel YC
Experiment: Perform ChIP-seq for glucocorticoid receptor in rat pituitary cells treated with dexamethasone, focusing on the Sstr5 locus to determine whether GR directly binds the promoter region or whether the effect is indirect.
Hypothesis: SSTR5 expression in rat pituitary is regulated at the transcriptional level by glucocorticoid receptor binding to the Sstr5 promoter.
Type: ChIP-seq
Experiment: Use proximity ligation assays (PLA) or BRET in primary rat pituitary cell cultures to detect SSTR2-SSTR5 heterodimers in situ, and correlate with GH secretion measurements in response to somatostatin analogs.
Hypothesis: SSTR5/SSTR2 heterodimerization occurs in rat pituitary somatotropes and modulates growth hormone secretion.
Type: Proximity ligation assay / BRET
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