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Review
. 2018 Oct;70(4):763-835.
doi: 10.1124/pr.117.015388.

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

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Free PMC article
Review

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

Thomas Günther et al. Pharmacol Rev. .
Free PMC article

Abstract

Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein-coupled receptors (GPCRs) called somatostatin receptor (SST)1-5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.

Figures

Fig. 1.
Fig. 1.
Historical perspective of somatostatin and somatostatin receptor research.
Fig. 2.
Fig. 2.
Primary and secondary amino acid structure of mammalian SRIF and CST isoforms. Color code: brown, binding motif; blue, identical in SRIF and CST; red, different in CST compared with SRIF; green, not present in rat/mouse CST-14.
Fig. 3.
Fig. 3.
Structure of human SST1. The primary and secondary amino acid structure of the human SST1 (UniProtKB - P30872) is shown in a schematic serpentine format. Glycosylation sites are colored in purple; the DRY motif is highlighted in green; the human SST motif is in light blue; potential phosphorylation sites are in gray; the PDZ ligand motif is in dark blue; the disulfide-forming cysteines are in pale blue; and the potential palmitoylation site is in orange. UMB-7 is a rabbit monoclonal antibody, which detects the carboxyl-terminal tail of SST1 in a phosphorylation-independent manner.
Fig. 4.
Fig. 4.
SST1 signaling leading to inhibition of hormone secretion, cell proliferation and migration, and angiogenesis. By coupling to Gi protein, SRIF-bound SST1 inhibits adenylate cyclase and reduces cAMP accumulation, as well as intracellular Ca2+ concentrations by regulating GIRK channels, which results in membrane hyperpolarization and subsequent reduction of Ca2+ influx through VOCC. This results in decreased hormone secretion. Inhibition of cell proliferation by SST1 involves upregulation of expression of the cyclin-dependent kinase inhibitor p21 (cip1/WAF1) and sequential activation through Src activity of tyrosine phosphatases (PTPη and SHP-2). Whereas p21 blocks cell cycling, tyrosine phosphatases block mitogenic signals through dephosphorylation (and inactivation) of effectors. Both PI3K–mTOR and MAPK pathways are inhibited, resulting in decreased cell growth and proliferation through inhibition of mRNA transcription and translation. SST1 also reduces endothelial NOS activation, resulting in reduced guanylate cyclase activity, cGMP production, and protein kinase G activity. Additionally, SST1 inhibits the NHE1 activity, resulting in a decrease of extracellular acidification rate. This involves inhibition of Rho activity through activation of Gα12 protein by SST1.
Fig. 5.
Fig. 5.
SST1 expression pattern in normal human tissues. Immunohistochemistry (red-brown color), counterstaining with hematoxylin; primary antibody: UMB-7; scale bar, 50 µm. SST1 displays both membranous and cytoplasmic expression.
Fig. 6.
Fig. 6.
Structures of synthetic SST1 ligands. L-797,591, SST1 agonist; SRA880, SST1 antagonist.
Fig. 7.
Fig. 7.
Structure of human SST2. The primary and secondary amino acid structure of the human SST2 (UniProtKB - P30874) is shown in a schematic serpentine format. Glycosylation sites are colored in purple; the DRY motif is highlighted in green; the human SST motif is in light blue; potential phosphorylation sites are in gray; identified GRK2/3 phosphorylation sites are in red; identified GRK2/3 or PKC phosphorylation sites are in dark green; the PDZ ligand motif is in dark blue; the disulfide-forming cysteines are in pale blue; and the potential palmitoylation site is in orange. UMB-1 is a rabbit monoclonal antibody, which detects the carboxyl-terminal tail of SST2 in a phosphorylation-independent manner.
Fig. 8.
Fig. 8.
SST2 signaling leading to inhibition of hormone secretion, cell proliferation and migration, and angiogenesis. By coupling to Gi proteins, SST2 inhibits adenylate cyclase and reduces cAMP accumulation, and reduces intracellular Ca2+ concentrations by activating GIRK channels, which results in membrane hyperpolarization and subsequent reduction of Ca2+ influx through VOCC. This results in decreased hormone secretion. By coupling to a pertussis toxin–independent G protein, SST2 activates PLC, triggering inositol-1,4,5-trisphosphate (IP3) production and subsequent Ca2+ release into the cytoplasm from the endoplasmic reticulum. Major downstream effectors of SST2 are the tyrosine phosphatases SHP-1 and SHP-2 and the tyrosine kinase Src, which subsequently inhibit the PI3K-mTOR, MAPK, JAK2, and neuronal NOS pathways, thereby decreasing cell growth and proliferation. SST2-dependent inhibition of cell proliferation involves upregulation of the transcription factor ZAC1, triggering cell cycle inhibition.
Fig. 9.
Fig. 9.
SST2 expression pattern in normal human and neoplastic tissues. Immunohistochemistry (red-brown color), counterstaining with hematoxylin; primary antibody: UMB-1; scale bar, 50 µm. Note that SST2 is predominantly expressed at the plasma membrane.
Fig. 10.
Fig. 10.
Structures of synthetic SST2 ligands. L-779,976 and BIM-23120, SST2 agonists; JR-11, SST2 antagonist.
Fig. 11.
Fig. 11.
Structure of human SST3. The primary and secondary amino acid structure of the human SST3 (UniProtKB - P32745) is shown in a schematic serpentine format. Glycosylation sites are colored in purple; the DRY motif is highlighted in green; the human SST motif is in light blue; potential phosphorylation sites are in gray; identified GRK2/3 phosphorylation sites are in red; the PDZ ligand motif is in dark blue; the cilia localization motif is in dark red; and the disulfide-forming cysteines are in pale blue. UMB-5 is a rabbit monoclonal antibody, which detects the carboxyl-terminal tail of SST3 in a phosphorylation-independent manner.
Fig. 12.
Fig. 12.
SST3 signaling leading to inhibition of hormone secretion, proliferation, and induction of apoptosis. By coupling to Gi proteins, SST3 inhibits adenylate cyclase and reduces cAMP accumulation and reduces intracellular Ca2+ concentrations by activating GIRK channels, which results in membrane hyperpolarization and subsequent reduction of Ca2+ influx through VOCC. This results in decreased hormone secretion. By coupling to a pertussis toxin–independent G protein (probably Gq), SST3 activates PLC, triggering inositol-1,4,5-trisphosphate (IP3) production and subsequent Ca2+ release into the cytoplasm from endoplasmic reticulum. SST3-dependent induction of apoptosis involves p53 and Bax.
Fig. 13.
Fig. 13.
SST3 expression pattern in human pituitary adenomas, human pancreatic islets, and rat neuronal cilia. Immunohistochemistry (red-brown color), counterstaining with hematoxylin; primary antibody: UMB-5; scale bar, 50 µm. SST3 displays both membranous and cytoplasmic expression. NFPA, clinically nonfunctioning pituitary adenoma.
Fig. 14.
Fig. 14.
Structures of synthetic SST3 ligands. L-796,776, SST3 agonist; ACQ090, sst3-ODN-8, and MK-4256, SST3 antagonists.
Fig. 15.
Fig. 15.
Structure of human SST4. The primary and secondary amino acid structure of the human SST4 (UniProtKB - P31391) is shown in a schematic serpentine format. The glycosylation site is colored in purple; the DRY motif is highlighted in green; the human SST motif is in light blue; potential phosphorylation sites are in gray; the PDZ ligand motif is in dark blue; the disulfide-forming cysteines are in pale blue; and the potential palmitoylation site is in orange.
Fig. 16.
Fig. 16.
SST4 signaling leading to inhibition of hormone secretion, proliferation, and migration. By coupling to Gi proteins, SST4 inhibits adenylate cyclase and reduces cAMP accumulation, and reduces intracellular Ca2+ concentrations by activating GIRK and M channels, which results in membrane hyperpolarization and subsequent reduction of Ca2+ and Na+ influx through VOCC and TRPV1. In addition, SST4 inhibits the NHE1 activity, resulting in a decrease of extracellular acidification rate. Another major effector of SST4 is the tyrosine phosphatase SHP-2, which mediates antiproliferative effects. SST4 also mediates a prolonged ERK activation and subsequent signal transducer and activator of transcription 3 phosphorylation, which is Gi/Go and PI3K dependent. Activation of SST4 can induce cell cycle arrest by upregulation of the cyclin-dependent kinase inhibitor p21 (cip1/WAF1).
Fig. 17.
Fig. 17.
Structures of synthetic SST4 ligands. J-2156 and L-803,087, SST4 agonists.
Fig. 18.
Fig. 18.
Structure of human SST5. The primary and secondary amino acid structure of the human SST5 (UniProtKB - P35346) as well as its truncated variants SST5TMD4 and SST5TMD5 are shown in a schematic serpentine format. Glycosylation sites are colored in purple; the DRY motif is highlighted in green; the human SST motif is in light blue; potential phosphorylation sites are in gray; identified GRK2/3 phosphorylation site is in red; constitutive phosphorylation site is in black; the PDZ ligand motif is in dark blue; the disulfide-forming cysteines are in pale blue; and the potential palmitoylation site is in orange. UMB-4 is a rabbit monoclonal antibody, which detects the carboxyl-terminal tail of SST5 in a phosphorylation-independent manner.
Fig. 19.
Fig. 19.
SST5 signaling leading to inhibition of hormone secretion and proliferation. By coupling to Gi proteins, SST5 inhibits adenylate cyclase and reduces cAMP accumulation, and reduces intracellular Ca2+ concentrations by activating GIRK channels, which results in membrane hyperpolarization and subsequent reduction of Ca2+ influx through VOCC. This results in decreased hormone secretion. By coupling to a pertussis toxin–independent G protein, SST5 activates PLC, triggering inositol-1,4,5-trisphosphate (IP3) production and subsequent Ca2+ release into the cytoplasm from endoplasmic reticulum. Major downstream effectors of SST5 are the tyrosine phosphatases SHP-1 and SHP-2, which subsequently inhibit mTOR pathway, thereby decreasing cell growth and proliferation. In addition, SST5 inhibits NHE1 activity, resulting in a decrease of extracellular acidification rate.
Fig. 20.
Fig. 20.
Differential trafficking of somatostatin receptors. Agonist activation of SSTs triggers activation of the associated heterotrimeric G protein that in turn stimulates a second messenger system. Quenching of this signal involves phosphorylation of the receptor by GRKs. Phosphorylation by GRKs increases the affinity for arrestins, which uncouple the receptor from the G protein and target the receptor to clathrin-coated pits for internalization. Return to its resting state requires dissociation or degradation of the agonist, dephosphorylation, and dissociation of arrestin. For SST5, the catalytic PP1γ subunit was identified to catalyze S/T dephosphorylation at the plasma membrane within seconds to minutes after agonist removal. SST5 forms unstable complexes with arrestins that are rapidly disrupted. After dephosphorylation, SST5 is either resensitized at the plasma membrane or recycled back through an endosomal pathway. For SST2, the catalytic PP1β subunit was identified to catalyze S/T dephosphorylation. SST2 forms stable complexes with arrestins that cointernalize into the same endocytic vesicles. This dephosphorylation process is initiated at the plasma membrane and continues along the endosomal pathway. PP1β-mediated dephosphorylation promotes dissociation of arrestins and, hence, facilitates quenching of arrestin-dependent signaling. Subsequently, SST2 is recycled back through an endosomal pathway to the plasma membrane. For SST3, the catalytic PP1α/β subunits were identified to catalyze S/T dephosphorylation at the plasma membrane within seconds to minutes after agonist removal. SST3 forms unstable complexes with arrestins that are rapidly disrupted. After dephosphorylation, SST3 is either subject to lysosomal degradation or recycled back to the plasma membrane through an endosomal pathway.
Fig. 21.
Fig. 21.
SST5 expression pattern in human normal and neoplastic tissues. Immunohistochemistry (red-brown color), counterstaining with hematoxylin; primary antibody: UMB-4; scale bar, 50 µm. SST5 displays a predominant membranous expression.
Fig. 22.
Fig. 22.
Structures of synthetic SST5 ligands. L-817,818 and BIM-23268, SST5 agonists; S5A1, SST5 antagonist.
Fig. 23.
Fig. 23.
Structures of SRIF ligands currently used in clinical practice.
Fig. 24.
Fig. 24.
Structures of SST ligands used for scintigraphy. [123I]Tyr3-octroeotide, the very first compound for SST-targeted scintigraphy. Conjugation of DTPA to octreotide and labeling with indium-111 resulted in Octreoscan (Mallinckrodt), the first approved SST agent for SPECT imaging. Advanced Accelerator Application recently received market authorization for 68Ga-labeled DOTA-TOC (SomatoKit TOC) by the European Medicines Agency and for 68Ga-DOTA-TATE (Netspot) by the FDA. It is expected that [177Lu]DOTATATE will soon be approved by FDA and European Medicines Agency as first agent for peptide receptor radiotherapy.
Fig. 25.
Fig. 25.
Representative examples of clinical PRRT images. PRRT in a 73-year-old patient with metastasized neuroendocrine cancer (G1). Pretherapeutic 68Ga-DOTANOC PET/computed tomography images show extensive metastases in the liver and additional abdominal lymph node metastases (A). Post-therapeutic whole-body scintigraphy after application of 177Lu-DOTATATE confirms uptake in metastatic lesions (B). After four cycles of 177Lu-DOTATATE, 68Ga-DOTANOC PET/computed tomography demonstrates considerable response of liver and abdominal lymph node metastases (C). Images courtesy of M. Eiber, Department of Nuclear Medicine, Technical University Munich, Germany.

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