The somatostatin receptor (SSTR) subtype 3 ACTS as an acceptor of vasocative intestinal peptide (VIP)

Somatostatin (SST) receptors (SSTRs) belong to the typical 7-transmembrane domain family of G-protein-coupled receptors. Five distinct subtypes (termed SSTR1-5) have been identified, with SSTR2 showing the highest affinity for natural SST and synthetic SST analogs. Most neuroendocrine tumors (NETs) have high expression levels of SSTRs, which opens the possibility for tumor imaging and therapy with radiolabeled SST analogs. A number of tracers have been developed for the diagnosis, staging, and treatment of NETs with impressive results, which facilitates the applications of human SSTR subtype 2 (hSSTr2) reporter gene based imaging and therapy in SSTR negative or weakly positive tumors to provide a novel approach for the management of tumors. The hSSTr2 gene can act as not only a reporter gene forin vivoimaging, but also a therapeutic gene for local radionuclide therapy. Even a second therapeutic gene can be transfected into the same tumor cells together with hSSTr2 reporter gene to obtain a synergistic therapeutic effect. However, additional preclinical and especially translational and clinical researches are needed to confirm the value of hSSTr2 reporter gene based imaging and therapy in tumors.

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Somatostatin decreases voltage-gated Ca2+ currents in GH3 cells through activation of somatostatin receptor 2

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00047.2007 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1863-E1870 ◽

Cited By ~ 18

Author(s):

Seung-Kwon Yang ◽

Helena C. Parkington ◽

Jacques Epelbaum ◽

Damien J. Keating ◽

Chen Chen

Keyword(s):

Somatostatin Receptor ◽

Gh3 Cells ◽

Channel Blockers ◽

Current Response ◽

Voltage Gated ◽

Gh Secretion ◽

Intracellular Ca ◽

Sstr Subtype ◽

Current Reduction ◽

Perforated Patch Clamp

The secretion of growth hormone (GH) is inhibited by hypothalamic somatostatin (SRIF) in somatotropes through five subtypes of the somatostatin receptor (SSTR1–SSTR5). We aimed to characterize the subtype(s) of SSTRs involved in the Ca2+ current reduction in GH3 somatotrope cells using specific SSTR subtype agonists. We used nystatin-perforated patch clamp to record voltage-gated Ca2+ currents, using a holding potential of −80 mV in the presence of K+ and Na+ channel blockers. We first established the presence of T-, L-, N-, and P/Q-type Ca2+ currents in GH3 cells using a variety of channel blockers (Ni+, nifedipine, ω-conotoxin GVIA, and ω-agatoxin IVA). SRIF (200 nM) reduced L- and N-type but not T- or P/Q-type currents in GH3 cells. A range of concentrations of each specific SSTR agonist was tested on Ca2+ currents to find the maximal effective concentration. Activation of SSTR2 with 10−7 and 10−8 M L-797,976 decreased the voltage-gated Ca2+ current and abolished any further decrease by SRIF. SSTR1, SSTR3, SSTR4, and SSTR5 agonists at 10−7 M did not modify the voltage-gated Ca2+ current and did not affect the Ca2+ current response to SRIF. These results indicate that SSTR2 is involved mainly in regulating voltage-gated Ca2+ currents by SRIF, which contributes to the decrease in intracellular Ca2+ concentration and GH secretion by SRIF.

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Correlation of Somatostatin Receptor 1–5 Expression, [68Ga]Ga-DOTANOC, [18F]F-FDG PET/CT and Clinical Outcome in a Prospective Cohort of Pancreatic Neuroendocrine Neoplasms

Cancers ◽

10.3390/cancers14010162 ◽

2021 ◽

Vol 14 (1) ◽

pp. 162

Author(s):

Susanna Majala ◽

Tiina Vesterinen ◽

Hanna Seppänen ◽

Harri Mustonen ◽

Jari Sundström ◽

...

Keyword(s):

Prospective Study ◽

Fdg Pet ◽

Somatostatin Receptor ◽

Proliferation Index ◽

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Pet Ct ◽

Sstr Subtype ◽

Node Metastases ◽

Fdg Pet Ct

Purpose: The aim of this study was to correlate immunohistochemical (IHC) tissue levels of SSTR1-5 with the receptor density generated from [68Ga]Ga-DOTANOC uptake in a prospective series of NF-PNENs. Methods: Twenty-one patients with a total of thirty-five NF-PNEN-lesions and twenty-one histologically confirmed lymph node metastases (LN+) were included in this prospective study. Twenty patients were operated on, and one underwent endoscopic ultrasonography and core-needle biopsy. PET/CT with both [68Ga]Ga-DOTANOC and [18F]F-FDG was performed on all patients. All histological samples were re-classified and IHC-stained with monoclonal SSTR1-5 antibodies and Ki-67 and correlated with [68Ga]Ga-DOTANOC and [18F]F-FDG PET/CT. Results: Expression of SSTR1-5 was detected in 74%, 91%, 80%, 14%, and 77% of NF-PNENs. There was a concordance of SSTR2 IHC with positive/negative [68Ga]Ga-DOTANOC finding (Spearman’s rho 0.382, p = 0.043). All [68Ga]Ga-DOTANOC-avid tumors expressed SSTR2 or SSTR3 or SSTR5. Expression of SSTR5 was higher in tumors with a low Ki-67 proliferation index (PI) (−0.353, 95% CI −0.654–0.039, p = 0.038). The mean Ki-67 PI for SSTR5 positive tumors was 2.44 (SD 2.56, CI 1.0–3.0) and 6.38 (SD 7.25, CI 2.25–8.75) for negative tumors. Conclusion: SSTR2 was the only SSTR subtype to correlate with [68Ga]Ga-DOTANOC PET/CT. Our prospective study confirms SSTR2 to be of the highest impact for SST PET/CT signal.

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Glycosylation affects agonist binding and signal transduction of the rat somatostatin receptor subtype 3

Journal of Physiology-Paris ◽

10.1016/s0928-4257(00)00203-5 ◽

2000 ◽

Vol 94 (3-4) ◽

pp. 185-192 ◽

Cited By ~ 19

Author(s):

Ralf Bernd Nehring ◽

Dietmar Richter ◽

Wolfgang Meyerhof

Keyword(s):

Signal Transduction ◽

Somatostatin Receptor ◽

Receptor Subtype ◽

Agonist Binding ◽

Subtype 3

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Somatostatin receptor subtype 3 mediates the inhibitory action of somatostatin on gastric smooth muscle cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1995.268.5.g739 ◽

1995 ◽

Vol 268 (5) ◽

pp. G739-G748 ◽

Cited By ~ 3

Author(s):

Z. F. Gu ◽

V. D. Corleto ◽

S. A. Mantey ◽

D. H. Coy ◽

P. N. Maton ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Protease Inhibitors ◽

Somatostatin Receptor ◽

Muscle Cells ◽

Receptor Subtype ◽

Binding Studies ◽

High Affinity ◽

Gastric Smooth Muscle ◽

Subtype 3

Previous functional studies show that somatostatin (SS) interacts with specific receptors to inhibit relaxation in gastric smooth muscle cells. There are no ligand binding studies, and it is unknown which of the five subtypes of SS receptors mediates the action. Dispersed gastric smooth muscle cells from guinea pig bound both 125I-labeled SS-14 and 125I-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Nal-NH2 (where Nal indicates N-naphthylalanine) (cyclo-SS-8), a synthetic peptidase-resistant octapeptide SS analogue. SS-28 and SS-14, cyclo-SS-8, and SS analogue D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol [SMS-(201-995) (octreotide)] inhibited 125I-cyclo-SS-8 binding with relative potencies of SS-28 = cyclo-SS-8 = SMS-(201-995) (octreotide), and the binding was not affected by the addition of protease inhibitors. SS-14 caused inhibition only in the presence of protease inhibitors. Ligand analysis demonstrated a two-binding-site model. Analysis of the relationship between biological function and binding suggested the high-affinity sites mediated the relaxant action of SS. 5'-Guanylylimidodiphosphate [Gpp-(NH)p] inhibited binding by reducing the affinity of the high-affinity site. Six SS-8 analogues that distinguish SS subtypes showed that 125I-SS-14 bound to somatostatin receptor subtype 3 (SSTR3). The results demonstrated that gastric smooth muscle cells possess distinct receptors for SS of the SSTR3 subtype. Occupation of these sites inhibits relaxation in gastric smooth muscle cells. Modulation between the high- and low- affinity binding states of SSTR3 is at least partially mediated by activation of guanine nucleotide regulatory proteins.

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Pasireotide and Pegvisomant Combination Treatment in Acromegaly Resistant to Second-Line Therapies: A Longitudinal Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00825 ◽

2019 ◽

Vol 104 (11) ◽

pp. 5478-5482 ◽

Cited By ~ 5

Author(s):

Sabrina Chiloiro ◽

Chiara Bima ◽

Tommaso Tartaglione ◽

Antonella Giampietro ◽

Marco Gessi ◽

...

Keyword(s):

Combination Treatment ◽

Somatostatin Receptor ◽

Combined Treatment ◽

Somatostatin Analogs ◽

Control Group ◽

Second Line ◽

Ki 67 ◽

Disease Markers ◽

Sstr Subtype ◽

New Generation

Abstract Context The treatment of acromegaly resistant to first- and second-line therapies can be extremely challenging. Design We have described six patients who were successfully treated with a combination therapy of pasireotide and pegvisomant and compared them with a control group of patients resistant to conventional somatostatin analogs (SSAs), whose disease was controlled with other treatment, such as pasireotide (as monotherapy) or pegvisomant (as monotherapy or combined with conventional SSAs). Results In these six patients, acromegaly was controlled with combined pasireotide and pegvisomant treatment after failure of all other treatments. Compared with the 49 patients in the control group, these six patients had giant and invasive pituitary adenomas (at both the cavernous sinus and other structures). Although not statistically significant, higher growth hormone levels, more elevated Ki-67 expression, greater somatostatin receptor (SSTR) subtype 5 expression, and lower SSTR subtype 2 expression at the diagnosis of acromegaly were detected in patients receiving combination treatment with pasireotide and pegvisomant compared with the control group. Conclusion Our data have reinforced the importance of personalized treatment of patients with acromegaly according to the clinical, biochemical, molecular, and morphological disease markers and suggest that combined treatment with pasireotide and pegvisomant can induce disease control in tumors with low SSTR2 expression, resistant to conventional SSAs (alone or combined with pegvisomant) and to new-generation SSAs alone (pasireotide).

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