Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Somatostatin Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_334



Historical Background

Somatostatin (SST) is a cyclopeptide that was first identified in the hypothalamus inhibiting GH secretion and immediately after in pancreatic islets inhibiting the insulin secretion in vitro, but it is produced also throughout the central and peripheral nervous system and in most major peripheral organs as endocrine pancreas, thyroid, adrenals, spleen, submandibular glands, gut, liver, kidneys, prostate, and placenta (Reisine and Bell 1995). SST is initially synthesized as a large precursor molecule, preprosomatostatin that undergoes tissue-specific enzymatic degradation generating two bioactive products: SST-14, identified in hypothalamus, and SST-28 that corresponds to somatostatin with a NH2-terminal extension of 14 amino acids. Nutrients (glucose, amino acids, lipids), neurotransmitters, neuropeptides (glucagons, growth hormone releasing hormone, bombesin), hormones (insulin, glucocorticoids) and cytokines (interleukin-1, interleukin-6, transforming growth factor-ß, tumor necrosis factor-α, insulin-like growth factor, leptin, interferon-γ, etc.), and several intracellular mediators including cyclic AMP, cyclic GMP, Ca2+, and nitric oxide, all influence the transcription and/or secretion of SST. The two peptides act through the inhibition of endocrine and exocrine secretion, inhibition of intestinal motility, absorption of nutrients and ions, vascular contractility, and immune cell functions. Moreover, they have a role in neurotransmission and cognitive functions, and they have antiproliferative effects acting on cell secretion, proliferation, and differentiation. SST can also inhibit angiogenesis in vitro and in vivo inhibiting the production of vascular endothelial growth factor and platelet-derived growth factor (Öberg et al. 2010).

Somatostatin Analogues

SST, which takes effect through high-affinity plasma membrane five SST receptors (SSTR1–5) (see below), has limited clinical use due to its short half-life (<3 min) but the identification of stable SST analogues with a longer half-life has raised new hopes for the treatment of tumors (Fig. 1). Octreotide, the first SST analogue available commercially, contains three substituted amino acids (d-Phe, LThr [ol], d-Trp) that make it resistant to metabolic degradation with a longer half-life (2 h). It is an SSTR2-preferring agonist with a moderate affinity for SSTR3 and SSTR5. Lanreotide is a second analogue with a similar binding profile of octreotide. Furthermore, radiolabeled SST analogues are used as diagnostic tools for the detection of endocrine tumors, as well as for the therapy. A novel multi-ligand SST analogue, a cyclohexapeptide named pasireotide, has a 20–30, 5, and 40–100 times higher binding affinity than octreotide and lanreotide for the receptors SSTR1, SSTR3, and SSTR5, respectively (Bruns et al. 2002). The very favorable 24 h elimination half-life of pasireotide makes this novel compound suitable for clinical application. Interestingly, pasireotide modulates SST receptor trafficking and leads to the formation of unstable SSTR2 complex with beta-arrestin that dissociate at or near the plasma membrane. Consequently, SSTR2 are recycled faster to the plasma membrane after endocytosis in cells treated with pasireotide than in those treated with octreotide. This finding suggests that a longer-lasting functional response could be achieved with pasireotide (Cescato et al. 2010).
Somatostatin Receptor, Fig. 1

Chemical structure of SST-14 and SST analogues

Somatostatin Receptors

SSTRs were first described in the pituitary GH4C1 cell line. Studies using a variety of techniques such as membrane binding analyses, in vivo and in vitro autoradiography, covalent cross-linking, and purification of a solubilized receptor showed SSTR expression in various densities in brain, gut, pituitary, endocrine and exocrine pancreas, adrenals, thyroid, kidneys, and immune cells. SSTRs have also been identified in a large variety of human cancers including pituitary adenomas, islet tumors, carcinoids, adenocarcinomas of the breast, prostate, ovary, kidney and colon origin, lymphomas, as well as astrocytomas, neuroblastomas, and medulloblastomas. Analyses of SSTR mRNAs demonstrate that various human tumors from neuroendocrine and gastroenteropancreatic origin, brain tumors, pheochromocytomas, medullary thyroid carcinomas, prostate, lung, and breast cancers express various SSTR mRNA, each tumor expressing more than one subtype and SSTR2 being the most frequently expressed (Benali et al. 2000).

Photoaffinity labeling and purification studies have provided evidence for the existence of several SSTR proteins of 32–85 kDa that are expressed in a tissue-specific manner and some that exhibit selective agonism for SST-14 or SST-28 (Patel 1999). The SSTR1–5, identified in the early 1990s (Yamada et al. 1992), are codified by five genes that segregate on five different chromosomes: 14q13, 17q24, 22q13.1, 20p11.2, and 16p13.3. Genes for SSTR1, 3, 4, and 5 lack classical introns, the SSTR2 gene displays a cryptic intron at the 3′ end of the coding segment, which determine two spliced variants, a long (SSTR2A) form and a short (SSTR2B) form. The 2A and 2B variants differ only in the length of the cytoplasmic tail. There are thus six putative SSTR subtypes of closely related size that present a high degree of sequence identity (39–57%), with seven α helical transmembrane domains (TM) typical of G-protein-coupled receptors (GPCR) (Fig. 2). The sequence differences reside in the extracellular and intracellular domains and are probably responsible for their signaling specificity. SST binding induces a conformational change in the receptor that results in activation of an associated heterotrimeric G protein complex leading to exchange of GTP for GDP on the α-subunit. The GTP bound form of the free α-subunit and ß/γ complex interact with the specific cellular effector pathways (Patel 1999). These receptors differ in their signaling pathways and cellular and tissue distribution, which are crucial factors determining tissue response to SST and SSTR agonists.
Somatostatin Receptor, Fig. 2

Model for the orientation of the SST receptors in the plasma membrane. The four potential sites for N-linked glycosylation, indicated by “CHO,” in the extracellular NH2-terminal domain are noted. PO4 are the putative sites for phosphorylation by protein kinase A, protein kinase C, and casein kinase in the extracellular COOH-terminal domain, shown by the closed red circles. The YANSCANPI/VLY sequence, shown by the closed blue circles, in the VIIth TM is highly conserved in all SSTRs. The cysteine residue 12 amino acids downstream from the VIIth TM is conserved in SSTR1,2,4,5 and may be the site of a potential palmitoyl membrane anchor. Residues Asp122, Asn276, and Phe294, shown by the closed yellow circles, in TMs III, VI, and VII, respectively, have been proposed to form part of a ligand-binding pocket for octreotide

Intracellular Pathways Coupled to SSTRs

Using recombinant SSTR expressed in various eukaryote cells, the intracellular signaling pathways coupled to SSTRs have been extensively studied; they are complex and vary among receptor, cell, and organ types. The complexity arises not only from the large number of SSTR subtypes and range of cell types that express them, but also because each receptor subtype is coupled to multiple intracellular transduction pathways (Table 1 and Fig. 3).
Somatostatin Receptor, Table 1

G-protein-coupled signal transduction: characteristics of SSTR subtypes







Molecular size (kDa)






Amino acids






mRNA (Kb)






Adenylate cyclase

Thyrosine phosphatase


MAP kinase (ERK)



K+ channels


Ca2+ channels


Na+/H+ exchanger


AMPA kainite glutamate channels


Phospholipase C/IP3


Phospholipase A2



Tissue distribution

Brain, pituitary, islet, stomach, liver, kidneys, hypothalamus

Brain, pituitary, islet, stomach, kidneys, lymphocytes, adrenals, hypothalamus

Brain, pituitary, islet, stomach, T cell, hypothalamus

Brain, stomach, islet, lungs, placenta, heart, hypothalamus, pituitary

Brain, pituitary, islet, stomach, hypothalamus, lymphoid cells

Somatostatin Receptor, Fig. 3

Intracellular signaling pathways coupled to SSTRs, leading to changes in hormone secretion, apoptosis, and cell growth. AC adenylyl cyclase, ER endoplasmic reticulum, ERK extracellular signal-regulated kinase, , , G protein subunit, IP3 inositol triphosphate, PLC phospholipase C, PTPase phosphotyrosine phosphatase

All five SSTRs are functionally coupled to inhibition of adenylate cyclase and cAMP production that is the first pathway implicated. In neuronal and neuroendocrine cells, SST and analogues also regulate several subsets of K+ channels causing hyperpolarization of the plasma membrane and leading to decreased Ca2+ influx through voltage-gated Ca2+ channels and consequently to a reduction in intracellular Ca2+. Moreover, a third pathway affected by SST and analogues is represented by the activation of a number of protein phosphatases including serine/threonine phosphatases, tyrosine phosphatases, and a Ca2+ -dependent phosphatase. Somatostatins inhibit proliferation directly by regulating tyrosine kinase, tyrosine phosphatase, nitric oxide synthase, cyclic guanosine 3′, 5′ cyclic monophosphate-dependent protein kinase, and RAS/extracellular signal-regulated kinase signaling pathways. The regulation of these pathways varies according to SSTR subtype and the cell environment. All five receptors stimulate phospholipase C and increase Ca2+ mobilization via both pertussis toxin–sensitive and pertussis toxin–insensitive G protein.

In vitro data and biodistribution studies in animals have shown that SST and agonists induce internalization of SSTR2, SSTR3, and also SSTR5 with a consequent desensitization and attenuated receptor relating signaling. This is a crucial feedback mechanism that prevents persistent stimulation by the agonist. Agonist-induced internalization is rapid; almost all SSTR2 moved from the cell membrane to endosome-like cellular structures within the cytoplasm. Agonist binding to SSTR5 induces mobilization of intracellular stores of the receptor to the cell membrane and then internalization of membrane SSTR5 following ligand binding (Öberg et al. 2010).

Biological Effects of Somatostatin Receptors

Because the same cell expresses multiple receptor subtypes and the coupling of SSTRs to similar transduction pathways, it can be assumed that the SSTR subtypes may act in concert (Table 2). In the cell, the blockade of secretion by SST is mediated through inhibition of Ca2+ and to a reduction of cAMP production. In the pituitary, SSTR2, SSTR5, and SSTR1 are involved in inhibiting growth hormone release. In the pancreas, SSTR2 mediates inhibition of glucagon release, whereas SSTR5 is a negative regulator of insulin secretion. SSTR2 also mediates insulin secretion in human pancreas. The high expression of SSTR1 in human pancreatic islet cells suggests that it may also be involved in regulating insulin release. SSTR5 is involved in the inhibition of pancreatic exocrine secretion. In the stomach, SSTR2 contributes to the inhibition of histamine and gastrin release and the inhibition of gastric acid secretion. SSTR1 and SSTR2 mediate the inhibition of intestinal ionic secretion. In human neuroendocrine gut tumor cells, SST and octreotide inhibit L-type voltage-dependent calcium channels with the same amplitude suggesting that at least SSTR2 and SST5R may be involved in the inhibition of Ca2+ influx and thereby inhibition of tumor-produced neurotransmitters and hormone. SSTR3 could be involved in the stimulation of gastric and intestinal smooth muscle cell contraction and SSTR5 in the inhibition of colonic muscle cell contraction (Benali et al. 2000).
Somatostatin Receptor, Table 2

Biological effect of each SSTR

Inhibitory effect on






Hormone and mediator secretion
























Cytokine (IL6, IFNγ), histamine




Exocrine secretion

Gastric acid







Intestinal Cl- secretion





Gastric and intestinal relaxation




Colonic contraction



Cell proliferation

Induction of G1 cell cycle arrest






Induction of apoptosis





SST analogues are also thought to inhibit cell proliferation by inducing apoptosis, which may be mediated through the SSTR2 and SSTR3. When SSTR3 is transfected into previously SST-free cell lines, addition of octreotide causes the upregulation of the tumor suppressor protein  p53, which subsequently induces apoptosis. Furthermore, in athymic mouse and in hamster models, SSTR2 re-expression caused dramatic decrease in tumor growth and inhibition of primary tumor growth without metastatic progression, respectively.

Homo- and Heterodimerization of SST and Dopamine (DA) Receptors

Membrane SSTRs exist in the basal state as a monomeric species, but activation by ligand induces SSTR dimerization (Rocheville et al. 2000a), both homo- and heterodimerization with other members of the SSTR family, and dimerization alters the functional properties of the receptor such as ligand binding affinity and agonist-induced receptor internalization and upregulation. Both homo- and heterooligomeric receptors are occupied by two ligand molecules. Evidences show that monomeric, homooligomeric, and heterooligomeric receptor species occur in the same cell cotransfected with two SSTRs, and that oligomerization of SSTRs is regulated by ligand binding by a selective process that is restricted to some (SSTR5) but not other (SSTR1) subtypes. SSTR5 formed heterodimers with SSTR1 but not with SSTR4 suggesting that heterodimerization is a specific process that is restricted to some but not all receptor subtype combinations (Patel et al. 2002).

SST and DA are two major neurotransmitter systems that share a number of structural and functional characteristics. SSTR and DA receptor (DR) families share about 30% sequence homology, are colocalized in neuronal subgroups, and SST is involved in modulating DA-mediated control of motor activity. DA, like SST, acts through its own family of five GPCRs (D1R to D5R). D2R and SSTR5 associate on the plasma membrane and the SSTR5-D2R heterooligomer displays enhanced signaling when simultaneously activated by both SST and DA ligands (Rocheville et al. 2000b). Hetero-oligomerization defines a new level of functional diversity in endogenous GPCR signaling, and should constitute novel unrecognized drug targets for combinations of agonists or antagonists.

Effect of SST Analogues on Various Tumors

SSTR2 and SSTR5 are the most important subtypes in inhibiting hormonal secretions in functioning gastrointestinal neuroendocrine tumors (GI-NETs) due to their wide-ranging effects; it is thought the dual inhibition of both subtypes may have an increased inhibitory effect (Öberg et al. 2010). The two subtypes may also mediate antiproliferative effects. Patients with NETs receiving SSTR2-preferring analogues such as octreotide and lanreotide may experience a loss of response. It has led to interest in new, multi-receptor ligand SST analogues that could be as effective and well tolerated in patients who experience an escape from response. Pasireotide may fulfill this role due to its high affinity for SSTR1–3 and SSTR5. Preliminary data are promising, with effective control of diarrhea and flushing observed in NET patients refractory or resistant to octreotide.

The SSTRs are also demonstrated expressed in neuroblastoma, therefore the treatment with SST analogues or radiolabeled SST could represent a new therapeutic possibility in patients with neuroblastoma where high-dose chemotherapy, irradiation, and autologous stem cell transplantation have failed (Georgantzi et al. 2010).

The finding of SSTRs ubiquitously distributed in normal kidney and IgA nephropathy suggests that the increased expression of these receptors might be the potential pathogenesis of inflammatory renal disease (Bhandari et al. 2008).

SST system, through SSTR1 and SSTR2, exerts mainly an immunosuppressive effect in human macrophages and may, therefore, represent a therapeutic window that can be exploited for the development of new strategies in pharmacological therapy of inflammation (Armani et al. 2007).

One of the organs in which SST has an important inhibitory effect on hormone secretion is the anterior pituitary gland (Hofland et al. 2010). SSTRs have a predominant inhibitory role of growth hormone secretion, although the secretion of other pituitary hormones, e.g., prolactin, thyroid stimulating hormone, and adrenocorticotropic hormone is regulated by SST as well. Also DRs, in particular the D2R, have an important regulatory role in the PRL secretion. Pituitary tumors express both SST and/or D2 receptors. The SSTR subtype, as well as the co-expression of SSTR and D2R, has significant impact on the possibility to treat patients with pituitary tumors with SST analogues and DA agonists to control hormonal hypersecretion and tumor growth. Pasireotide is also a promising pituitary-directed medical therapy for patients with persistent or recurrent Cushing’s disease after unsuccessful surgery, in patients awaiting the effects of pituitary radiation or in inoperable patients (Arnaldi and Boscaro 2010).

Moreover, pasireotide affects cell growth, apoptosis, and catecholamine levels in pheochromocytoma (Pasquali et al. 2008). Finally, a markedly reduced cortisol and aldosterone secretion by pasireotide was also evident in human adrenocortical cell line (H295R) and in primary adrenocortical cultures that strongly expressed SSTR5 and SSTR2 (Mariniello et al. 2010).

However, with the availability of newer SST analogues such as pasireotide, the determination of differential expression of various SSTR subtypes and an assessment of heterogeneity of such expression in larger series of primary and metastatic tumors is clinically relevant. Furthermore, SSTR subtype expression should be correlated with the pattern of clinical response of such patients to SST analogue therapies.


SST and all five receptor subtypes were ubiquitously distributed in many organs and in a large variety of human cancers. Synthetic derivatives of SST have similar activity to native SST but with a longer half-life, they lack the key enzyme cleavage sites and are more stable than native SST. The analogues, such as octreotide, lanreotide, and the multiple SSTR ligand, pasireotide, are currently in preclinical evaluation or in early clinical trials. There is evidence for a number of direct and indirect mechanisms by which SST analogues can exert antitumor effects. Direct antitumor activities, mediated through SSTRs expressed in tumor cells, include blockade of autocrine/paracrine growth-promoting hormone and growth factor production, inhibition of growth factor-mediated mitogenic signals, and induction of apoptosis. Indirect antitumor effects, that do not require the presence of SSTRs in tumor cells, include inhibition of growth-promoting hormone and growth factor secretion, and antiangiogenic actions. Therefore, not only the receptor profiles but also the cell types, as well as the dimerization, are responsible for the final effect of a given ligand. These elements open new perspectives for the use of the new chimeric compounds in human tumors.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Endocrinology Unit, Department of Medical and Surgical SciencesUniversity of PaduaPaduaItaly