General

The somatostatin receptor family is a member of the G-protein-coupled receptor superfamily and consists of 5 subtypes each differentially distributed throughout the CNS and periphery. These receptors bind with high affinity to the endogenous polypeptides somatostatin-14 (SRIF-14), somatostatin-28 (SRIF-28) and cortistatin, as well as a vast array of synthetic ligands. Receptor activation stimulates multiple intracellular signalling mechanisms giving rise to many tissue functions such as inhibition of growth hormone (GH) release and modulation of neuronal activity.

Somatostatin

Somatostatin, also known as SRIF (somatotropin release inhibiting factor) is an endogenous cyclic 14 amino acid polypeptide (SRIF-14, a tetradecapeptide). It was first identified by Krulich et al. in 1968 [38] as an endogenous factor released from the hypothalamus and found to inhibit the release of growth hormone (GH, somatotropin) from the rat anterior pituitary. A second active endogenous form of somatostatin is SRIF-28, which consists of SRIF-14 extended by another 14 amino acid residues at the N-terminal [62]. The human gene for SRIF was found to be located on chromosome 3 using chromosome mapping studies. Human-rodent hybrids were used to locate the gene to the distal region of the long arm of chromosome 3 [54], and in situ hybridisation techniques were used to locate the gene to 3q28 [92]. The primary translation product is a 116 amino acid precursor protein, preprosomatostatin, containing SRIF-14 and SRIF-28 at its C-terminus [79]. This precursor contains a signal region of 24 amino acids, which targets the molecule for secretion and is subsequently removed. This leaves a 92 amino acid polypeptide called prosomatostatin which is processed enzymatically to generate SRIF-14 or SRIF-28. These two forms of somatostatin are differentially synthesised in a tissue-specific manner; for example, SRIF-14 was found to be the predominant form within the hypothalamus and amygdala, and equal amounts of the two were found in the median eminence [60]. They may involve different processing enzymes which are present in some cell types but not others, leading to a greater diversity of SRIF function [78]. SRIF-14 and SRIF-28 have a wide distribution throughout the central nervous system as well as in peripheral tissues, for example in the pituitary, pancreas and stomach. They have been found to regulate the secretion of various hormones as well as GH, such as thyroid-stimulating hormone (TSH), insulin and glucagon (as discussed by [46]). Other effects of SRIF include modulation of cell proliferation and angiogenesis (as discussed by [19]). The side effects of endogenous somatostatin are low due to it being produced and inactivated around the local sites of action [56].

Cortistatin

Cortistatin (CST) is an endogenous polypeptide structurally related to SRIF but produced by a different gene. It was first found to depress neuronal excitability in the rat CNS [21] and, unlike SRIF, is only found within certain parts of the CNS (often co-expressed with SRIF) and not in the periphery. Rat and mouse CST is a tetradecapeptide (CST-14), sharing 11 of its amino acids with SRIF, whereas the human form contains 17 amino acid residues (CST-17), an N-terminally extended form of rodent CST-14. Like SRIF, CST is also formed via the processing of a precursor, preprocortistatin, containing 112 amino acid residues. This is processed to procortistatin, containing 29 amino acids (CST-29) and then further processed to CST-14 (in rat) [22]. Cortistatin mediates several of its effects via activation of somatostatin receptors [21], but the possible existance of a cortistatin-specific receptor has been suggested. One group [72] have proposed that the orphan receptor MRGX2 may fulfil this role.

Receptor family

For a recent review of the somatostatin receptor family see Günter et al., 2018 [31]. Evidence of receptors for somatostatin was first found in the rat pituitary tumour cell line, GH4C1, where radiolabelled somatostatin was found to bind to a limited number of high-affinity binding sites on the cell membrane. Here, somatostatin was also shown to inhibit prolactin and GH secretion from these cells, indicating that it is the binding of SRIF to a cell surface receptor which mediates these effects [76]. Ligand binding studies using various cell types revealed differential receptor binding potencies, suggesting the existence of multiple receptor subtypes. The development of somatostatin analogues helped to further characterise these receptors, firstly revealing 2 distinct receptor types, later revealing further distinction of 5 cloned receptor subtypes, separated into 2 groups. The cloning of these 5 receptor genes for the rat, mouse and human combined with studies using cell lines (such as CCL29 or COS-7 cells) transfected with the recombinant receptors have provided much of the information we now have on ligand binding properties and signal transduction mechanisms. The two groups of receptors, distinguishable by their affinities for the SRIF analogues octreotide (SMS-201,995) and seglitide (MK-678), were named SRIF1 and SRIF2 [34]. The SRIF₁ group of receptors has a high affinity for octreotide and seglitide, and were later found to contain 3 receptor subtypes, now named SST₂ [87,90], SST₃ [17] and SST₅ [5,29,47]. The SRIF₂ group was found to have a lower affinity for these two SRIF analogues, and were later found to contain two distinct subtypes, now named SST₁ [44,90] and SST₄ [10,73,77]. These receptors were classified into these groups based on their ligand binding, amino acid sequence and receptor signalling mechanisms. Ligand binding affinities are found using a radioactive somatostatin analogue in competitive radioligand binding studies [81]. All 5 receptor subtypes are found to bind SRIF-14 and SRIF-28 with similar high affinities, except SST₄, which has a much lower affinity for SRIF-28 than SRIF-14. The development of ligands selective for each receptor subtype is important when producing new therapies to minimise interaction with other receptor subtypes and therefore reduce unwanted side effects. A common therapeutic use for somatostatin agonists is their anti-secretory effect on neuroendocrine tumours.

Receptor structure

The 5 receptors of the somatostatin receptor family belong to the G-protein coupled receptor superfamily (GPCR). They contain the characteristic seven transmembrane (TM) spanning alpha helical regions, have an extracellular C-terminal, an intracellular N-terminal [90] and range from 362 to 428 amino acids. The genes for the receptors are all intronless, except that of SST₂ which exhibits alternate mRNA splicing at the 3' end of the coding segment to produce two isoforms, SST_2A and SST_2B. These splice variants differ only in length and in the amino acid composition of the cytoplasmic C-tail [57,75,87]. There is greatest similarity between the 5 receptor subtypes at the transmembrane spanning domains, and least similarity at the C-termini. There is most overall amino acid homology between the SST₁ and SST₄ receptors of the SRIF₂ group. All the receptor subtypes have extracellular N-linked glycosylation sites (N-termini, second extracellular loop), a disulphide bridge (between the first two extracellular loops) and many intracellular phosphorylation sites (second and third intracellular loops and C-termini) [58].

Signal transduction

It has been found that the somatostatin receptors are coupled to pertussis toxin (PTX)-sensitive G-proteins: including the subunits G_iα1, G_iα3 and G_oα, as well as G_β36 and G_γ3 [41]. The coupling of each receptor subtype with different G-protein subunits may be how the receptors have such a wide functional diversity. All 5 somatostatin subtypes have been found to couple to adenylyl cyclase (AC) [80,91] and some have also been found to modulate L-type Ca²⁺ [86] and K⁺ channel [37,42] activity. The effect of SRIF on ion channels may be directly via the G-protein, or indirectly via second messenger pathways (such as via the AC/cAMP cascade). Both inhibition of K⁺ channels (via hyperpolarisation) and inhibition of Ca²⁺ channels cause a reduction in calcium entry, preventing hormone/neurotransmitter release. Phospholipase C (PLC) activity increases due to activation of some receptor subtypes [2,89] leading to increased inositol-1,4,5-trisphosphate (IP₃) formation and Ca²⁺ mobilisation. Phospholipase A₂ (PLA₂) activity is also thought to be modulated by somatostatin receptors with both activation and inhibition of PLA₂ thought to occur via different subtypes. Activation of PLA₂ leads to a release of arachidonic acid (AA) from the cell membrane (AA mobilisation) [8], whist inhibition of PLA₂ leads to an inhibition of AA mobilisation [20]. Activation of protein tyrosine phosphatases (PTPs) by some somatostatin receptor subtypes [12,27,63-64] is thought to be via PTX-insensitive G-proteins and may play a part in the anti-proliferative effects of somatostatin. Modulation of the mitogen-activated protein (MAP) kinase cascade is another result of receptor activation. Some SRIF receptor subtypes are known to mediate inhibition of the Na-H exchanger (NHE1), via a PTX-insensitive G-protein [33,45]. Inhibition of this transporter causes a reduction in outward proton transport across the cell membrane [15].

Tissue distribution

Somatostatin receptors have a very widespread distribution throughout the brain and peripheral tissues. mRNA of all the 5 subtypes has been found within the human and rodent brain, differentially distributed among regions such as the cerebral cortex [9,82], cerebellum [11,32,50,55,74,82], cerebrum [90], pituitary [11,20,24,51,55], hippocampus [11,32,74], hypothalamus [12], thalamus [82], amygdala [9,11], striatum [12] and olfactory bulb [11]. The SST₅ receptor is less abundant in the brain than the other subtypes. Other areas of the body where somatostatin receptor mRNA and/or protein has been found include: the pancreatic islets [39,69,73,90], intestine [30,55], stomach [30,43,90], lung [73], kidney [11,68,73,90], liver [11,73], jejunum [90], spleen [11], skeletal muscle [55], heart [11,55], retina [49], blood vessels [18,71], placenta [14,55] and in some elements of the peripheral nervous system (myenteric and submucous plexus, Cajal cells) [66,70,83]. Somatostatin receptors are also expressed in tumours [67], in peritumoral vessels [23] and various blood cells [59].

Functions

Since SRIF was discovered as a GH inhibitor [38] this GH inhibition has been reproduced [36,53,65], and a range of other tissue functions of somatostatin, acting through the 5 somatostatin receptors, has been found. These include: modulation of glucagon secretion [85], insulin secretion [84], cell proliferation [13,27], gastric acid secretion [48], angiogenesis [3], peristalsis in the jejunum [1] and neuronal activity [4,40]. There is evidence that SST₁ is an autoreceptor in the retina, modulating SRIF levels [49]. The development of somatostatin receptor knock-out mice has given further evidence towards the functions of the receptors.

Somatostatin released from the hypothalamus activates somatostatin receptors located within the anterior pituitary to cause inhibition of GH secretion [65]. Somatostatin works alongside another hypothalamic regulatory hormone, GHRH (growth hormone releasing hormone), to regulate a pulsatile GH release (reviewed in [28]) before acting on peripheral tissues and endocrine organs to regulate cell growth. Feedback mechanisms are present in order to regulate GH secretion: for example, GH can stimulate insulin-like growth factors (IGF-I and IGF-II) that can stimulate SRIF secretion from the hypothalamus (reviewed in [28]). SRIF can also regulate its own release via autoreceptors, thought to be the SST₁ subtype [6]. Knock-out mice showing the physiological effects of removal of somatostatin receptor subtypes confirm these effects on GH secretion [36,93].

The anti-proliferative effects of somatostatin are due to a negative control of cell growth, of both normal cells and tumours (discussed by [19]). These effects are suggested to be mediated via stimulation of PTP activity [12], stimulation of the MAPK cascade [16] and subsequent induction of G1 cell cycle arrest (receptors SST₁, SST₄, SST₅) [25] and promotion of apoptosis (SST₂, SST₃) [25]. Somatostatin has also been shown to inhibit the growth and proliferation of blood vessels (angiogenesis), by inhibition of endothelial cell growth, resulting in an inhibition of tumour cell growth [3]. Inhibition of angiogenesis has been shown to be via the SST₃ receptor subtype, and involve inhibition of MAPK and endothelial nitric oxide synthase (eNOS) activity [26].

Somatostatin modulates neuronal activity by altering the AMPA/Kainate receptor-mediated response to glutamate. Receptors SST₁, SST₂ and SST₄, located on neurones in the hypothalamus, were thought to mediate opposing effects via different signal transduction mechanisms: SST₁ and SST₄ enhancing the response to glutamate; SST₂ attenuating the response to glutamate [40]. However, a study involving SST₂ receptor knock-out mice suggests that the SST₂ receptor may not be mediating this decrease in neuronal excitability and that there may be interaction between the SST₂ and SST₄ subtypes resulting in the SST₄ receptor only inducing its excitatory effects in the presence of SST₂ [52]. Studies involving SST₂ knock-out mice have also shown the involvement of SRIF in mediating fine motor control [4] as well as affecting locomotor activity and emotional reactivity (coupled with an increase in pituitary ACTH release, a regulator of the stress response) [88].

Somatostatin is a known regulator of insulin and glucagon secretion (which control glucose homeostasis) from pancreatic islets (reviewed by [46]). Beta cells of the pancreas secrete insulin and contain mainly SST₅ receptors. Alpha cells of the pancreas secrete glucagon and contain mainly SST₂ receptors. SST₂ [85] and SST₅ [84] receptor knock-out mice affirm these affects.

Somatostatin, released from cells located in the stomach, potently inhibits gastric acid secretion through inhibition of histamine release and through direct inhibition on parietal cells [35]. This is not shown in SST₂ receptor knock-out mice despite it having been shown that the effects of peripheral somatostatin on gastric acid secretion are via the SST₂ subtype. This suggests there are somatostatin-independent mechanisms compensating for the lack of inhibitory input by somatostatin [61]. Another study involving SST₂ knock-out mice shows that somatostatin suppresses gastric acid secretion via the SST₂ receptor subtype, by inhibiting the actions of gastrin [48].

The SST₁ receptor is an autoreceptor in the rat retina, modulating SRIF levels [49]. This has been confirmed using SST₁ knock-out mice, where there was an increase in SST levels accompanied by up-regulation of the SST₂ receptors. In SST₂ knock-out mice there was a reciprocated up-regulation of SST₁ receptors and consequently a decrease in SRIF levels due to SST₁ acting as an autoreceptor [7,19].

Activation of somatostatin receptors is known to result in the inhibition of peristalsis in the jejunum, and knock-out studies provided evidence of SST₂-mediated as well as non-SST₂-mediated constituents of this inhibition [1].

Summary

The somatostatin family of receptors consists of five subtypes, differentially distributed throughout the CNS and periphery. Activation of these receptors stimulates multiple intracellular cascades to modulate growth hormone release, insulin and glucagon secretion, gastric acid secretion and neuronal activity. Many synthetic ligands for the receptors have been produced and are under trial for use as treatment for endocrine tumours. As yet there is a lack of subtype-selective ligands which limits their usage as well as hindering further functional studies of the receptor subtypes. There is currently only a limited number of selective and non-selective antagonists available, and future development of these will prove useful in discovering more about this family of receptors.

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