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Production, Action, and Degradation of Somatostatin

Yogesh C. Patel, Jun‐Li Liu, Aristea Galanopoulou, Dimitri N. Papachristou

10.1002/cphy.cp070209

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Anatomical Distribution of Somatostatin Cells
1.1 Localization
1.2 Pancreatic Somatostatin Cells
2 Biosynthesis, Processing, and Intracellular Targeting
2.1 Somatostatin Genes and Gene Products
3 Regulation of Islet Somatostatin
3.1 Regulation of Secretion
3.2 Regulation of Gene Expression
4 Actions and Mechanism of Action of Somatostatin
4.1 Islet Cell Actions
4.2 Extra‐Islet Actions
4.3 Somatostatin Agonists
4.4 Somatostatin Receptors
5 Metabolism of Somatostatin
6 Circulating Somatostatin
7 Islet Somatostatin Function
7.1 Paracrine Regulation
7.2 Regulation via the Microcirculation
7.3 Gap Junctional Coupling
7.4 Independent Regulation by Somatostatin‐14 and Somatostatin‐28
8 Somatostatin and Diabetes
8.1 Experimental Insulinopenic Diabetes
8.2 Experimental Hyperinsulinemic Diabetes
8.3 Human Diabetes
9 Concluding Remarks
Figure 1. Figure 1.

Structure of somatostatin (SST)‐14, SST‐28, the putative human cortistatin (CST)‐17 peptide, and various synthetic SST analogues. Residues critical for biological activity are shown in bold.
Figure 2. Figure 2.

Schematic representation of mammalian prosomatostatin (Pro‐SST) and its cleavage products. Processing occurs at three sites marked by the presence of either paired Arg–Lys or single (Lys or Arg) basic amino acid residues. Although each of these forms is capable of release from somatostatin cells, only SST‐14 and SST‐28 are biologically active.
Figure 3. Figure 3.

Schematic depiction of preprosomatostatin (PPSST) and pre‐procortistatin (PPCST) molecules sequenced by cloning techniques in human, frog, and teleost species. The biologically active SSTs in each instance are located in the C‐terminal segment of the precursor and consist of SST‐14, SST‐28, CST‐14, and the putative cleavage product CST‐29 in humans; SST‐14, frog SST‐14 (FSST), and FSST‐28 in frogs; SST‐14 and anglerfish SST‐28 (AFSST‐28) in anglerfish; and SST‐14 and catfish SST‐22 (CFSST‐22) in catfish.
Figure 4. Figure 4.

Effects of endogenous or exogenous somatostatin (SST), insulin, and glucagon on the function of pancreatic islet cells. Somatostatin inhibits insulin and glucagon release, glucagon stimulates insulin and SST release, and insulin inhibits the release of glucagon and possibly of SST. In addition, all three islet hormones inhibit their own secretion by an autocrine mechanism. Physiologically, intra‐islet insulin and glucagon regulate the secretion of SST, and intra‐islet insulin regulates glucagon release. The precise physiological role of intra‐islet SST remains unclear (see text for details).

[From Patel 231 with permission.]
Figure 5. Figure 5.

Schematic depiction of the rat somatostatin gene and its regulatory domains. The mRNA coding region consists of two exons, of 238 and 367 bp, separated by an intron of 621 bp. Located upstream (5′ end) from the start site of mRNA transcription (arrow) axe the regulatory elements TATA (−26 bp), cAMP‐response element (CRE, −48/−41 bp), atypical glucocorticoid response element (aGRE, −250/−71 bp), and a somatostatin promoter silencer element (SMS‐PS, −260/−189 bp). Tissue‐specific elements (TSE) consisting of TAAT motifs that operate in concert with CRE to provide high‐level constitutive activity are located within the TSE I (−104/−86 bp) and TSE II (−303/−286 bp) regions.
Figure 6. Figure 6.

Schematic model of cAMP‐mediated target gene regulation. The level of intracellular cAMP is regulated by extracellular hormones, which bind to their transmembrane receptors and activate/inactivate adenylate cyclase (AC) via G proteins. Cyclic AMP binds to the regulatory subunit of protein kinase A (PKA), leading to dissociation and activation of the catalytic subunit, which then translocates to the nucleus, where it phosphorylates cAMP‐response element (CRE)–binding protein (CREB) and CREB‐binding protein (CBP). Phosphorylated CREB recruits CBP, which acts as an adaptor molecule, linking the kinase inducible domain (KID) of CREB with the basal transcriptional complex via transcription Factor (TF) II B. The glutamine‐rich Q2 domain of CREB also interacts with the basal transcriptional complex via a TBP associated factor (TAF) 110‐like molecule, which links Q2 with TATA box binding protein (TBP) (see text for details).
Figure 7. Figure 7.

Principal actions of somatostatin (SST). It inhibits both the basal and the stimulated secretion of growth hormone (GH), thyroid‐stimulating hormone (TSH), and islet hormones. It has no effect on luteinizing hormone, follicle‐stimulating hormone, prolactin, or corticotropin (ACTH) in normal subjects. It does, however, suppress elevated corticotropin levels in Addison's disease and in corticotropin‐producing tumors. In addition, it inhibits the basal and the thyrotropin‐releasing hormone (TKH)–stimulated release of prolactin in vitro and diminishes elevated prolactin levels in acromegaly. In the gastrointestinal tract, SST inhibits the release of virtually every gut hormone that has been tested. It has a generalized inhibitory effect on gut exocrine secretion (gastric acid, pepsin, bile, colonic fluid) and suppresses motor activity generally through inhibition of gastric emptying, gallbladder contraction, and small intestine segmentation. However, SST stimulates migrating motor complex activity. The effects of SST on the thyroid include inhibition of the TSH‐stimulated release of thyroxine (T4) and Triiodothyronine (T3). The adrenal effects include inhibition of angiotensin II–stimulated aldosterone secretion and of acetylcholine‐stimulated medullary catecholamine secretion. In the kidneys, SST inhibits the release of renin stimulated by hypovolemia and antidiuretic hormone–mediated water absorption. CCK, cholecystokinin; CRH, corticotropin‐releasing hormone; VIP, vasoactive intestinal peptide.

[From Patel 231 with permission.]
Figure 8. Figure 8.

Schematic depiction of SSTR signalling pathways leading to inhibition of secretion (a) and cell proliferation and induction of apoptosis (b). (a) Receptor activation leads to a fall in intracellular cAMP (due to inhibition of adenylyl cyclase), a fall in Ca2+ influx (due to activation of K+ and Ca2+ ion channels), and stimulation of phosphatases such as calcineurin (which inhibits exocytosis) and serine threonine phosphatases (which dephospharylate and activate Ca2+ and K+ channel proteins). Blockade of secretion by SST is in part mediated through inhibition of Ca2+ and cAMP (proximal effect) and through a more potent distal effect involving direct inhibition of exocytosis via SRIF‐dependent activation of calcineurin. (b) Induction of protein tyrosine phosphatase by SRIF plays a key role in mediating cell growth arrest (via SSTRs1, 2, 4, 5) or apoptosis (via SSTR3). Cell growth arrest is dependent on activation of the MAPK pathway and induction of Rb (Retinoblastoma tumor suppressor protein) and p21 (cyclin‐dependent kinase inhibitor). c‐src, which associates with both the activated receptor and PTP may provide the link between the receptor, PTP, and the mitogenic signaling complex. Induction of apoptosis is associated with dephosphorylation‐dependant activation of p53 and of Bax.

(Reproduced from Patel Y.C. 233 with permission).
Figure 9. Figure 9.

Quantitative analysis of the expression of somatostatin receptors (SSTRs) 1 to 5 in β, α, and δ cells from human islets determined by double‐label confocal immunofluorescence immunocytochemistry. Bars represent the mean ± SE (n = 3) percent of cells positive for a given SSTR subtype in 8 to 20 islets from each of three pancreata. Means of 1081 ± 80 β cells, 432 ± 28 α cells, and 221 ± 12 δ cells were analyzed. Note the preferential expression of SSTR1 in β cells and of SSTR2 in α cells. In β cells only, SSTR4 is weakly expressed in islets.

[From Kumar et al. 154 with permission.]


Figure 1.

Structure of somatostatin (SST)‐14, SST‐28, the putative human cortistatin (CST)‐17 peptide, and various synthetic SST analogues. Residues critical for biological activity are shown in bold.



Figure 2.

Schematic representation of mammalian prosomatostatin (Pro‐SST) and its cleavage products. Processing occurs at three sites marked by the presence of either paired Arg–Lys or single (Lys or Arg) basic amino acid residues. Although each of these forms is capable of release from somatostatin cells, only SST‐14 and SST‐28 are biologically active.



Figure 3.

Schematic depiction of preprosomatostatin (PPSST) and pre‐procortistatin (PPCST) molecules sequenced by cloning techniques in human, frog, and teleost species. The biologically active SSTs in each instance are located in the C‐terminal segment of the precursor and consist of SST‐14, SST‐28, CST‐14, and the putative cleavage product CST‐29 in humans; SST‐14, frog SST‐14 (FSST), and FSST‐28 in frogs; SST‐14 and anglerfish SST‐28 (AFSST‐28) in anglerfish; and SST‐14 and catfish SST‐22 (CFSST‐22) in catfish.



Figure 4.

Effects of endogenous or exogenous somatostatin (SST), insulin, and glucagon on the function of pancreatic islet cells. Somatostatin inhibits insulin and glucagon release, glucagon stimulates insulin and SST release, and insulin inhibits the release of glucagon and possibly of SST. In addition, all three islet hormones inhibit their own secretion by an autocrine mechanism. Physiologically, intra‐islet insulin and glucagon regulate the secretion of SST, and intra‐islet insulin regulates glucagon release. The precise physiological role of intra‐islet SST remains unclear (see text for details).

[From Patel 231 with permission.]


Figure 5.

Schematic depiction of the rat somatostatin gene and its regulatory domains. The mRNA coding region consists of two exons, of 238 and 367 bp, separated by an intron of 621 bp. Located upstream (5′ end) from the start site of mRNA transcription (arrow) axe the regulatory elements TATA (−26 bp), cAMP‐response element (CRE, −48/−41 bp), atypical glucocorticoid response element (aGRE, −250/−71 bp), and a somatostatin promoter silencer element (SMS‐PS, −260/−189 bp). Tissue‐specific elements (TSE) consisting of TAAT motifs that operate in concert with CRE to provide high‐level constitutive activity are located within the TSE I (−104/−86 bp) and TSE II (−303/−286 bp) regions.



Figure 6.

Schematic model of cAMP‐mediated target gene regulation. The level of intracellular cAMP is regulated by extracellular hormones, which bind to their transmembrane receptors and activate/inactivate adenylate cyclase (AC) via G proteins. Cyclic AMP binds to the regulatory subunit of protein kinase A (PKA), leading to dissociation and activation of the catalytic subunit, which then translocates to the nucleus, where it phosphorylates cAMP‐response element (CRE)–binding protein (CREB) and CREB‐binding protein (CBP). Phosphorylated CREB recruits CBP, which acts as an adaptor molecule, linking the kinase inducible domain (KID) of CREB with the basal transcriptional complex via transcription Factor (TF) II B. The glutamine‐rich Q2 domain of CREB also interacts with the basal transcriptional complex via a TBP associated factor (TAF) 110‐like molecule, which links Q2 with TATA box binding protein (TBP) (see text for details).



Figure 7.

Principal actions of somatostatin (SST). It inhibits both the basal and the stimulated secretion of growth hormone (GH), thyroid‐stimulating hormone (TSH), and islet hormones. It has no effect on luteinizing hormone, follicle‐stimulating hormone, prolactin, or corticotropin (ACTH) in normal subjects. It does, however, suppress elevated corticotropin levels in Addison's disease and in corticotropin‐producing tumors. In addition, it inhibits the basal and the thyrotropin‐releasing hormone (TKH)–stimulated release of prolactin in vitro and diminishes elevated prolactin levels in acromegaly. In the gastrointestinal tract, SST inhibits the release of virtually every gut hormone that has been tested. It has a generalized inhibitory effect on gut exocrine secretion (gastric acid, pepsin, bile, colonic fluid) and suppresses motor activity generally through inhibition of gastric emptying, gallbladder contraction, and small intestine segmentation. However, SST stimulates migrating motor complex activity. The effects of SST on the thyroid include inhibition of the TSH‐stimulated release of thyroxine (T4) and Triiodothyronine (T3). The adrenal effects include inhibition of angiotensin II–stimulated aldosterone secretion and of acetylcholine‐stimulated medullary catecholamine secretion. In the kidneys, SST inhibits the release of renin stimulated by hypovolemia and antidiuretic hormone–mediated water absorption. CCK, cholecystokinin; CRH, corticotropin‐releasing hormone; VIP, vasoactive intestinal peptide.

[From Patel 231 with permission.]


Figure 8.

Schematic depiction of SSTR signalling pathways leading to inhibition of secretion (a) and cell proliferation and induction of apoptosis (b). (a) Receptor activation leads to a fall in intracellular cAMP (due to inhibition of adenylyl cyclase), a fall in Ca2+ influx (due to activation of K+ and Ca2+ ion channels), and stimulation of phosphatases such as calcineurin (which inhibits exocytosis) and serine threonine phosphatases (which dephospharylate and activate Ca2+ and K+ channel proteins). Blockade of secretion by SST is in part mediated through inhibition of Ca2+ and cAMP (proximal effect) and through a more potent distal effect involving direct inhibition of exocytosis via SRIF‐dependent activation of calcineurin. (b) Induction of protein tyrosine phosphatase by SRIF plays a key role in mediating cell growth arrest (via SSTRs1, 2, 4, 5) or apoptosis (via SSTR3). Cell growth arrest is dependent on activation of the MAPK pathway and induction of Rb (Retinoblastoma tumor suppressor protein) and p21 (cyclin‐dependent kinase inhibitor). c‐src, which associates with both the activated receptor and PTP may provide the link between the receptor, PTP, and the mitogenic signaling complex. Induction of apoptosis is associated with dephosphorylation‐dependant activation of p53 and of Bax.

(Reproduced from Patel Y.C. 233 with permission).


Figure 9.

Quantitative analysis of the expression of somatostatin receptors (SSTRs) 1 to 5 in β, α, and δ cells from human islets determined by double‐label confocal immunofluorescence immunocytochemistry. Bars represent the mean ± SE (n = 3) percent of cells positive for a given SSTR subtype in 8 to 20 islets from each of three pancreata. Means of 1081 ± 80 β cells, 432 ± 28 α cells, and 221 ± 12 δ cells were analyzed. Note the preferential expression of SSTR1 in β cells and of SSTR2 in α cells. In β cells only, SSTR4 is weakly expressed in islets.

[From Kumar et al. 154 with permission.]
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Article Title: Production, Action, and Degradation of Somatostatin
 

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Yogesh C. Patel, Jun‐Li Liu, Aristea Galanopoulou, Dimitri N. Papachristou. Production, Action, and Degradation of Somatostatin. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 267-302. First published in print 2001. doi: 10.1002/cphy.cp070209