Somatostatin is a neuropeptide produced by neuroendocrine, inflammatory and immune cells in response to different stimuli. Somatostatin inhibits various cellular functions including secretions, motility and proliferation 1.
Related Peptides
Mammalian brain contains 3 peptides related to the pro-somatostatin molecule: somatostatin-14 (SS14), the form originally identified from hypothalamic extracts, somatostatin-28 (SS28) and somatostatin 28 (1-12) (SS28 (1-12)) 2.
Structural Characteristics
Two forms of somatostatin are synthesized. They are referred to as SS-14 and SS-28, reflecting their amino acid chain length. Both forms of somatostatin are generated by proteolytic cleavage of prosomatostatin, which itself is derived from preprosomatostatin. Two cysteine residules in SS-14 allow the peptide to form an internal disulfide bond. The relative amounts of SS-14 versus SS-28 secreted depends upon the tissue. For example, SS-14 is the predominant form produced in the nervous system and apparently the sole form secreted from pancreas, whereas the intestine secretes mostly SS-28. In addition to tissue-specific differences in secretion of SS-14 and SS-28, the two forms of this hormone can have different biological potencies. SS-28 is roughly ten-fold more potent in inhibition of growth hormone secretion, but less potent that SS-14 in inhibiting glucagon release.
Mode of Action
Five stomatostatin receptors(sst1-sst5) have been identified and characterized, all of which are members of the G protein-coupled receptor superfamily. The five receptors bind the natural peptide with high affinity but only sst2, sst5 and sst3 bind the short synthetic analogues used to treat patients with neuroendocrine tumors. The five receptors are expressed in various normal and tumor cells, the expression of each receptor being receptor subtype and cell-type specific. Each receptor subtype is coupled to different signal transduction pathways through G protein-dependent and -independent mechanisms. sst1, 2 and 5 mediate inhibition of GH secretion whereas sst2 and sst5 mediate inhibition of glucagon secretion and insulin secretion, respectively1.
The different signaling pathways activated by the various SSTR subtypes vary according to the receptor subtype and tissue localization. However, all SSTR subtypes inhibit adenylate cyclase and cAMP production upon ligand binding.
A second signaling pathway that is activated following engagement of all SSTR subtypes (save for SSTR1) is the activation of G-protein regulated inward rectifier (GIRK or Kir3) K+ channel family. Activation of these K+ channels leads to depolarization of the cell membrane and consequently to a decrease in Ca2+ flux through voltage-dependent Ca2+ channels leading to a decrease in intracellular Ca2+ concentration. As reduced cytosolic cAMP levels and intracellular Ca2+ concentrations are known to induce blocking of regulated secretion, activation of these two signaling pathways could explain the inhibitory effects of SST in neurotransmitter and hormone secretion.
A third pathway linked to SST signaling is the regulation of protein phosphatases. SST activates (upon binding to its receptor) a number of protein phosphatases from different families including serine/threonine phosphatases, tyrosine phosphatase (i.e. SHP-1 and SHP-2) and Ca2+ dependent phosphatases (i.e. calcineurin) 3.
Functions
Physiologic Effects: Somatostatin acts by both endocrine and paracrine pathways to affect its target cells. A majority of the circulating somatostatin appears to come from the pancreas and gastrointestinal tract.
Effects on the Pituitary Gland: Somatostatin was named for its effect of inhibiting secretion of growth hormone from the pituitary gland.
Effects on the Pancreas: Somatostatin appears to act primarily in a paracrine manner to inhibit the secretion of both insulin and glucagon. It also has the effect in suppressing pancreatic exocrine secretions, by inhibiting cholecystokinin-stimulated enzyme secretion and secretin-stimulated bicarbonate secretion.
Effects on the Gastrointestinal (GI) Tract: Somatostatin has been shown to inhibit secretion of many of the other GI hormones, including gastrin, cholecystokinin, secretin and vasoactive intestinal peptide. In addition to the direct effects of inhibiting secretion of other GI hormones, somatostatin has a variety of other inhibitory effects on the GI tract, which may reflect its effects on other hormones, plus some additional direct effects. Somatostatin suppresses secretion of gastric acid and pepsin, lowers the rate of gastric empDefinition
Somatostatin is a neuropeptide produced by neuroendocrine, inflammatory and immune cells in response to different stimuli. Somatostatin inhibits various cellular functions including secretions, motility and proliferation 1.
Related Peptides
Mammalian brain contains 3 peptides related to the pro-somatostatin molecule: somatostatin-14 (SS14), the form originally identified from hypothalamic extracts, somatostatin-28 (SS28) and somatostatin 28 (1-12) (SS28 (1-12)) 2.
Structural Characteristics
Two forms of somatostatin are synthesized. They are referred to as SS-14 and SS-28, reflecting their amino acid chain length. Both forms of somatostatin are generated by proteolytic cleavage of prosomatostatin, which itself is derived from preprosomatostatin. Two cysteine residules in SS-14 allow the peptide to form an internal disulfide bond. The relative amounts of SS-14 versus SS-28 secreted depends upon the tissue. For example, SS-14 is the predominant form produced in the nervous system and apparently the sole form secreted from pancreas, whereas the intestine secretes mostly SS-28. In addition to tissue-specific differences in secretion of SS-14 and SS-28, the two forms of this hormone can have different biological potencies. SS-28 is roughly ten-fold more potent in inhibition of growth hormone secretion, but less potent that SS-14 in inhibiting glucagon release.
Mode of Action
Five stomatostatin receptors(sst1-sst5) have been identified and characterized, all of which are members of the G protein-coupled receptor superfamily. The five receptors bind the natural peptide with high affinity but only sst2, sst5 and sst3 bind the short synthetic analogues used to treat patients with neuroendocrine tumors. The five receptors are expressed in various normal and tumor cells, the expression of each receptor being receptor subtype and cell-type specific. Each receptor subtype is coupled to different signal transduction pathways through G protein-dependent and -independent mechanisms. sst1, 2 and 5 mediate inhibition of GH secretion whereas sst2 and sst5 mediate inhibition of glucagon secretion and insulin secretion, respectively1.
The different signaling pathways activated by the various SSTR subtypes vary according to the receptor subtype and tissue localization. However, all SSTR subtypes inhibit adenylate cyclase and cAMP production upon ligand binding.
A second signaling pathway that is activated following engagement of all SSTR subtypes (save for SSTR1) is the activation of G-protein regulated inward rectifier (GIRK or Kir3) K+ channel family. Activation of these K+ channels leads to depolarization of the cell membrane and consequently to a decrease in Ca2+ flux through voltage-dependent Ca2+ channels leading to a decrease in intracellular Ca2+ concentration. As reduced cytosolic cAMP levels and intracellular Ca2+ concentrations are known to induce blocking of regulated secretion, activation of these two signaling pathways could explain the inhibitory effects of SST in neurotransmitter and hormone secretion.
A third pathway linked to SST signaling is the regulation of protein phosphatases. SST activates (upon binding to its receptor) a number of protein phosphatases from different families including serine/threonine phosphatases, tyrosine phosphatase (i.e. SHP-1 and SHP-2) and Ca2+ dependent phosphatases (i.e. calcineurin) 3.
Functions
Physiologic Effects: Somatostatin acts by both endocrine and paracrine pathways to affect its target cells. A majority of the circulating somatostatin appears to come from the pancreas and gastrointestinal tract.
Effects on the Pituitary Gland: Somatostatin was named for its effect of inhibiting secretion of growth hormone from the pituitary gland.
Effects on the Pancreas: Somatostatin appears to act primarily in a paracrine manner to inhibit the secretion of both insulin and glucagon. It also has the effect in suppressing pancreatic exocrine secretions, by inhibiting cholecystokinin-stimulated enzyme secretion and secretin-stimulated bicarbonate secretion.
Effects on the Gastrointestinal (GI) Tract: Somatostatin has been shown to inhibit secretion of many of the other GI hormones, including gastrin, cholecystokinin, secretin and vasoactive intestinal peptide. In addition to the direct effects of inhibiting secretion of other GI hormones, somatostatin has a variety of other inhibitory effects on the GI tract, which may reflect its effects on other hormones, plus some additional direct effects. Somatostatin suppresses secretion of gastric acid and pepsin, lowers the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine. Collectively, these activities seem to have the overall effect of decreasing the rate of nutrient absorption.
Related Peptides
Mammalian brain contains 3 peptides related to the pro-somatostatin molecule: somatostatin-14 (SS14), the form originally identified from hypothalamic extracts, somatostatin-28 (SS28) and somatostatin 28 (1-12) (SS28 (1-12)) 2.
Structural Characteristics
Two forms of somatostatin are synthesized. They are referred to as SS-14 and SS-28, reflecting their amino acid chain length. Both forms of somatostatin are generated by proteolytic cleavage of prosomatostatin, which itself is derived from preprosomatostatin. Two cysteine residules in SS-14 allow the peptide to form an internal disulfide bond. The relative amounts of SS-14 versus SS-28 secreted depends upon the tissue. For example, SS-14 is the predominant form produced in the nervous system and apparently the sole form secreted from pancreas, whereas the intestine secretes mostly SS-28. In addition to tissue-specific differences in secretion of SS-14 and SS-28, the two forms of this hormone can have different biological potencies. SS-28 is roughly ten-fold more potent in inhibition of growth hormone secretion, but less potent that SS-14 in inhibiting glucagon release.
Mode of Action
Five stomatostatin receptors(sst1-sst5) have been identified and characterized, all of which are members of the G protein-coupled receptor superfamily. The five receptors bind the natural peptide with high affinity but only sst2, sst5 and sst3 bind the short synthetic analogues used to treat patients with neuroendocrine tumors. The five receptors are expressed in various normal and tumor cells, the expression of each receptor being receptor subtype and cell-type specific. Each receptor subtype is coupled to different signal transduction pathways through G protein-dependent and -independent mechanisms. sst1, 2 and 5 mediate inhibition of GH secretion whereas sst2 and sst5 mediate inhibition of glucagon secretion and insulin secretion, respectively1.
The different signaling pathways activated by the various SSTR subtypes vary according to the receptor subtype and tissue localization. However, all SSTR subtypes inhibit adenylate cyclase and cAMP production upon ligand binding.
A second signaling pathway that is activated following engagement of all SSTR subtypes (save for SSTR1) is the activation of G-protein regulated inward rectifier (GIRK or Kir3) K+ channel family. Activation of these K+ channels leads to depolarization of the cell membrane and consequently to a decrease in Ca2+ flux through voltage-dependent Ca2+ channels leading to a decrease in intracellular Ca2+ concentration. As reduced cytosolic cAMP levels and intracellular Ca2+ concentrations are known to induce blocking of regulated secretion, activation of these two signaling pathways could explain the inhibitory effects of SST in neurotransmitter and hormone secretion.
A third pathway linked to SST signaling is the regulation of protein phosphatases. SST activates (upon binding to its receptor) a number of protein phosphatases from different families including serine/threonine phosphatases, tyrosine phosphatase (i.e. SHP-1 and SHP-2) and Ca2+ dependent phosphatases (i.e. calcineurin) 3.
Functions
Physiologic Effects: Somatostatin acts by both endocrine and paracrine pathways to affect its target cells. A majority of the circulating somatostatin appears to come from the pancreas and gastrointestinal tract.
Effects on the Pituitary Gland: Somatostatin was named for its effect of inhibiting secretion of growth hormone from the pituitary gland.
Effects on the Pancreas: Somatostatin appears to act primarily in a paracrine manner to inhibit the secretion of both insulin and glucagon. It also has the effect in suppressing pancreatic exocrine secretions, by inhibiting cholecystokinin-stimulated enzyme secretion and secretin-stimulated bicarbonate secretion.
Effects on the Gastrointestinal (GI) Tract: Somatostatin has been shown to inhibit secretion of many of the other GI hormones, including gastrin, cholecystokinin, secretin and vasoactive intestinal peptide. In addition to the direct effects of inhibiting secretion of other GI hormones, somatostatin has a variety of other inhibitory effects on the GI tract, which may reflect its effects on other hormones, plus some additional direct effects. Somatostatin suppresses secretion of gastric acid and pepsin, lowers the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine. Collectively, these activities seem to have the overall effect of decreasing the rate of nutrient absorption.
Effects on the Nervous System: Somatostatin is often referred to as having neuromodulatory activity within the central nervous sytem, and appears to have a variety of complex effects on neural transmission. Injection of somatostatin into the brain of rodents leads to such things as increased arousal and decreased sleep, and impairment of some motor responses. Pharmacologic Uses: Somatostatin and its synthetic analogs are used clinically to treat a variety of neoplasms. It is also 1used in to treat giantism and acromegaly, due to its ability to inhibit growth hormone secretion. Somatostatin analogs: Octreotide has been registered in most countries for the control of hormonal symptoms in patients with gastrointestinal and pancreatic NETs (neuroendocrine tumors), as well as in patients with acromegaly. The slow-release intramuscular (i.m.) formulation of octreotide (Sandostatin LAR®) is usually administered once every 4 weeks, and that of lanreotide (Somatuline® LA) is administered once every 2 weeks. Tumors and metastases that bear sst2 or sst5 can be visualized in vivo after injection of radiolabeled octapeptide analogs such as 111In-pentetreotide [OctreoScan® ([111In-DTPA0]octreotide)] and [111In-DOTA0]lanreotide. Radiolabeled octapeptide analogs such as 111In-pentetreotide [90Y-DOTA0,Tyr3]octreotide (OctreoTher®), [177Lu-DOTA0Tyr3]octreotate, [111In-DOTA0]lanreotide and [90Y-DOTA0]lanreotide, us normal and tumor cells, the expression of each receptor being receptor subtype and cell-type specific. Each receptor subtype is coupled to different signal transduction pathways through G protein-dependent and -independent mechanisms. sst1, 2 and 5 mediate inhibition of GH secretion whereas sst2 and sst5 mediate inhibition of glucagon secretion and insulin secretion, respectively1.
The different signaling pathways activated by the various SSTR subtypes vary according to the receptor subtype and tissue localization. However, all SSTR subtypes inhibit adenylate cyclase and cAMP production upon ligand binding.
A second signaling pathway that is activated following engagement of all SSTR subtypes (save for SSTR1) is the activation of G-protein regulated inward rectifier (GIRK or Kir3) K+ channel family. Activation of these K+ channels leads to depolarization of the cell membrane and consequently to a decrease in Ca2+ flux through voltage-dependent Ca2+ channels leading to a decrease in intracellular Ca2+ concentration. As reduced cytosolic cAMP levels and intracellular Ca2+ concentrations are known to induce blocking of regulated secretion, activation of these two signaling pathways could explain the inhibitory effects of SST in neurotransmitter and hormone secretion.
A third pathway linked to SST signaling is the regulation of protein phosphatases. SST activates (upon binding to its receptor) a number of protein phosphatases from different families including serine/threonine phosphatases, tyrosine phosphatase (i.e. SHP-1 and SHP-2) and Ca2+ dependent phosphatases (i.e. calcineurin) 3.
Functions
Physiologic Effects: Somatostatin acts by both endocrine and paracrine pathways to affect its target cells. A majority of the circulating somatostatin appears to come from the pancreas and gastrointestinal tract.
Effects on the Pituitary Gland: Somatostatin was named for its effect of inhibiting secretion of growth hormone from the pituitary gland.
Effects on the Pancreas: Somatostatin appears to act primarily in a paracrine manner to inhibit the secretion of both insulin and glucagon. It also has the effect in suppressing pancreatic exocrine secretions, by inhibiting cholecystokinin-stimulated enzyme secretion and secretin-stimulated bicarbonate secretion.
Effects on the Gastrointestinal (GI) Tract: Somatostatin has been shown to inhibit secretion of many of the other GI hormones, including gastrin, cholecystokinin, secretin and vasoactive intestinal peptide. In addition to the direct effects of inhibiting secretion of other GI hormones, somatostatin has a variety of other inhibitory effects on the GI tract, which may reflect its effects on other hormones, plus some additional direct effects. Somatostatin suppresses secretion of gastric acid and pepsin, lowers the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine. Collectively, these activities seem to have the overall effect of decreasing the rate of nutrient absorption.
Effects on the Nervous System: Somatostatin is often referred to as having neuromodulatory activity within the central nervous sytem, and appears to have a variety of complex effects on neural transmission. Injection of somatostatin into the brain of rodents leads to such things as increased arousal and decreased sleep, and impairment of some motor responses.
Pharmacologic Uses: Somatostatin and its synthetic analogs are used clinically to treat a variety of neoplasms. It is also 1used in to treat giantism and acromegaly, due to its ability to inhibit growth hormone secretion.
Somatostatin analogs: Octreotide has been registered in most countries for the control of hormonal symptoms in patients with gastrointestinal and pancreatic NETs (neuroendocrine tumors), as well as in patients with acromegaly. The slow-release intramuscular (i.m.) formulation of octreotide (Sandostatin LAR®) is usually administered once every 4 weeks, and that of lanreotide (Somatuline® LA) is administered once every 2 weeks.
Tumors and metastases that bear sst2 or sst5 can be visualized in vivo after injection of radiolabeled octapeptide analogs such as 111In-pentetreotide [OctreoScan® ([111In-DTPA0]octreotide)] and [111In-DOTA0]lanreotide. Radiolabeled octapeptide analogs such as 111In-pentetreotide [90Y-DOTA0,Tyr3]octreotide (OctreoTher®), [177Lu-DOTA0Tyr3]octreotate, [111In-DOTA0]lanreotide and [90Y-DOTA0]lanreotide, can also be used for radiotherapy of sst2- and sst5-positive advanced or metastatic endocrine tumors 4.
References
1.Benali N, Ferjoux G, Puente E, Buscail L, Susini C (2000). Somatostatin Receptors. Digestion,62:27-32.
2.Morrison JH, Benoit R, Magistretti PJ, Bloom FE (1983). Immunohistochemical distribution of pro-somatostatin-related peptides in cerebral cortex. Brain Res., 62(2):344-351.
3.Sitton NB (2006). Somatostatin and the Somatostatin Receptors: Versatile Regulators of Biological Activity. Pathways, 2:25-27.
4.Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B (2004). Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol.,15(6):966-973.
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1 comment:
So, if one wanted to neutralize or compensate for the inhibitory effect of somatostain on CCK, how would that be accomplished?
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