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Gastric Peptides—Gastrin and Somatostatin

Mitchell L. Schubert, Jens F. Rehfeld

10.1002/cphy.c180035

Source: Volume 10, Issue 1, January 2020

Published online: December 2019

Full Article on Wiley Online Library



Abstract

Gastric acid secretion (i) facilitates digestion of protein as well as absorption of micronutrients and certain medications, (ii) kills ingested microorganisms, including Helicobacter pylori, and (iii) prevents bacterial overgrowth and enteric infection. The principal regulators of acid secretion are the gastric peptides gastrin and somatostatin. Gastrin, the major hormonal stimulant for acid secretion, is synthesized in pyloric mucosal G cells as a 101‐amino acid precursor (preprogastrin) that is processed to yield biologically active amidated gastrin‐17 and gastrin‐34. The C‐terminal active site of gastrin (Trp‐Met‐Asp‐Phe‐NH2) binds to gastrin/CCK2 receptors on parietal and, more importantly, histamine‐containing enterochromaffin‐like (ECL) cells, located in oxyntic mucosa, to induce acid secretion. Histamine diffuses to the neighboring parietal cells where it binds to histamine H2‐receptors coupled to hydrochloric acid secretion. Gastrin is also a trophic hormone that maintains the integrity of gastric mucosa, induces proliferation of parietal and ECL cells, and is thought to play a role in carcinogenesis. Somatostatin, present in D cells of the gastric pyloric and oxyntic mucosa, is the main inhibitor of acid secretion, particularly during the interdigestive period. Somatostatin exerts a tonic paracrine restraint on gastrin secretion from G cells, histamine secretion from ECL cells, and acid secretion from parietal cells. Removal of this restraint, for example by activation of cholinergic neurons during ingestion of food, initiates and maximizes acid secretion. Knowledge regarding the structure and function of gastrin, somatostatin, and their respective receptors is providing novel avenues to better diagnose and manage acid‐peptic disorders and certain cancers. Published 2020. Compr Physiol 10:197‐228, 2020.

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Figure 1. Figure 1. Functional gastric anatomy. The stomach consists of three anatomic (fundus, corpus or body, and antrum) and two functional (oxyntic and pyloric gland; 80% and 20%, respectively) areas. The hallmark of the oxyntic gland area is the acid‐secreting parietal cell. Also present are histamine‐secreting enterochromaffin‐like (ECL) cells. The hallmark of the pyloric gland area is the gastrin‐secreting G cell. Somatostatin‐secreting D cells are present in both areas and exert a tonic inhibitory restraint on secretions from G, ECL, and parietal cells. +, stimulatory; −, inhibitory.
Figure 2. Figure 2. Gastric gland anatomy. Somatostatin‐containing D cells possess cytoplasmic processes that terminate near (i) gastrin‐secreting G and pepsinogen‐secreting chief cells in the pyloric gland (antrum) and (ii) histamine‐secreting enterochromaffin‐like, acid‐secreting parietal, and pepsinogen‐secreting chief cells in the oxyntic gland (fundus and corpus). The functional correlate of this anatomic coupling is a tonic paracrine restraint exerted by somatostatin on the secretion of gastrin, histamine, acid, and pepsinogen. Somatostatin inhibits acid secretion directly as well as indirectly by inhibiting the secretion of gastrin and histamine.
Figure 3. Figure 3. (A) Structure of human gastrin‐17. The N‐ and C‐terminus are pyroglutaminated and carboxyamidated, respectively, which protect the peptide against amino‐ and carboxypeptidase degradation. The single tyrosyl (Tyr) residue is O‐sulfated in approximately half of the gastrins. (B) Overall structure of bioactive/amidated gastrins and their relationship to human preprogastrin (101 amino acids). The mono‐ and dibasic cleavage sites in progastrin (80 amino acids) are indicated as R, RR, and KK. The seryl site from where the signal peptide is removed is indicated as S. s, sulfated; ns, nonsulfated.
Figure 4. Figure 4. Overall structure of the human gastrin gene, mRNA, and prepropeptide. Exons are shown as boxes and introns as straight lines. The shaded area of the mRNA indicates the coding region. Numbers show base pairs (bp) or kilobase pairs (kb) in each region of the gene. In preprogastrin, the position occupied by gastrin‐34 is shown by shading.
Figure 5. Figure 5. Primary structures of mammalian preprogastrins deduced from cloned cDNAs (monoletter code). Letters in bold are residues common in most species. |→ indicates point and length of major gastrins (gastrin‐71, ‐34, and ‐17). The box contains the iconic C‐terminal tetrapeptide sequence, which constitutes the “active site” that is preserved during evolution and common to all bioactive members of the gastrin family. Courtesy to A.H. Johnsen; for review and sources, see Ref. 205.
Figure 6. Figure 6. Schematic illustration of the posttranslational maturation process of gastrins derived from progastrin in antral G cells. Mono‐ and dibasic cleavage sites are shown on the upper structure of preprogastrin. The main organelles in the cellular processing pathway are indicated on the left side of the figure. The main processing enzymes are indicated on the right side of the figure.
Figure 7. Figure 7. Primary structure of the canine gastrin/CCK2 receptor, a G protein‐coupled receptor with seven‐transmembrane domains. Shaded amino acid residues indicate identity with corresponding residues in the CCK1 receptor. Symbols on the extracellular N(Asn) residues indicate glycosylation sites.
Figure 8. Figure 8. The C‐terminal amino acid sequences of members of the gastrin/cholecystokinin family in vertebrates (upper part) and the partly homologous sequences of sulfakinins in insects (lower part). In the boxes are the evolutionarily preserved, carboxyamidated tetrapeptide sequence (Trp‐Met‐Asp‐Phe‐NH2) required for binding to the gastrin/CCK2 receptor.
Figure 9. Figure 9. Model illustrating the gastrin‐enterochromaffin‐like (ECL) cell‐parietal cell axis. Although gastrin/CCK2 receptors are present on both ECL and parietal cells, gastrin stimulates gastric acid secretion mainly by releasing histamine from ECL cells. Histamine then diffuses to the neighboring parietal cells where it binds to histamine H2‐receptors coupled to the generation of cAMP and activation of the proton pump, H+/K+‐ATPase. Courtesy to R. Håkanson 159.
Figure 10. Figure 10. Model illustrating the roles of gastrin and somatostatin (SST) and their receptors in the regulation of gastric acid secretion. Gastrin, secreted into the local circulation by G cells of the gastric antrum (pyloric mucosa), is the main hormonal stimulant for acid secretion. Acting via gastrin/CCK2 receptors, gastrin stimulates the parietal cell directly and, most importantly, indirectly by releasing histamine from enterochromaffin (ECL) cells. Histamine diffuses to the neighboring parietal cells (paracrine action) where it binds to histamine H2‐receptors coupled to the generation of cAMP and subsequent activation of the proton pump, H+/K+‐ATPase. Somatostatin, acting in a paracrine manner, is the main inhibitor of acid secretion. Somatostatin, secreted by D cells in both the pyloric and oxyntic mucosa, binds to somatostatin subtype‐2 (SST2) receptors located on G, ECL, and parietal cells. Somatostatin, secreted by D cells in the antrum, exerts a tonic inhibitory influence on gastrin secretion. Somatostatin, secreted by D cells in the fundus/corpus, exerts a tonic inhibitory influence on histamine secretion from ECL cells and acid secretion from parietal cells. Withdrawal of the inhibitory influence of somatostatin (i.e., disinhibition) by activation of cholinergic neurons initiates acid secretion and permits a maximal acid secretory response. A feedback pathway exists in both the antrum and the corpus/fundus whereby luminal acid stimulates somatostatin secretion and thus restrains acid secretion. +, stimulation; −, inhibition.
Figure 11. Figure 11. Model illustrating the neural and paracrine pathways regulating gastrin and somatostatin (SST) secretion in the stomach. Preganglionic efferent vagal nerve fibers synapse, within the wall of the stomach, with intramural cholinergic (ACh) and peptidergic [gastrin‐releasing peptide (GRP) and vasoactive intestinal peptide (VIP)] neurons that regulate gastrin and somatostatin secretion. In the antrum, reciprocal paracrine pathways link somatostatin‐secreting D cells and gastrin‐secreting G cells. In the fundus/corpus, reciprocal paracrine pathways link somatostatin‐secreting D cells to acid‐secreting parietal and histamine‐secreting enterochromaffin‐like (ECL) cells. During the basal interdigestive state, gastric acid secretion is maintained at low levels by the tonic inhibitory influence of somatostatin‐secreting D cells on (i) parietal and ECL cells in the fundus/corpus and (ii) G cells in the antrum. During ingestion of food, cholinergic neurons are activated by the thought, smell, sight, and taste of food as well as by protein components of the food and gastric distension. In the fundus/body, ACh, released from intramural cholinergic neurons, stimulates the parietal cell directly as well as indirectly by eliminating the inhibitory paracrine influence of somatostatin on parietal and ECL cells. The resultant increase in histamine stimulates the parietal cell directly via H2 receptors and indirectly via H3 receptors that further suppress somatostatin secretion. In the antrum, cholinergic neurons, activated by anticipation of food as well as luminal protein and high distension, stimulate gastrin secretion directly as well as indirectly by suppressing somatostatin secretion. Protein, acting via GRP neurons, directly stimulates gastrin secretion. It should be emphasized that suppression of somatostatin permits an optimal gastrin response. As the food empties the stomach, a number of pathways are actuated that restore somatostatin and thus restrain gastrin and acid secretion: (i) a paracrine pathway links gastrin to stimulation of somatostatin secretion, (ii) cholinergic neurons are less activated by anticipation of food as well by protein and distension, (iii) VIP neurons that stimulate somatostatin secretion are preferentially activated by low levels of distension, (iv) unbuffered luminal acid activates calcitonin gene‐related peptide (CGRP) extrinsic sensory neurons that stimulate somatostatin secretion, and (v) enterogastrones (e.g., cholecystokinin), released from the small intestine, stimulate somatostatin secretion. +, stimulation; −, inhibition.
Figure 12. Figure 12. Model illustrating the regulation of somatostatin and gastrin secretion in the antrum of the stomach by luminal acid, amino acids, and calcium as well as infection with Helicobacter pylori (HP). Unbuffered luminal acid activates calcitonin gene‐related peptide (CGRP) extrinsic sensory neurons that, via an axon reflex, stimulate somatostatin secretion from D cells and thus inhibit gastrin secretion from G cells. Antisecretory agents, such as proton pump inhibitors, inhibit acid secretion and thus lessen activation of CGRP neurons, leading to a decrease in somatostatin and reciprocal increase in gastrin secretion (hypergastrinemia). Protein stimulates gastrin secretion via activation of intramural neurons (Figure 11), but amino acids and calcium may act directly on the G cell. Acute infection with H. pylori (HP) activates CGRP neurons to stimulate somatostatin and thus inhibit gastrin (and acid) secretion; inhibition of acid facilitates colonization and infection. In patients with duodenal ulcer who have chronic HP infection of the antrum, the bacteria and/or cytokines released by the inflammatory infiltrate inhibit somatostatin and thus stimulate gastrin (and acid) secretion. +, stimulation; −, inhibition.
Figure 13. Figure 13. Electromicroscopic image of a rat G cell. The cell expresses polarity with the apical border, lined by microvilli, exposed to the glandular lumen and the basolateral aspect packed with gastrin‐containing secretory granules. The apical membrane may “taste” luminal contents, whereas gastrin is secreted across the basolateral membrane into the local circulation. Courtesy to L.‐I. Larsson.
Figure 14. Figure 14. Model illustrating the amino acid structure of somatostatin‐14 (SST‐14), somatostatin‐28 (SST‐28), and the synthetic somatostatin analogue, octreotide. The four amino acids, Phe‐Trp‐Lys‐Thr, shaded in color, are crucial for the binding of somatostatin to its receptor. The disulfide bridge between two cysteine residues, present in each structure, is represented as ‐S‐S‐.


Figure 1. Functional gastric anatomy. The stomach consists of three anatomic (fundus, corpus or body, and antrum) and two functional (oxyntic and pyloric gland; 80% and 20%, respectively) areas. The hallmark of the oxyntic gland area is the acid‐secreting parietal cell. Also present are histamine‐secreting enterochromaffin‐like (ECL) cells. The hallmark of the pyloric gland area is the gastrin‐secreting G cell. Somatostatin‐secreting D cells are present in both areas and exert a tonic inhibitory restraint on secretions from G, ECL, and parietal cells. +, stimulatory; −, inhibitory.


Figure 2. Gastric gland anatomy. Somatostatin‐containing D cells possess cytoplasmic processes that terminate near (i) gastrin‐secreting G and pepsinogen‐secreting chief cells in the pyloric gland (antrum) and (ii) histamine‐secreting enterochromaffin‐like, acid‐secreting parietal, and pepsinogen‐secreting chief cells in the oxyntic gland (fundus and corpus). The functional correlate of this anatomic coupling is a tonic paracrine restraint exerted by somatostatin on the secretion of gastrin, histamine, acid, and pepsinogen. Somatostatin inhibits acid secretion directly as well as indirectly by inhibiting the secretion of gastrin and histamine.


Figure 3. (A) Structure of human gastrin‐17. The N‐ and C‐terminus are pyroglutaminated and carboxyamidated, respectively, which protect the peptide against amino‐ and carboxypeptidase degradation. The single tyrosyl (Tyr) residue is O‐sulfated in approximately half of the gastrins. (B) Overall structure of bioactive/amidated gastrins and their relationship to human preprogastrin (101 amino acids). The mono‐ and dibasic cleavage sites in progastrin (80 amino acids) are indicated as R, RR, and KK. The seryl site from where the signal peptide is removed is indicated as S. s, sulfated; ns, nonsulfated.


Figure 4. Overall structure of the human gastrin gene, mRNA, and prepropeptide. Exons are shown as boxes and introns as straight lines. The shaded area of the mRNA indicates the coding region. Numbers show base pairs (bp) or kilobase pairs (kb) in each region of the gene. In preprogastrin, the position occupied by gastrin‐34 is shown by shading.


Figure 5. Primary structures of mammalian preprogastrins deduced from cloned cDNAs (monoletter code). Letters in bold are residues common in most species. |→ indicates point and length of major gastrins (gastrin‐71, ‐34, and ‐17). The box contains the iconic C‐terminal tetrapeptide sequence, which constitutes the “active site” that is preserved during evolution and common to all bioactive members of the gastrin family. Courtesy to A.H. Johnsen; for review and sources, see Ref. 205.


Figure 6. Schematic illustration of the posttranslational maturation process of gastrins derived from progastrin in antral G cells. Mono‐ and dibasic cleavage sites are shown on the upper structure of preprogastrin. The main organelles in the cellular processing pathway are indicated on the left side of the figure. The main processing enzymes are indicated on the right side of the figure.


Figure 7. Primary structure of the canine gastrin/CCK2 receptor, a G protein‐coupled receptor with seven‐transmembrane domains. Shaded amino acid residues indicate identity with corresponding residues in the CCK1 receptor. Symbols on the extracellular N(Asn) residues indicate glycosylation sites.


Figure 8. The C‐terminal amino acid sequences of members of the gastrin/cholecystokinin family in vertebrates (upper part) and the partly homologous sequences of sulfakinins in insects (lower part). In the boxes are the evolutionarily preserved, carboxyamidated tetrapeptide sequence (Trp‐Met‐Asp‐Phe‐NH2) required for binding to the gastrin/CCK2 receptor.


Figure 9. Model illustrating the gastrin‐enterochromaffin‐like (ECL) cell‐parietal cell axis. Although gastrin/CCK2 receptors are present on both ECL and parietal cells, gastrin stimulates gastric acid secretion mainly by releasing histamine from ECL cells. Histamine then diffuses to the neighboring parietal cells where it binds to histamine H2‐receptors coupled to the generation of cAMP and activation of the proton pump, H+/K+‐ATPase. Courtesy to R. Håkanson 159.


Figure 10. Model illustrating the roles of gastrin and somatostatin (SST) and their receptors in the regulation of gastric acid secretion. Gastrin, secreted into the local circulation by G cells of the gastric antrum (pyloric mucosa), is the main hormonal stimulant for acid secretion. Acting via gastrin/CCK2 receptors, gastrin stimulates the parietal cell directly and, most importantly, indirectly by releasing histamine from enterochromaffin (ECL) cells. Histamine diffuses to the neighboring parietal cells (paracrine action) where it binds to histamine H2‐receptors coupled to the generation of cAMP and subsequent activation of the proton pump, H+/K+‐ATPase. Somatostatin, acting in a paracrine manner, is the main inhibitor of acid secretion. Somatostatin, secreted by D cells in both the pyloric and oxyntic mucosa, binds to somatostatin subtype‐2 (SST2) receptors located on G, ECL, and parietal cells. Somatostatin, secreted by D cells in the antrum, exerts a tonic inhibitory influence on gastrin secretion. Somatostatin, secreted by D cells in the fundus/corpus, exerts a tonic inhibitory influence on histamine secretion from ECL cells and acid secretion from parietal cells. Withdrawal of the inhibitory influence of somatostatin (i.e., disinhibition) by activation of cholinergic neurons initiates acid secretion and permits a maximal acid secretory response. A feedback pathway exists in both the antrum and the corpus/fundus whereby luminal acid stimulates somatostatin secretion and thus restrains acid secretion. +, stimulation; −, inhibition.


Figure 11. Model illustrating the neural and paracrine pathways regulating gastrin and somatostatin (SST) secretion in the stomach. Preganglionic efferent vagal nerve fibers synapse, within the wall of the stomach, with intramural cholinergic (ACh) and peptidergic [gastrin‐releasing peptide (GRP) and vasoactive intestinal peptide (VIP)] neurons that regulate gastrin and somatostatin secretion. In the antrum, reciprocal paracrine pathways link somatostatin‐secreting D cells and gastrin‐secreting G cells. In the fundus/corpus, reciprocal paracrine pathways link somatostatin‐secreting D cells to acid‐secreting parietal and histamine‐secreting enterochromaffin‐like (ECL) cells. During the basal interdigestive state, gastric acid secretion is maintained at low levels by the tonic inhibitory influence of somatostatin‐secreting D cells on (i) parietal and ECL cells in the fundus/corpus and (ii) G cells in the antrum. During ingestion of food, cholinergic neurons are activated by the thought, smell, sight, and taste of food as well as by protein components of the food and gastric distension. In the fundus/body, ACh, released from intramural cholinergic neurons, stimulates the parietal cell directly as well as indirectly by eliminating the inhibitory paracrine influence of somatostatin on parietal and ECL cells. The resultant increase in histamine stimulates the parietal cell directly via H2 receptors and indirectly via H3 receptors that further suppress somatostatin secretion. In the antrum, cholinergic neurons, activated by anticipation of food as well as luminal protein and high distension, stimulate gastrin secretion directly as well as indirectly by suppressing somatostatin secretion. Protein, acting via GRP neurons, directly stimulates gastrin secretion. It should be emphasized that suppression of somatostatin permits an optimal gastrin response. As the food empties the stomach, a number of pathways are actuated that restore somatostatin and thus restrain gastrin and acid secretion: (i) a paracrine pathway links gastrin to stimulation of somatostatin secretion, (ii) cholinergic neurons are less activated by anticipation of food as well by protein and distension, (iii) VIP neurons that stimulate somatostatin secretion are preferentially activated by low levels of distension, (iv) unbuffered luminal acid activates calcitonin gene‐related peptide (CGRP) extrinsic sensory neurons that stimulate somatostatin secretion, and (v) enterogastrones (e.g., cholecystokinin), released from the small intestine, stimulate somatostatin secretion. +, stimulation; −, inhibition.


Figure 12. Model illustrating the regulation of somatostatin and gastrin secretion in the antrum of the stomach by luminal acid, amino acids, and calcium as well as infection with Helicobacter pylori (HP). Unbuffered luminal acid activates calcitonin gene‐related peptide (CGRP) extrinsic sensory neurons that, via an axon reflex, stimulate somatostatin secretion from D cells and thus inhibit gastrin secretion from G cells. Antisecretory agents, such as proton pump inhibitors, inhibit acid secretion and thus lessen activation of CGRP neurons, leading to a decrease in somatostatin and reciprocal increase in gastrin secretion (hypergastrinemia). Protein stimulates gastrin secretion via activation of intramural neurons (Figure 11), but amino acids and calcium may act directly on the G cell. Acute infection with H. pylori (HP) activates CGRP neurons to stimulate somatostatin and thus inhibit gastrin (and acid) secretion; inhibition of acid facilitates colonization and infection. In patients with duodenal ulcer who have chronic HP infection of the antrum, the bacteria and/or cytokines released by the inflammatory infiltrate inhibit somatostatin and thus stimulate gastrin (and acid) secretion. +, stimulation; −, inhibition.


Figure 13. Electromicroscopic image of a rat G cell. The cell expresses polarity with the apical border, lined by microvilli, exposed to the glandular lumen and the basolateral aspect packed with gastrin‐containing secretory granules. The apical membrane may “taste” luminal contents, whereas gastrin is secreted across the basolateral membrane into the local circulation. Courtesy to L.‐I. Larsson.


Figure 14. Model illustrating the amino acid structure of somatostatin‐14 (SST‐14), somatostatin‐28 (SST‐28), and the synthetic somatostatin analogue, octreotide. The four amino acids, Phe‐Trp‐Lys‐Thr, shaded in color, are crucial for the binding of somatostatin to its receptor. The disulfide bridge between two cysteine residues, present in each structure, is represented as ‐S‐S‐.
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Teaching Material

Mitchell L. Schubert, Jens F. Rehfeld. Gastric Peptides—Gastrin and Somatostatin. Compr Physiol 10: 2020, 197-228.

Didactic Synopsis

Major Teaching Points:

*Gastrin, present in G cells of the gastric antrum (pyloric mucosa), is the main hormonal stimulant of acid secretion during ingestion of a meal.

*Gastrin stimulates acid secretion directly and, more importantly, indirectly, by inducing histamine synthesis and secretion from enterochromaffin-like (ECL) cells located in the body and fundus of the stomach (oxyntic mucosa). Histamine, acting in a paracrine manner, diffuses to neighboring parietal cells where it binds to histamine H2-receptors coupled to secretion of hydrochloric acid.

*Gastrin, synthesized as a 101-amino acid precursor (preprogastrin), is processed to yield a variety of forms, the principal of which are gastrin-17 and gastrin-34. Although antral G cells produce predominantly gastrin-17, the peripheral blood contains almost equal amounts of gastrin-17 and gastrin-34 due to the slower metabolic clearance of large gastrins.

*Gastrin exerts its biologic actions through binding of its C-terminal active site, -Trp-Met-Asp-Phe-NH2, to the gastrin/CCK2 receptor, a G protein-coupled receptor formerly referred to as the CCKB or gastrin receptor.

*Gastrin is also a trophic hormone that (i) maintains the integrity of gastric mucosa by stimulating proliferation, cell migration, and angiogenesis as well as inhibiting apoptosis and (ii) may play a role in carcinogenesis (gastric adenocarcinoma, neuroendocrine tumor, and esophageal adenocarcinoma).

*Somatostatin, present in D cells of gastric pyloric and oxyntic glands, functions in a paracrine manner as the main inhibitor of gastric exocrine (acid and pepsinogen) and endocrine (gastrin, histamine, and ghrelin) secretion.

*Somatostatin, synthesized as a 116-amino acid precursor (preprosomatostatin), is processed to yield somatostatin-14 and somatostatin-28. Gastric D cells produce almost exclusively somatostatin-14.

*Somatostatin exerts it biologic actions through a family of G protein-coupled receptors termed SSTR1-SSTR5; SSTR2 is the subtype ubiquitously expressed in the gastrointestinal tract and involved in the regulation of gastric acid secretion.

*Endogenous somatostatin also plays a role in H. pylori-induced disease whereas exogenous somatostatin is used clinically to manage neuroendocrine tumors.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Fig 1. Functional gastric anatomy. The stomach consists of three anatomic (fundus, corpus or body, and antrum) and two functional (oxyntic and pyloric gland areas; 80% and 20%, respectively). The hallmark of the oxyntic gland area is the acid-secreting parietal cell. Also present are histamine-secreting enterochromaffin-like (ECL) cells. The hallmark of the pyloric gland area is the gastrin-secreting G cell. Somatostatin-secreting D cells are present in both areas and exert a tonic inhibitory restraint on secretions from G, ECL, and parietal cells. +, stimulatory; -, inhibitory.

Fig 2. Gastric gland anatomy. Somatostatin-containing D cells possess cytoplasmic processes that terminate near (i) gastrin-secreting G and pepsinogen-secreting chief cells in the pyloric gland (antrum) and (ii) histamine-secreting enterochromaffin-like, acid-secreting parietal, and pepsinogen-secreting chief cells in the oxyntic gland (fundus and corpus). The functional correlate of this anatomic coupling is a tonic paracrine restraint exerted by somatostatin on the secretion of gastrin, histamine, acid, and pepsinogen. Somatostatin inhibits acid secretion directly as well as indirectly by inhibiting the secretion of gastrin and histamine.

Fig 3. (A) Structure of human gastrin-17. The N- and C-termini are pyroglutaminated and carboxyamidated, respectively, which protects the peptide against amino- and carboxypeptidase degradation. the single tyrosyl (Tyr) residue is O-sulfated in ~half of the gastrins.

(B) Overall structure of bioactive/amidated gastrins and their relationship to human preprogastrin (101 amino acids). The mono- and dibasic cleavage sites in progastrin (80 amino acids) are indicated as R, RR, and KK. The seryl site from where the signal peptide is removed is indicated as S. s = sulfated; ns = nonsulfated.

Fig. 4. Overall structure of the human gastrin gene, mRNA, and prepropeptide. Exons are shown as boxes and introns as straight lines. The shaded area of the mRNA indicates the coding region. Numbers show base pairs (bp) or kilobase pairs (kb) in each region of the gene. In preprogastrin the position occupied by gastrin-34 is shown by shading.

Fig. 5. Primary structures of mammalian preprogastrins deduced from cloned cDNAs (monoletter code). Letters in bold are residues common in most species. │→ indicates point and length of major gastrins (gastrin-71, -34, and -17). The box contains the iconic C-terminal tetrapeptide sequence, which constitutes the "active site" that is preserved during evolution and common to all bioactive members of the gastrin family. (Courtesy to A.H. Johnsen; for review and sources, see ref 119 Fuller).

Fig. 6. Schematic illustration of the posttranslational maturation process of gastrins derived from progastrin in antral G-cells. Mono- and dibasic cleavage-sites are shown on the upper structure of preprogastrin. Main organelles in the cellular processing pathway are indicated on the left side of the figure. Main processing enzymes are indicated on the right side of the figure.

Fig. 7. Primary structure of the canine gastrin/CCK2 receptor, a G-protein coupled with seven-transmembrane domains. Shaded amino acid residues indicate identity with corresponding residues in the CCK1 receptor. Symbols on the extracellular N(Asn) residues indicate glycosylation sites.

Fig. 8. The C-terminal amino acid sequences of members of the gastrin/cholecystokinin family in vertebrates (upper part) and the partly homologous sequences of sulfakinins in insects (lower part). In the boxes are the evolutionarily preserved, carboxyamidated tetrapeptide sequence (Trp-Met-Asp-Phe-NH2) required for binding to the gastrin/CCK2 receptor.

Fig. 9. Model illustrating the gastrin – enterochromaffin-like (ECL)-cell – parietal cell axis. Altlhough gastrin/CCK2 receptors are present on both ECL and parietal cells, gastrin stimulates gastric acid secretion mainly by releasing histamine from ECL cells. Histamine then diffuses to neighboring parietal cells where it binds to histamine H2-receptors coupled to generation of cAMP and activation of the the proton pump, H+/K+-ATPase. (Courtesy to R. Håkanson (ref. 155)).

Fig 10. Model illustrating the roles of gastrin and somatostatin (SST) and their receptors in the regulation of gastric acid secretion. Gastrin, secreted into the local circulation by G cells of the gastric antrum (pyloric mucosa), is the main hormonal stimulant for acid secretion. Acting via gastrin/CCK2 receptors, gastrin stimulates the parietal cell directly and, most importantly, indirectly by releasing histamine from enterochromaffin (ECL) cells. Histamine diffuses to neighboring parietal cells (paracrine action) where it binds to histamine H2-receptors coupled to generation of cAMP and subsequent activation of the proton pump, H+/K+-ATPase. Somatostatin, acting in a paracrine manner, is the main inhibitor of acid secretion. Somatostatin, secreted by D cells in both the pyloric and oxyntic mucosa, binds to somatostatin subtype-2 (SST2) receptors located on G, ECL, and parietal cells. Somatostatin, secreted by D cells in the antrum, exerts a tonic inhibitory influence on gastrin secretion. Somatostatin, secreted by D cells in the fundus/corpus, exerts a tonic inhibitory influence on histamine secretion from ECL cells and acid secretion from parietal cells. Withdrawal of the inhibitory influence of somatostatin (i.e., disinhibition) by activation of cholinergic neurons initiates acid secretion and permits a maximal acid secretory response. A feedback pathway exists in both the antrum and corpus/fundus whereby luminal acid stimulates somatostatin secretion and thus restrains acid secretion. +, stimulation; -, inhibition.

Fig 11. Model illustrating the neural and paracrine pathways regulating gastrin and somatostatin (SST) secretion in the stomach. Preganglionic efferent vagal nerve fibers synapse, within the wall of the stomach, with intramural cholinergic (ACh) and peptidergic (gastrin-releasing peptide (GRP) and vasoactive intestinal peptide (VIP)) neurons that regulate gastrin and somatostatin secretion. In antrum, reciprocal paracrine pathways link somatostatin-secreting D cells and gastrin-secreting G cells. In fundus/corpus, reciprocal paracrine pathways link somatostatin-secreting D cells to acid-secreting parietal and histamine-secreting enterochromaffin-like (ECL) cells. During the basal interdigestive state, gastric acid secretion is maintained at low levels by the tonic inhibitory influence of somatostatin-secreting D cells on (i) parietal and ECL cells in the fundus/corpus and (ii) G cells in the antrum. During ingestion of a meal, cholinergic neurons are activated by the thought, smell, sight, and taste of food as well as by protein components of the meal and gastric distension. In the fundus/body, ACh, released from intramural cholinergic neurons, stimulates the parietal cell directly as well as indirectly by eliminating the inhibitory paracrine influence of somatostatin on parietal and ECL cells. The resultant increase in histamine stimulates the parietal cell directly via H2 receptors and indirectly via H3 receptors that further suppress somatostatin secretion. In the antrum, cholinergic neurons, activated by anticipation of the meal as well as luminal protein and high distension, stimulate gastrin secretion directly as well as indirectly by suppressing somatostatin secretion. Protein, acting via GRP neurons directly stimulates gastrin secretion. It should be emphasized that suppression of somatostatin permits an optimal gastrin response. As the meal empties the stomach, a number of pathways are actuated that restore somatostatin and thus restrain gastrin and acid secretion: (i) a paracrine pathway links gastrin to stimulation of somatostatin secretion, (ii) cholinergic neurons are less activated by anticipation of a meal as well by protein and distension, (iii) VIP neurons that stimulate somatostatin secretion are preferentially activated by low levels of distension, (iv) unbuffered luminal acid activates calcitonin gene-related peptide (CGRP) extrinsic sensory neurons that stimulate somatostatin secretion, and (v) enterogastrones (e.g. cholecystokinin), released from the small intestine, stimulate somatostatin secretion. +, stimulation; -, inhibition

Fig 12. Model illustrating the regulation of somatostatin and gastrin secretion in the antrum of the stomach by luminal acid, amino acids, and calcium as well as infection with Helicobacter pylori (HP). Unbuffered luminal acid activates calcitonin gene-related peptide (CGRP) extrinsic sensory neurons that, via an axon reflex, stimulate somatostatin secretion from D cells and thus inhibit gastrin secretion from G cells. Antisecretory agents, such as proton pump inhibitors, inhibit acid secretion and thus lessen activation of CGRP neurons leading to a decrease in somatostatin and reciprocal increase in gastrin secretion (hypergastrinemia). Protein stimulates gastrin secretion via activation of intramural neurons (Fig 11) but amino acids and calcium may act directly on the G cell. Acute infection with H. pylori (HP) activates CGRP neurons to stimulate somatostatin and thus inhibit gastrin (and acid) secretion; inhibition of acid facilitates colonization and infection. In patients with duodenal ulcer who have chronic HP infection of the antrum, the bacteria and/or cytokines released by the inflammatory infiltrate inhibit somatostatin and thus stimulate gastrin (and acid) secretion. +, stimulation; -, inhibition

Fig 13. Electromicroscopic image of a rat G cell. The cell expresses polarity with the apical border, lined by microvilli, exposed to the glandular lumen and the basolateral aspect packed with gastrin-containing secretory granules. The apical membrane may "taste" luminal contents whereas gastrin is secreted across the basolateral membrane into the local circulation. Courtesy to L.-I Larsson).

Fig. 14. Model illustrating the amino acid structure of somatostatin-14 (SST-14), somatostatin-28 (SST-28), and the synthetic somatostatin analogue, octreotide. The four amino acids, Phe-Trp-Lys-Thr, shaded in color, are crucial for the binding of somatostatin to its receptor. The disulfide bridge between two cysteine residues, present in each structure, is represented as -S-S-.

 


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Article Title: Gastric Peptides—Gastrin and Somatostatin
 

How to Cite

Mitchell L. Schubert, Jens F. Rehfeld. Gastric Peptides—Gastrin and Somatostatin. Compr Physiol 2019, 10: 197-228. doi: 10.1002/cphy.c180035