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The Gastrin-ECL Cell Axis. Functional Aspects

Björkqvist, Maria LU (2002)
Abstract (Swedish)
Popular Abstract in Swedish

Mag-tarmkanalen utgör kroppens största hormon-producerande organ. Många av de hormon-producerande cellernas funktion är ännu okänd och mycket lite är känt om den betydelse de kan ha vid olika sjukdomar i mag-tarmkanalen. I magsäckens syraproducerande del (fundus) finns 4 hormon-producerande celler, av vilka ECL cellen (65 %) och A-lika cellen (25 %) tillsammans utgör ca 90 %. ECL cellen är en histamin-innehållande cell som har en nyckelfunktion vid magsyraproduktion. De A-lika cellerna, vars hormon (ghrelin) nyligen upptäckts, förmodas delta i metabol regleringen. När maten når magen stimuleras gastrin-producerande celler i antrum. Dessa frisätter gastrin till blodet, som därefter når... (More)
Popular Abstract in Swedish

Mag-tarmkanalen utgör kroppens största hormon-producerande organ. Många av de hormon-producerande cellernas funktion är ännu okänd och mycket lite är känt om den betydelse de kan ha vid olika sjukdomar i mag-tarmkanalen. I magsäckens syraproducerande del (fundus) finns 4 hormon-producerande celler, av vilka ECL cellen (65 %) och A-lika cellen (25 %) tillsammans utgör ca 90 %. ECL cellen är en histamin-innehållande cell som har en nyckelfunktion vid magsyraproduktion. De A-lika cellerna, vars hormon (ghrelin) nyligen upptäckts, förmodas delta i metabol regleringen. När maten når magen stimuleras gastrin-producerande celler i antrum. Dessa frisätter gastrin till blodet, som därefter når ECL-cellerna i den syraproducerande delen av magen (fundus). ECL-cellerna styr magsäckens saltsyrasekretion genom att frisätta histamin som i sin tur stimulerar parietalcellen att producera saltsyra. Gastrins främsta effekter är att stimulera ECL cellens frisättning och verka tillväxtstimulerande för magslemhinnan.



Vi har utvecklat en metod för att isolera ECL celler från råttans mage, vilken ger oss ett stort antal väl fungerande ECL-celler med hög renhet. Vi har kunnat visa att gastrin stimulerar dylika ECL celler till att frisätta histamin. Dessutom kontrolleras ECL cellernas aktivitet av neuropeptider såsom PACAP och VIP. ECL-cellens frisättning av histamin hämmas av somatostatin och av prostaglandiner och neuropeptiden galanin. Vi har även studerat de intracellulära processerna inne i ECL cellen som svar på stimulering och hämmning. En ökning av intracellulärt calcium är en viktig del i frisättningsmekanismen i dessa celler. Vi har studerat vikten av att calcium tas in i cellen och hur detta sker vid olika stimuli. Vi har även studerat hur hämmare av sekretion verkar, genom att blockera calciumflödet in i cellen.



Gastrins effekt på ECL cellen medieras av CCK2 receptorn. Denna receptor går att blockera med hjälp av en CCK2 receptor antagonist. Vi har studerat effektiviteten hos olika CCK2 receptor antagonister. Vi har även med hjälp av CCK2 receptor blockad studerat betydelsen av gastrin för magslemhinnan i sin helhet och för ECL cellen. Gastrin har betydelse för magslemhinnans funktion (syra-sekretion) och tillväxt. Gastrin kontrollerar ECL-cellernas aktivitet och antal och detta i sin tur har återverkningar på resten av magslemhinnan. Gastrins kontroll funktion är ej etablerad hos den nyfödda och unga råttan förrän efter avvänjning. (Less)
Abstract
The ECL cells constitute a prominent endocrine cell population in the acid-producing part of the stomach. They are controlled by circulating gastrin released from G-cells in the antrum. In response to gastrin, they secrete histamine, that in turn stimulates the parietal cell to secrete acid. The first aim of the study was to prepare isolated ECL cells of high purity and to study and identify regulators of secretion from such cells in primary culture. Gastrin and pituitary adenylate cyclase activating peptide (PACAP) effectively evoked ECL-cell secretion. Vasoactive intestinal peptide (VIP) and adrenaline also evoked secretion but with a lower efficacy. Somatostatin, galanin and prostaglandins inhibited stimulated ECL-cell... (More)
The ECL cells constitute a prominent endocrine cell population in the acid-producing part of the stomach. They are controlled by circulating gastrin released from G-cells in the antrum. In response to gastrin, they secrete histamine, that in turn stimulates the parietal cell to secrete acid. The first aim of the study was to prepare isolated ECL cells of high purity and to study and identify regulators of secretion from such cells in primary culture. Gastrin and pituitary adenylate cyclase activating peptide (PACAP) effectively evoked ECL-cell secretion. Vasoactive intestinal peptide (VIP) and adrenaline also evoked secretion but with a lower efficacy. Somatostatin, galanin and prostaglandins inhibited stimulated ECL-cell secretion.



Elevation of the intracellular calcium concentration ([Ca2+]i) is a key event in the regulation of many cellular processes. Gastrin binds to the CCK2 receptor causing Ca2+ entry through L-type and N-type Ca2+ channels followed by exocytosis. PACAP binds to PAC1 receptors, causing Ca2+ entry through L-type and receptor-operated channels. Somatostatin, misoprostol and galanin bind to receptors that are coupled to inhibitory G-proteins that block conductance through Ca2+ channels. Somatostatin and misoprostol interfere with L-type, N-type and receptor-operated Ca2+ channels, thereby preventing Ca2+ influx following either gastrin or PACAP challenge. For unknown reasons, galanin interfere with L-type Ca2+ channels only.



Gastrin is a recognized growth-promoting hormone for the acid-producing part of the stomach and for the ECL cells in particular. The trophic effect of gastrin is probably exerted on stem cells and ECL cells. The ECL cells are known to respond to gastrin not only with the mobilization of secretory products, but also with increased expression of proteins, such as the histamine-forming enzyme histidine decarboxylase (HDC). To elucidate the action of gastrin on the stomach we attempted to identify genes that are regulated by gastrin in oxyntic mucosa and in isolated ECL cells. In order to detect altered gene expression in oxyntic mucosa and in ECL cells in response to sustained hypergastrinemia, differential display reverse transcriptase reactions were conducted. Our results revealed gastrin-evoked upregulation of several genes that may be involved in secretory processes, e.g. mRNA for HDC and synaptotagmin V.



The effects of gastrin on the ECL cell can be prevented by a CCK2 receptor antagonist. We conducted a pharmacological analysis of a series of CCK2 receptor antagonists on gastrin-stimulated secretion from ECL cells in primary culture. The most potent of the antagonists were YM022 and YF476. Both agents produced a rightward and parallell shift in the gastrin dose-response curve, suggesting surmountable and competitive antagonism. The effects of CCK2 receptor blockade on oxyntic mucosa and ECL cells were studied in the developing and mature rat. CCK2 receptor blockade in the rat affected the oxyntic mucosa but not extra-gastric sites. In the developing rat, neither the post-natal body weight gain nor the onset of weaning were affected by CCK2 receptor blockade. ECL cells failed to respond to gastrin before weaning, but their activity was clearly gastrin-dependent after weaning. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Professor Jens Rehfeld, Jens Rehfeld, Copenhagen, Denmark
organization
publishing date
type
Thesis
publication status
published
subject
keywords
pharmacognosy, pharmacy, toxicology, Farmakologi, farmakognosi, farmaci, toxikologi, Pharmacological sciences, Calcium channels, CCK receptor antagonists, Misoprostol, Galanin, Somatostatin, Pancreastatin, Histamine, VIP, Gastrin, PACAP
pages
176 pages
publisher
Maria Björkqvist, Department of Physiological Sciences, Pharmacology, BMC F13, 221 84 LUND,
defense location
Rune-Grubb Lecture Hall, BMC, Sölvegatan 19, LUND
defense date
2002-10-10 09:15
external identifiers
  • Other:ISRN: LUMEDW/MEFA--1043--SE
language
English
LU publication?
yes
id
c026a804-70b1-4dd6-b342-be7a37ffa90d (old id 464860)
date added to LUP
2007-09-10 10:48:36
date last changed
2016-09-19 08:45:15
@phdthesis{c026a804-70b1-4dd6-b342-be7a37ffa90d,
  abstract     = {The ECL cells constitute a prominent endocrine cell population in the acid-producing part of the stomach. They are controlled by circulating gastrin released from G-cells in the antrum. In response to gastrin, they secrete histamine, that in turn stimulates the parietal cell to secrete acid. The first aim of the study was to prepare isolated ECL cells of high purity and to study and identify regulators of secretion from such cells in primary culture. Gastrin and pituitary adenylate cyclase activating peptide (PACAP) effectively evoked ECL-cell secretion. Vasoactive intestinal peptide (VIP) and adrenaline also evoked secretion but with a lower efficacy. Somatostatin, galanin and prostaglandins inhibited stimulated ECL-cell secretion.<br/><br>
<br/><br>
Elevation of the intracellular calcium concentration ([Ca2+]i) is a key event in the regulation of many cellular processes. Gastrin binds to the CCK2 receptor causing Ca2+ entry through L-type and N-type Ca2+ channels followed by exocytosis. PACAP binds to PAC1 receptors, causing Ca2+ entry through L-type and receptor-operated channels. Somatostatin, misoprostol and galanin bind to receptors that are coupled to inhibitory G-proteins that block conductance through Ca2+ channels. Somatostatin and misoprostol interfere with L-type, N-type and receptor-operated Ca2+ channels, thereby preventing Ca2+ influx following either gastrin or PACAP challenge. For unknown reasons, galanin interfere with L-type Ca2+ channels only.<br/><br>
<br/><br>
Gastrin is a recognized growth-promoting hormone for the acid-producing part of the stomach and for the ECL cells in particular. The trophic effect of gastrin is probably exerted on stem cells and ECL cells. The ECL cells are known to respond to gastrin not only with the mobilization of secretory products, but also with increased expression of proteins, such as the histamine-forming enzyme histidine decarboxylase (HDC). To elucidate the action of gastrin on the stomach we attempted to identify genes that are regulated by gastrin in oxyntic mucosa and in isolated ECL cells. In order to detect altered gene expression in oxyntic mucosa and in ECL cells in response to sustained hypergastrinemia, differential display reverse transcriptase reactions were conducted. Our results revealed gastrin-evoked upregulation of several genes that may be involved in secretory processes, e.g. mRNA for HDC and synaptotagmin V.<br/><br>
<br/><br>
The effects of gastrin on the ECL cell can be prevented by a CCK2 receptor antagonist. We conducted a pharmacological analysis of a series of CCK2 receptor antagonists on gastrin-stimulated secretion from ECL cells in primary culture. The most potent of the antagonists were YM022 and YF476. Both agents produced a rightward and parallell shift in the gastrin dose-response curve, suggesting surmountable and competitive antagonism. The effects of CCK2 receptor blockade on oxyntic mucosa and ECL cells were studied in the developing and mature rat. CCK2 receptor blockade in the rat affected the oxyntic mucosa but not extra-gastric sites. In the developing rat, neither the post-natal body weight gain nor the onset of weaning were affected by CCK2 receptor blockade. ECL cells failed to respond to gastrin before weaning, but their activity was clearly gastrin-dependent after weaning.},
  author       = {Björkqvist, Maria},
  keyword      = {pharmacognosy,pharmacy,toxicology,Farmakologi,farmakognosi,farmaci,toxikologi,Pharmacological sciences,Calcium channels,CCK receptor antagonists,Misoprostol,Galanin,Somatostatin,Pancreastatin,Histamine,VIP,Gastrin,PACAP},
  language     = {eng},
  pages        = {176},
  publisher    = {Maria Björkqvist, Department of Physiological Sciences, Pharmacology, BMC F13, 221 84 LUND,},
  school       = {Lund University},
  title        = {The Gastrin-ECL Cell Axis. Functional Aspects},
  year         = {2002},
}