Gastric chief cells: Receptors and signal-transduction mechanisms

Raufman, Jean‐Pierre

doi:10.1016/0016-5085(92)90124-h

Cited by 61 publications

(38 citation statements)

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“…28 and 31). Secretagogues that stimulate pepsinogen secretion can be separated into two major categories: agents that activate adenylyl cyclase, thereby causing an increase in cellular cAMP, and agents that activate phospholipase C, thereby increasing cell calcium (25). Secretin, VIP, and histamine are agents in the former and carbamylcholine (carbachol) and CCK are agents in the latter category.…”

Section: Resultsmentioning

confidence: 99%

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Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M₁and M₃muscarinic receptors

Xie¹,

Drachenberg²,

Yamada³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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-Muscarinic cholinergic mechanisms play a key role in stimulating gastric pepsinogen secretion. Studies using antagonists suggested that the M3 receptor subtype (M3R) plays a prominent role in mediating pepsinogen secretion, but in situ hybridization indicated expression of M1 receptor (M1R) in rat chief cells. We used mice that were deficient in either the M1 (M1R Ϫ/Ϫ ) or M3 (M3R Ϫ/Ϫ ) receptor or that lacked both receptors (M1/3R Ϫ/Ϫ ) to determine the role of M1R and M3R in mediating cholinergic agonistinduced pepsinogen secretion. Pepsinogen secretion from murine gastric glands was determined by adapting methods used for rabbit and rat stomach. In wild-type (WT) mice, maximal concentrations of carbachol and CCK caused a 3.0-and 2.5-fold increase in pepsinogen secretion, respectively. Maximal carbachol-induced secretion from M1R Ϫ/Ϫ mouse gastric glands was decreased by 25%. In contrast, there was only a slight decrease in carbachol potency and no change in efficacy when comparing M3R Ϫ/Ϫ with WT glands. To explore the possibility that both M1R and M3R are involved in carbachol-mediated pepsinogen secretion, we examined secretion from glands prepared from M1/3R Ϫ/Ϫ double-knockout mice. Strikingly, carbacholinduced pepsinogen secretion was nearly abolished in glands from M 1/3R Ϫ/Ϫ mice, whereas CCK-induced secretion was not altered. In situ hybridization for murine M 1R and M3R mRNA in gastric mucosa from WT mice revealed abundant signals for both receptor subtypes in the cytoplasm of chief cells. These data clearly indicate that, in gastric chief cells, a mixture of M 1 and M3 receptors mediates cholinergic stimulation of pepsinogen secretion and that no other muscarinic receptor subtypes are involved in this activity. The development of a murine secretory model facilitates use of transgenic mice to investigate the regulation of pepsinogen secretion.carbamylcholine; cholecystokinin; chief cells; gastric glands; knockout mice; in situ hybridization STUDIES USING ANIMAL AND TISSUE models have identified a variety of agents that stimulate gastric pepsinogen secretion. Stimulation by the vagus nerve, which is mediated by release of the neurotransmitter ACh, is probably the most important physiological mechanism for increasing pepsinogen release in the gastric lumen during the digestive process (see Ref. 26 for review of the regulation of pepsinogen secretion). Cholinergic stimulation of gastric acid and pepsinogen secretion also contributes to the pathogenesis of stomach and duodenal ulcers, and surgical vagotomy and the use of anticholinergic agents have been important modes of therapy for these conditions (26). Cholinergic agonists like ACh interact with muscarinic receptors on chief cells, thereby causing activation of phospholipase C and production of second messengers (28, 31). In turn, these second messengers cause an increase in intracellular calcium concentration (27, 35) that activates protein kinases and phosphatases, ultimately resulting in pepsinogen release (24,29,30).Molecular cloning studies re...

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Section: Resultsmentioning

confidence: 99%

“…For example, pharmacological and PCR analysis of muscarinic receptor expression in dispersed acini from rat pancreas are consistent with expression of both M 1 and M 3 muscarinic receptors (33). It is of interest that the cellular biology of the gastric chief cell and pancreatic acinar cell is very similar (25).…”

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confidence: 87%

Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M₁and M₃muscarinic receptors

Xie¹,

Drachenberg²,

Yamada³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…On day 1 subconfluent monolayers of porcine gastric chief cells (25 cm') were washed twice with serum-free Ham's F-10 before adding the DNNlipofectin mixture. After 20 h of incubation, 3 ml chief cell medium with 20% fetal calf serum, 1 mg/ml gentamycin, 10 mM sodium butyrate (Gorman, 1985), and 0.2 mM dibutyryl cyclic AMP (Sigma; Raufman, 1992) was added and incubation continued.…”

Section: Dna Transfections and Transient Expression Assaysmentioning

confidence: 99%

Gastric chief cell‐specific transcription of the pepsinogen A gene

Meijerink¹,

Bebelman²,

Oldenburg³

et al. 1993

European Journal of Biochemistry

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The molecular mechanisms underlying the regulation of pepsinogen A (PGA) gene expression in mammalian cells are poorly understood. In this paper we describe the structural and functional analysis of the pepsinogen A gene promoter in the pig. By genomic Southern analyses we demonstrate that, in contrast with human PGA genes which are amplified and organized in haplotypes, only a single PGA gene is present per haploid porcine genome. With the aim of identifying promoter elements mediating the gastric mucosa cell-specific transcription of the PGA gene in pig, we isolated a PGA gene from a porcine genomic library. The nucleotide sequence of the first exon and 1.7 kb of the upstream DNA region were determined and compared with the corresponding regions of the human PGA gene encoding isozymogen Pg5. In order to study the promoter activity of the PGA gene a functional assay was developed: we succeeded in obtaining primary monolayer cultures of porcine gastric mucosal chief cells, suitable for transfection. Fragments of 5'-flanking and noncoding first exon sequences of the porcine and human PGA genes were linked to the chloramphenicol acetyltransferase (CAT) gene. The transcriptional activity of these hybrid genes was assessed in transient expression assays upon transfection (lipofection) of gastric and nongastric cells. Whereas PGA 5'-flanking sequences showed no promoter activity in nongastric cell types, the DNA region from -205 to +21 was found to be sufficient to direct expression of the porcine PGA constructs in a cell-specific manner. Further deletion analysis of the proximal promoter fragment identified several regions (-205 to -167, -127 to -67 and +2 to +21) acting synergistically in the transcriptional regulation of the PGA gene. In contrast, all human PGA-CAT constructs used failed to show promoter activity in porcine gastric chief cells, indicating species-specific control of PGA gene expression. In addition, the transcriptional activity of the porcine PGA promoter in chief cells from pig was completely abolished by in vitro CpG methylation. Footprint analyses of the proximal promoter fragment using nuclear extracts from either porcine gastric mucosal chief cells or liver revealed some notable differences between both extracts, which might reflect the interaction with (a) cell-specific factor(s).

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“…It profoundly altered epithelial Cl Ϫ secretion (22, 2) and potentiated secretory responses evoked by cAMP in T84 (6), C127 (7), and pancreatic duct cells (36). In the gastrointestinal tract, PKC is also involved in regulation of gastric acid and pepsinogen secretion (21,30). However, the role of PKC in duodenal mucosal bicarbonate secretion is less clear.…”

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confidence: 99%

Protein kinase C potentiates cAMP-stimulated mouse duodenal mucosal bicarbonate secretion in vitro

Tuo

Chow

Barrett

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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; 10.1152/ajpgi.00251.2003.-PKC has been shown to regulate epithelial Cl Ϫ secretion in a variety of models. However, the role of PKC in duodenal mucosal bicarbonate secretion is less clear. We aimed to investigate the role of PKC in regulation of duodenal mucosal bicarbonate secretion. Bicarbonate secretion by murine duodenal mucosa was examined in vitro in Ussing chambers using a pH-stat technique. PKC isoform expression and activity were assessed by Western blotting and in vitro kinase assays, respectively. PMA (an activator of PKC) alone had no effect on duodenal bicarbonate secretion or short-circuit current (Isc). When PMA and dibutyrylcAMP (db-cAMP) were added simultaneously, PMA failed to alter db-cAMP-stimulated duodenal bicarbonate secretion or Isc (P Ͼ 0.05). However, a 1-h preincubation with PMA potentiated db-cAMPstimulated duodenal bicarbonate secretion and Isc in a concentrationdependent manner (from 10 Ϫ8 to 10 Ϫ5 M) (P Ͻ 0.05). PMA preincubation had no effects on carbachol-or heat-stable toxin-stimulated bicarbonate secretion. Western blot analysis revealed that PKC␣, -␥, -⑀, -, -, and -/ were expressed in murine duodenal mucosa. Ro 31-8220 (an inhibitor active against PKC⑀, -␣, -␤, and -␥), but not Gö 6983 (an inhibitor active against PKC␣, -␥, -␤, and -␦), reversed the potentiating effect of PMA on db-cAMP-stimulated bicarbonate secretion. PMA also time-and concentration-dependently increased the activity of PKC⑀, an effect that was prevented by Ro 31-8220 but not Gö 6983. These results demonstrate that activation of PKC potentiates cAMP-stimulated duodenal bicarbonate secretion, whereas it does not modify basal secretion. The effect of PKC on cAMP-stimulated bicarbonate secretion is mediated by the PKC⑀ isoform.

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Gastric chief cells: Receptors and signal-transduction mechanisms

Cited by 61 publications

References 60 publications

Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M₁and M₃muscarinic receptors

Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M₁and M₃muscarinic receptors

Gastric chief cell‐specific transcription of the pepsinogen A gene

Protein kinase C potentiates cAMP-stimulated mouse duodenal mucosal bicarbonate secretion in vitro

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Gastric chief cells: Receptors and signal-transduction mechanisms

Cited by 61 publications

References 60 publications

Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M1and M3muscarinic receptors

Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M1and M3muscarinic receptors

Gastric chief cell‐specific transcription of the pepsinogen A gene

Protein kinase C potentiates cAMP-stimulated mouse duodenal mucosal bicarbonate secretion in vitro

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Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M₁and M₃muscarinic receptors

Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M₁and M₃muscarinic receptors