Different actions of protein kinase C isoforms α and ε on gastric acid secretion

Fährmann, Michael; Kaufhold, Marc; Rieg, Timo; Seidler, Ursula

doi:10.1038/sj.bjp.0704790

Cited by 13 publications

(11 citation statements)

References 44 publications

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“…Secondly, the CaSR stimulation requires an intact PLC activity and several Ca 2+ -dependent and -independent protein kinase C isoforms. The involvement of similar PKC isoforms in basal and ACh stimulated acid-secretion has recently been described in a parietal cell culture model [12,14]. The role of PKC is further corroborated by the fact that DOG, an activator of PKC, mimics the stimulatory effect of CaSR activation and that CaSR has been shown to signal via PKC in other cells [7,11].…”

Section: Discussionmentioning

confidence: 76%

“…Among them, the Ca 2+ -dependent PKC-and the Ca 2+ -independent PKC-isoforms were detected in rabbit parietal cells on protein level [12][13][14]. Incubation of parietal cells with chelerythrine (1µM), a pan-PKC inhibitor, resulted in a significant reduction of the H + /K + -ATPase activity despite stimulation of the Calcium-Sensing receptor with Gadolinium (0.022 ± 0.003 pH units/min) ( Figure 4A).…”

Section: Different Protein Kinase C Isoforms Are Involved In the Downmentioning

confidence: 99%

“…Gastric parietal cells express different protein kinase C (PKC) isoforms which belong to three distinct subfamilies [12][13][14]. Among them, the Ca 2+ -dependent PKC-and the Ca 2+ -independent PKC-isoforms were detected in rabbit parietal cells on protein level [12][13][14].…”

Section: Different Protein Kinase C Isoforms Are Involved In the Downmentioning

confidence: 99%

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Stimulatory Pathways of the Calcium-Sensing Receptor on Acid Secretion in Freshly Isolated Human Gastric Glands

Remy¹,

Kirchhoff²,

Hafner³

et al. 2007

Cell Physiol Biochem

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Gastric acid secretion is not only stimulated via the classical known neuronal and hormonal pathways but also by the Ca²⁺-Sensing Receptor (CaSR) located at the basolateral membrane of the acid-secretory gastric parietal cell. Stimulation of CaSR with divalent cations or the potent agonist Gd³⁺ leads to activation of the H⁺/K⁺-ATPase and subsequently to gastric acid secretion. Here we investigated the intracellular mechanism(s) mediating the effects of the CaSR on H⁺/K⁺-ATPase activity in freshly isolated human gastric glands. Inhibition of heterotrimeric G-proteins (G_i and G_o) with pertussis toxin during stimulation of the CaSR with Gd³⁺ only partly reduced the observed stimulatory effect. A similar effect was observed with the PLC inhibitor U73122. The reduction of the H⁺/K⁺-ATPase activity measured after incubation of gastric glands with BAPTA-AM, a chelator of intracellular Ca²⁺, showed that intracellular Ca²⁺ plays an important role in the signalling cascade. TMB-8, a ER Ca²⁺store release inhibitor, prevented the stimulation of H⁺/K⁺-ATPase activity. Also verapamil, an inhibitor of L-type Ca²⁺-channels reduced stimulation suggesting that both the release of intracellular Ca²⁺ from the ER as well as Ca²⁺ influx into the cell are involved in CaSR-mediated H⁺/K⁺-ATPase activation. Chelerythrine, a general inhibitor of protein kinase C, and Gö 6976 which selectively inhibits Ca²⁺-dependent PKC_α and PKC_βI-isozymes completely abolished the stimulatory effect of Gd³⁺. In contrast, Ro 31-8220, a selective inhibitor of the Ca²⁺-independent PKCε and PKC-δ isoforms reduced the stimulatory effect of Gd³⁺ only about 60 %. On the other hand, activation of PKC with DOG led to an activation of H⁺/K⁺-ATPase activity which was only about 60 % of the effect observed with Gd³⁺. Incubation of the parietal cells with PD 098059 to inhibit ERK1/2 MAP-kinases showed a significant reduction of the Gd³⁺ effect. Thus, in the human gastric parietal cell the CaSR is coupled to pertussis toxin sensitive heterotrimeric G-Proteins and requires calcium to enhance the activity of the proton-pump. PLC, ERK 1/2 MAP-kinases as well as Ca²⁺ dependent and Ca²⁺-independent PKC isoforms are part of the down-stream signalling cascade.

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Section: Discussionmentioning

confidence: 76%

Section: Different Protein Kinase C Isoforms Are Involved In the Downmentioning

confidence: 99%

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Stimulatory Pathways of the Calcium-Sensing Receptor on Acid Secretion in Freshly Isolated Human Gastric Glands

Remy¹,

Kirchhoff²,

Hafner³

et al. 2007

Cell Physiol Biochem

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“…The CaMKII transcriptional pathway regulates the expression of both Bcl‐2 and Bax through phosphorylation (Vanderheyden et al ., ). Exposure to LPS results in Ca 2+ influx into neurons, which led to the activation of Ca 2+ ‐mediated signal transduction, including activation of CaMK and PKC isoenzymes (Fährmann et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Neuroprotective activities of catalpol against CaMKII‐dependent apoptosis induced by LPS in PC12 cells

Chen

et al. 2013

British J Pharmacology

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Background and Purpose Neurodegenerative diseases present progressive neurological disorder induced by cell death or apoptosis. Catalpol, an iridoid glucoside isolated from the root of Rehmannia glutinosa Libosch, is present in a wide range of plant families. Although catalpol is an effective anti‐apoptotic agent in LPS‐induced neurodegeneration, the underlying mechanism has not been established. Here we have identified some of the mechanisms involved the prevention by catalpol of apoptosis induced by LPS in an experimental model of neurodegeneration in vitro. Experimental Approach Apoptosis was induced by adding LPS (80 ng·mL−1) to pheochromocytoma (PC12) cells, pretreated with catalpol for 12 h. We measured intracellular reactive oxygen species (ROS), apoptosis and intracellular calcium concentration ( [Ca2+]i) by flow cytometry or laser confocal scanning microscopy. We also analysed the protein expression of Bcl‐2, Bax and Ca2+‐calmodulin‐dependent protein kinase II (CaMKII)‐dependent apoptosis signal‐regulating kinase‐1 (ASK‐1)/JNK/p38 signalling pathway in PC12 cells by Western blot. Key Results Catalpol stimulated expression of Bcl‐2 and inhibited the expression of Bax. Catalpol also attenuated the increase in Ca2+ concentration induced by LPS in PC12 cells and down‐regulated CaMK phosphorylation. The CaMKII‐dependent ASK‐1/JNK/p38 signalling cascade was blocked by catalpol. All these changes were accompanied by a decrease of apoptosis induced by LPS in PC12 cells. Conclusions and Implications The data presented here provide new mechanistic insights into the links between the CaMKII‐dependent ASK‐1/JNK/p38 signalling pathway and the protective effect of catalpol on apoptosis induced by LPS in PC12 cells.

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“…Some studies suggest that activation leads to weak stimulation of acid secretion; others indicate an inhibitory effect (Chew et al 1997; Yao & Forte, 2003). The picture is somewhat complicated by the fact that different PKC isoforms may have different roles so, for example, PKCα appears to inhibit acid secretion while PKCɛ stimulates it (Fahrmann et al 2002, 2003). Further work will be needed to determine the isoforms relevant for parietal cell maturation.…”

Section: Discussionmentioning

confidence: 99%

Identification of ezrin as a target of gastrin in immature mouse gastric parietal cells

Pagliocca

Hegyi

Venglovecz

et al. 2008

Experimental Physiology

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The gastric acid-secreting parietal cell exhibits profound morphological changes on stimulation. Studies in gastrin null (Gas-KO) mice indicate that maturation of parietal cell function depends on the hormone gastrin acting at the G-protein-coupled cholecystokinin 2 receptor. The relevant cellular mechanisms are unknown. The application of differential mRNA display to samples of the gastric corpus of wild-type (C57BL/6) and Gas-KO mice identified the cytoskeletal linker protein, ezrin, as a previously unsuspected target of gastrin. Gastrin administered in vivo or added to gastric glands in vitro increased ezrin abundance in Gas-KO parietal cells. In parietal cells of cultured gastric glands from wild-type mice treated with gastrin, histamine or carbachol, ezrin was localized to vesicular structures resembling secretory canaliculi. In contrast, in cultured parietal cells from Gas-KO mice, ezrin was typically distributed in the cytosol, and this did not change after incubation with gastrin, histamine or carbachol. However, priming with gastrin for approximately 24 h, either in vivo prior to cell culture or by addition to cultured gastric glands, induced the capacity for secretagogue-stimulated localization of ezrin to large vesicular structures in Gas-KO mice. Similarly, in a functional assay based on measurement of intracellular pH, cultured parietal cells from Gas-KO mice were refractory to gastrin unless primed. The priming effect of gastrin was not attributable to the paracrine mediator histamine, but was prevented by inhibitors of protein kinase C and transactivation of the epidermal growth factor receptor. We conclude that in gastrin null mice there is reduced ezrin expression and a defect in ezrin subcellular distribution in gastric parietal cells, and that both can be reversed by priming with gastrin.

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Different actions of protein kinase C isoforms α and ε on gastric acid secretion

Cited by 13 publications

References 44 publications

Stimulatory Pathways of the Calcium-Sensing Receptor on Acid Secretion in Freshly Isolated Human Gastric Glands

Stimulatory Pathways of the Calcium-Sensing Receptor on Acid Secretion in Freshly Isolated Human Gastric Glands

Neuroprotective activities of catalpol against CaMKII‐dependent apoptosis induced by LPS in PC12 cells

Identification of ezrin as a target of gastrin in immature mouse gastric parietal cells

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