scholarly journals Modulatory role of phosphoinositide 3-kinase in gastric acid secretion

2007 ◽  
Vol 293 (3) ◽  
pp. G532-G543 ◽  
Author(s):  
S. E. Mettler ◽  
S. Ghayouri ◽  
G. P. Christensen ◽  
J. G. Forte
Keyword(s):  
Acid Secretion ◽  
Parietal Cell ◽  
Phosphodiesterase Inhibitors ◽  
Dominant Negative ◽  
Gastric Glands ◽  
Gastric Parietal Cell ◽  
Pi3k Inhibitor Ly294002 ◽  
Akt Phosphorylation ◽  
Phosphoinositide 3 Kinase

The gastric parietal cell is responsible for the secretion of HCl into the lumen of the stomach mainly due to stimulation by histamine via the cAMP pathway. However, the participation of several other receptors and pathways have been discovered to influence both stimulation and inhibition of acid secretion (e.g., cholinergic). Here we examine the role of phosphoinositide 3-kinase (PI3K) in the modulation of acid secretion. Treatment of isolated gastric glands and parietal cells with the PI3K inhibitor, LY294002 (LY), potentiated acid secretion in response to histamine to nearly the maximal secretion obtained with histamine plus phosphodiesterase inhibitors. As cAMP levels were elevated in response to histamine plus LY, but other means of elevating cAMP (e.g., forskolin, dbcAMP) were not influenced by LY, we posited that the effect might require activation of G-protein-coupled histamine H2 receptors, possibly through the protein kinase B pathway (also known as Akt). Study of downstream effectors of PI3K showed that histaminergic stimulation increased Akt phosphorylation, which in turn was blocked by inhibition of PI3K. Expression studies showed that high expression of active Akt decreased acid secretion, whereas dominant-negative Akt increased acid secretion. Taken together, these data suggest stimulation with histamine increases the activity of PI3K leading to increased activity of Akt and decreased levels of cAMP in the parietal cell.

Enhanced calcium signaling and acid secretion in parietal cells isolated from gastrin-deficient mice

2003 ◽  
Vol 284 (1) ◽  
pp. G145-G153 ◽  
Author(s):  
Karen L. Hinkle ◽  
Gina C. Bane ◽  
Ali Jazayeri ◽  
Linda C. Samuelson
Keyword(s):  
Acid Secretion ◽  
Parietal Cell ◽  
Mutant Cell ◽  
Flow Cytometric Analysis ◽  
Cell Number ◽  
Parietal Cells ◽  
Gastric Glands ◽  
Deficient Mice ◽  
Cell Defect

Gastrin-deficient mice have impaired basal and agonist-stimulated gastric acid secretion. To analyze whether an intrinsic parietal cell defect contributed to the reduced acid secretion, we analyzed parietal cell calcium responses and acid secretory function in vitro. Parietal cells were purified by light-scatter cell sorting and calcium responses to gastrin, histamine, and carbachol were measured in gastrin-deficient and wild-type mice cell preparations. Surprisingly, basal and histamine-induced calcium concentrations were higher in the mutant cell preparations. [14C]aminopyrine uptake analysis in acutely isolated gastric glands revealed that basal acid accumulation was enhanced in gastrin-deficient cell preparations as well as on treatment with carbachol or histamine. These results suggested that an intrinsic parietal cell defect was not responsible for the reduced acid secretion in gastrin-deficient mice. Flow cytometric analysis of dispersed, H+-K+-ATPase-immunostained gastric mucosal preparations revealed a marked increase in parietal cell number in gastrin-deficient mice, which may have accounted for the enhanced in vitro acid secretion detected in this study. Parietal cells were found to be significantly smaller in the mutant cell preparations, suggesting that gastrin stimulation modulates parietal cell morphology.

Gastric acid secretion and parietal cell mass: effects of thyroidectomy and thyroxine

1989 ◽  
Vol 256 (6) ◽  
pp. G975-G978 ◽  
Author(s):  
K. O. Adeniyi ◽  
M. O. Olowookorun
Keyword(s):  
Gastric Mucosa ◽  
Thyroid Hormones ◽  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Parietal Cell ◽  
Cell Function ◽  
Cell Mass ◽  
Chronic Administration ◽  
Basal Acid

The role of thyroid hormones on parietal cell function and number was studied in the rat. Chronic administration of thyroxine (6-8 micrograms/100 g body wt/day) for 35 days significantly increased parietal cell mass (from 21.18 +/- 0.13 x 10(6) to 26.71 +/- 0.14 x 10(6] as well as basal acid secretion (from 3.69 +/- 0.08 to 4.99 +/- 0.16 mueq/10 min) and histamine-stimulated acid secretion (from 2.45 +/- 0.12 to 3.69 +/- 0.21 mueq/10 min). Thyroidectomy decreased the number of parietal cells in the gastric mucosa (to 10.48 +/- 0.09 x 10(6] and basal acid secretion (to 3.09 +/- 0.08 mueq/10 min). Histamine (0.2 mg) injection into the thyroidectomized rats increased acid secretion by only 1.41 +/- 0.06 mueq/10 min as against 2.45 +/- 0.12 mueq/10 min obtained for control rats. The results suggest that thyroid hormones regulate basal and secretagogue-stimulated acid secretion via their effects on parietal cell mass.

Functionally distinct pools of actin in secretory cells

2001 ◽  
Vol 281 (2) ◽  
pp. C407-C417 ◽  
Author(s):  
David A. Ammar ◽  
Phuong N. B. Nguyen ◽  
John G. Forte
Keyword(s):  
Parietal Cell ◽  
Cultured Cells ◽  
Parietal Cells ◽  
Secretory Cells ◽  
Resting Cells ◽  
Gastric Glands ◽  
Gastric Parietal Cell ◽  
Actin Organization ◽  
Isolated Gastric Glands ◽  
High Concentrations

Acid secretion by the gastric parietal cell is controlled through movement of vesicles containing the proton pump, the H+-K+-ATPase (HK). We have used latrunculin B (Lat B), which binds to monomeric actin, to investigate actin turnover in the stimulated parietal cell. In isolated gastric glands, relatively high concentrations of Lat B were required to inhibit acid accumulation (ED50∼70 μM). Cultured parietal cells stimulated in the presence of low Lat B (0.1–1 μM) have reduced lamellipodia formation and some aberrant punctate phalloidin-stained structures, but translocation of HK and vacuolar swelling appeared unaffected. High Lat B (10–50 μM) resulted in gross changes in actin organization (punctate phalloidin-stained structures throughout the cell and nucleus) and reduced translocation of HK and vacuolar swelling. Resting parietal cells treated with high Lat B showed minor effects on morphology and F-actin staining. If resting cells treated with high Lat B were washed immediately before stimulation, they exhibited a normal stimulated morphology. These data suggest distinct pools of parietal cell actin: a pool highly susceptible to Lat B primarily involved in motile function of cultured cells; and a Lat B-resistant pool, most likely microvillar filaments, that is essential for secretion. Furthermore, the stimulation process appears to accentuate the effects of Lat B, most likely through Lat B binding to monomer actin liberated by the turnover of the motile actin filament pool.

scholarly journals IGF-I increases the expression of fibronectin by Nox4-dependent Akt phosphorylation in renal tubular epithelial cells

2012 ◽  
Vol 302 (1) ◽  
pp. C122-C130 ◽  
Author(s):  
David D. New ◽  
Karen Block ◽  
Basant Bhandhari ◽  
Yves Gorin ◽  
Hanna E. Abboud
Keyword(s):  
Epithelial Cells ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Dominant Negative ◽  
Tubular Epithelial Cells ◽  
Nadph Oxidase Activity ◽  
Akt Phosphorylation ◽  
Fibronectin Expression ◽  
Igf I

Extracellular matrix accumulation contributes to the progression of chronic kidney disease. Many growth factors including insulin-like growth factor-I (IGF-I) enhance matrix protein accumulation. Proximal tubular epithelial cells (PTCs) synthesize matrix proteins. NADPH oxidases are major sources of reactive oxygen species (ROS), important signaling molecules that mediate biological responses in a variety of cells and tissue. We investigated the mechanism by which IGF-I regulates fibronectin accumulation in PTCs and the role of a potential redox-dependent signaling pathway. IGF-I induces an increase in NADPH-dependent superoxide generation, enhances the release of hydrogen peroxide, and increases the expression of NADPH oxidase 4 (Nox4) in PTCs. IGF-I also stimulates phosphorylation of Akt, and inhibition of Akt or its upstream activator phosphatidylinositol 3-kinase attenuates IGF-I-induced fibronectin accumulation. Expression of dominant negative Akt also inhibits IGF-I-induced expression of fibronectin, indicating a role for this kinase in fibronectin accumulation. Expression of dominant negative adenovirus Nox4 inhibits IGF-I-induced NADPH oxidase activity, Akt phosphorylation, and fibronectin protein expression. Moreover, transfection of small interfering RNA targeting Nox4 decreases Nox4 protein expression and blocks IGF-I-induced Akt phosphorylation and the increase in fibronectin, placing Nox4 and ROS upstream of Akt signaling pathway. To confirm the role of Nox4, PTCs were infected with adenovirus construct expressing wild-type Nox4. Ad-Nox4, but not control Ad-green fluorescent protein, upregulated Nox4 expression and increased NADPH oxidase activity as well as fibronectin expression. Taken together, these results provide the first evidence for a role of Nox4 in IGF-I-induced Akt phosphorylation and fibronectin expression in tubular epithelial cells.

Phospholipase D1 mediates bFGF-induced Bcl-2 expression leading to neurite outgrowth in H19-7 cells

2011 ◽  
Vol 441 (1) ◽  
pp. 407-416 ◽  
Author(s):  
Sung Nyo Yoon ◽  
Kang Sik Kim ◽  
Ju Hwan Cho ◽  
Weina Ma ◽  
Hye-Jin Choi ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Dominant Negative ◽  
Signal Transducer ◽  
Downstream Effector ◽  
Phospholipase D1 ◽  
Protein Kinase Cα ◽  
Phosphoinositide 3 Kinase ◽  
Interfering Rna ◽  
Transcription 3

The purpose of the present study was to investigate the role of PLD (phospholipase D) in bFGF (basic fibroblast growth factor)-induced Bcl-2 expression and to examine whether overexpressed Bcl-2 influences neurite outgrowth in immortalized hippocampal progenitor cells (H19-7 cells). We found that Bcl-2 expression was maximally induced by bFGF within 24 h, and that this effect was reduced by inhibiting PLD1 expression with PLD1 small interfering RNA or by overexpressing DN (dominant-negative)-PLD1, whereas PLD1 overexpression markedly induced Bcl-2 expression. bFGF treatment activated Ras, Src, PI3K (phosphoinositide 3-kinase), PLCγ (phospholipase Cγ) and PKCα (protein kinase Cα). Among these molecules, Src and PKCα were not required for Bcl-2 expression. PLD activity was decreased by Ras, PI3K or PLCγ inhibitor, suggesting that PLD1 activation occurred through Ras, PI3K or PLCγ. We found that Ras was the most upstream molecule among these proteins, followed by the PI3K/PLCγ pathway, indicating that bFGF-induced PLD activation took place through the Ras/PI3K/PLCγ pathway. Furthermore, PLD1 was required for activation of JNK (c-Jun N-terminal kinase), which led to activation of STAT3 (signal transducer and activator of transcription 3) and finally Bcl-2 expression. When Bcl-2 was overexpressed, neurite outgrowth was stimulated along with induction of neurotrophic factors such as brain-derived neurotrophic factor and neurotrophin 4/5. In conclusion, PLD1 acts as a downstream effector of bFGF/Ras/PI3K/PLCγ signalling and regulates Bcl-2 expression through JNK/STAT3, which leads to neurite outgrowth in H19-7 cells.

scholarly journals Translation Initiation Factor 4E Inhibits Differentiation of Erythroid Progenitors

2005 ◽  
Vol 25 (19) ◽  
pp. 8496-8506 ◽  
Author(s):  
Montserrat Blázquez-Domingo ◽  
Godfrey Grech ◽  
Marieke von Lindern
Keyword(s):  
Target Genes ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Erythroid Progenitors ◽  
Major Pathway ◽  
Pi3k Inhibitor Ly294002 ◽  
Specific Mrnas ◽  
Phosphoinositide 3 Kinase

ABSTRACT Stem cell factor (SCF) delays differentiation and enhances the expansion of erythroid progenitors. Previously, we performed expression-profiling experiments to link signaling pathways to target genes using polysome-bound mRNA. SCF-induced phosphoinositide-3-kinase (PI3K) appeared to control polysome recruitment of specific mRNAs associated with neoplastic transformation. To evaluate the role of mRNA translation in the regulation of expansion versus differentiation of erythroid progenitors, we examined the function of the eukaryote initiation factor 4E (eIF4E) in these cells. SCF induced a rapid and complete phosphorylation of eIF4E-binding protein (4E-BP). Overexpression of eIF4E did not induce factor-independent growth but specifically impaired differentiation into mature erythrocytes. Overexpression of eIF4E rendered polysome recruitment of mRNAs with structured 5′ untranslated regions largely independent of growth factor and resistant to the PI3K inhibitor LY294002. In addition, overexpression of eIF4E rendered progenitors insensitive to the differentiation-inducing effect of LY294002, indicating that control of mRNA translation is a major pathway downstream of PI3K in the regulation of progenitor expansion.

Drebrin E2 is differentially expressed and phosphorylated in parietal cells in the gastric mucosa

2005 ◽  
Vol 289 (2) ◽  
pp. G320-G331 ◽  
Author(s):  
Catherine S. Chew ◽  
Curtis T. Okamoto ◽  
Xunsheng Chen ◽  
Ruby Thomas
Keyword(s):  
Gastric Mucosa ◽  
Actin Filament ◽  
Parietal Cell ◽  
Active Role ◽  
Cell Types ◽  
Parietal Cells ◽  
Dominant Negative ◽  
Filament Formation ◽  
Differential Distribution ◽  
Gastric Parietal Cell

Developmentally regulated brain proteins (drebrins) are highly expressed in brain where they may regulate actin filament formation in dendritic spines. Recently, the drebrin E2 isoform was detected in certain epithelial cell types including the gastric parietal cell. In gastric parietal cells, activation of HCl secretion is correlated with actin filament formation and elongation within intracellular canaliculi, which are the sites of acid secretion. The aim of this study was to define the pattern of drebrin expression in gland units in the intact rabbit oxyntic gastric mucosa and to initiate approaches to define the functions of this protein in parietal cells. Drebrin E2 expression was limited entirely or almost entirely to parietal cells and depended upon the localization of parietal cells along the gland axis. Rabbit drebrin E2 was cloned and found to share 86% identity with human drebrin 1a and to possess a number of cross-species conserved protein-protein interaction and phosphorylation consensus sites. Two-dimensional Western blot and phosphoaffinity column analyses confirmed that drebrin is phosphorylated in parietal cells, and several candidate phosphorylation sites were identified by mass spectrometry. Overexpression of epitope-tagged drebrin E2 led to the formation of microspikes and F-actin-rich ring-like structures in cultured parietal cells and suppressed cAMP-dependent acid secretory responses. In Madin-Darby canine kidney cells, coexpression of epitope-tagged drebrin and the Rho family GTPase Cdc42, which induces filopodial extension, produced an additive increase in the length of microspike projections. Coexpression of dominant negative Cdc42 with drebrin E2 did not prevent drebrin-induced microspike formation. These findings suggest that 1) drebrin can induce the formation of F-actin-rich membrane projections by Cdc42-dependent and -independent mechanisms; and that 2) drebrin plays an active role in directing the secretagogue-dependent formation of F-actin-rich filaments on the parietal cell canalicular membrane. Finally, the differential distribution of drebrin in parietal cells along the gland axis suggests that drebrin E2 may be an important marker of parietal cell differentiation and functionality.

scholarly journals Genetic Ablation of the ClC-2 Cl- Channel Disrupts Mouse Gastric Parietal Cell Acid Secretion

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0138174 ◽  
Author(s):  
Meghali P. Nighot ◽  
Prashant K. Nighot ◽  
Thomas Y. Ma ◽  
Danuta H. Malinowska ◽  
Gary E. Shull ◽  
...  
Keyword(s):  
Acid Secretion ◽  
Parietal Cell ◽  
Gastric Parietal Cell ◽  
Genetic Ablation ◽  
Cl Channel ◽  
Cell Acid

scholarly journals Curcumin Inhibits HGF-Induced EMT by Regulating c-MET-Dependent PI3K/Akt/mTOR Signaling Pathways in Meningioma

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Xiaodong Chen ◽  
Fen Tian ◽  
Peng Lun ◽  
Yugong Feng
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Mtor Signaling ◽  
Malignant Meningioma ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Pi3k Inhibitor Ly294002 ◽  
Tyrosine Protein Kinase ◽  
Phosphoinositide 3 Kinase ◽  
Mtor Modulation

Meningiomas, which are the most common primary intracranial tumors, have highly aggressive cells in malignant cases. Due to its extensive antitumor effects, curcumin is widely used in experimental and clinical studies. However, the role of curcumin during the epithelial-mesenchymal transition (EMT) in meningioma has not been established. We found that curcumin blocks hepatocyte growth factor- (HGF-) induced proliferation, migration, invasion, and EMT of human malignant meningioma cells by regulating the PI3K/Akt/mTOR signaling pathway. In addition, treatment of human malignant meningioma cells with the tyrosine protein kinase (c-MET) inhibitor (SU11274) or the phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) suppressed HGF-induced migration and EMT. Furthermore, we found that curcumin inhibited tumor growth and HGF-induced EMT in mice subjected to subcutaneous xenotransplantation. These findings indicate that HGF regulates EMT in human malignant meningioma cells through c-MET/PI3K/Akt/mTOR modulation. In conclusion, curcumin inhibits HGF-induced EMT by targeting c-MET and subsequently blocking the PI3K/Akt/mTOR pathway.

Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice

2011 ◽  
Vol 301 (3) ◽  
pp. G537-G546 ◽  
Author(s):  
Michael K. Jones ◽  
Ercheng Zhu ◽  
Edna V. Sarino ◽  
Oscar R. Padilla ◽  
Takamune Takahashi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Acid Secretion ◽  
Parietal Cell ◽  
Nitrosative Stress ◽  
Cell Function ◽  
Acute Injury ◽  
Gastric Injury ◽  
Gastric Parietal Cell ◽  
Deficient Mice

Mitochondrial superoxide dismutase (SOD2) prevents accumulation of the superoxide that arises as a consequence of oxidative phosphorylation. However, SOD2 is a target of oxidative/nitrosative inactivation, and reduced SOD2 activity has been demonstrated to contribute to portal hypertensive gastropathy. We investigated the consequences of gastric parietal cell-specific SOD2 deficiency on mitochondrial function and gastric injury susceptibility. Mice expressing Cre recombinase under control of the parietal cell Atpase4b gene promoter were crossed with mice harboring loxP sequences flanking the sod2 gene (SOD2 floxed mice). Cre-positive mice and Cre-negative littermates (controls) were used in studies of SOD2 expression, parietal cell function (ATP synthesis, acid secretion, and mitochondrial enzymatic activity), increased oxidative/nitrosative stress, and gastric susceptibility to acute injury. Parietal cell SOD2 deficiency was accompanied by a 20% ( P < 0.05) reduction in total gastric SOD activity and a 93% ( P < 0.001) reduction in gastric SOD2 activity. In SOD2-deficient mice, mitochondrial aconitase and ATP synthase activities were impaired by 36% ( P < 0.0001) and 44% ( P < 0.005), respectively. Gastric tissue ATP content was reduced by 34% ( P < 0.002). Basal acid secretion and peak secretagogue (histamine)-induced acid secretion were reduced by 43% ( P < 0.0001) and 40% ( P < 0.0005), respectively. There was a fourfold ( P < 0.02) increase in gastric mucosal apoptosis and 41% ( P < 0.001) greater alcohol-induced gastric damage in the parietal cell SOD2-deficient mice. Our findings indicate that loss of parietal cell SOD2 leads to mitochondrial dysfunction, resulting in perturbed energy metabolism, impaired parietal cell function, and increased gastric mucosal oxidative stress. These alterations render the gastric mucosa significantly more susceptible to acute injury.

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