Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ME-3407 is a newly developed antiulcer drug that markedly promoted the healing of acetic acid-induced chronic ulcers in rats presumably due to potent inhibition of acid secretion. ME-3407 and its metabolites, the sulfoxide of which was preserved, produced dosedependent inhibition of aminopyrine accumulation by rabbit gastric glands stimulated by any agonist, suggesting that the site of their action was downstream from the production of second messengers. Although one of the metabolites, EF-4025, showed some inhibitory effects on functional activities of H(+)-K(+)-ATPase, ME-3407 itself was not a proton pump inhibitor. ME-3407, but not omeprazole, inhibited the stimulation-associated redistribution of H(+)-K(+)-ATPase from microsomes into the apical membranes in addition to delocalizing ezrin, a putative F-actin-membrane linker, from apical plasma membrane. ME-3407 and EF-4025 inhibited myosin light chain kinase (MLCK) and protein kinase A activities. Because another MLCK inhibitor, wortmannin, showed the same properties as ME-3407, i.e., inhibition of aminopyrine accumulation, inhibition of stimulation-associated redistribution of H(+)-K(+)-ATPase, and abnormal distribution of ezrin, we hypothesize that MLCK is one of the potential targets for the drug. We conclude that ME-3407 is a promising drug for treating peptic ulcers, as well as a useful tool for studying mechanisms of parietal cell activation, especially related to the recruitment and recycling of the proton pump.
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PMID:ME-3407, a new antiulcer agent, inhibits acid secretion by interfering with redistribution of H(+)-K(+)-ATPase. 917 22

The ion physiology of osmotic swelling and a consequent loss of epithelial patency was examined in the ovaries of the moth Hyalophora cecropia. After 30 min in the presence of an activator of cyclic-AMP-dependent protein kinase (PKA), the membrane potentials of both oocyte and follicle cells had hyperpolarized by approximately 30 %, cytoplasmic pH had dropped from 7.26 to 7.06, a normally low Cl- conductance had increased and the follicle cells had begun to swell. Since ion distribution studies have indicated that conductance increases should depolarize membranes in this system, it is proposed that hyperpolarization may be effected by an azide-inhibitable component of the membrane potential. Nanomolar levels of bafilomycin, an inhibitor of H+ V-ATPase, blocked the active component and prevented osmotic swelling in response to PKA activation. Under a variety of circumstances, correlations were seen between membrane potential and cytoplasmic pH, suggesting that substrate availability to the proton pump may contribute to hyperpolarization. H+ V-ATPases are known to energize ion and water transport across many epithelia, but in this case they generate water absorption by the epithelium. The increase in Cl- conductance was also required for the swelling response: the Cl- channel blocker anthracene-9-carboxylic acid prevented both swelling and hyperpolarization, as did Cl- substitution in the medium. Differences in isotope loading rates between 36Cl- and 86Rb+ suggested that, after PKA activation, Cl- functions other than as a counterion for K+ uptake.
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PMID:Cyclic-AMP-induced water uptake in a moth ovary: inhibition by bafilomycin and anthracene-9-carboxylic acid. 955 43

Cultured rabbit parietal cells were used to evaluate morphological responses to activators and inhibitors of HCl secretion. Immunofluorescence was used to localize the proton pump protein, H, K-ATPase, and the apical membrane-cytoskeletal linker protein, ezrin; fluorescent-labeled phalloidin was used as a marker of F-actin. Treatment of healthy control parietal cells with secretagogues resulted in exaggerated swelling of apical membrane vacuoles, presumably with the accumulation of HCl and water. Thus stimulation-associated swelling of apical vacuoles was blocked by inhibitors that work at various steps in the secretion-activation cascade. When secretion was blocked by agents that prevent the translocation of H,K-ATPase-rich tubulovesicles to apical membrane vacuoles (such as H2-receptor antagonists and protein kinase A inhibitors), the general resting morphology was maintained. ME-3407 (a functional analogue of wortmannin) was unique in preventing H, K-ATPase redistribution and effecting the delocalization of ezrin from apical membrane vacuoles. When secretion was blocked by agents that inhibit the H+ pump or induce H+ backflux, the translocation of H,K-ATPase to apical membrane vacuoles occurred but the large vacuolar swelling associated with HCl and H2O accumulation was greatly diminished. These data support the membrane recycling/recruitment hypothesis of HCl secretion in which H, K-ATPase-rich tubulovesicles are recruited from a cytoplasmic domain to the apical surface, and they are inconsistent with models proposing that the tubulovesicles, regardless of shape, are contiguous with the apical plasma membrane. These studies also demonstrate the utility of the parietal cell culture model in distinguishing a general site of action for various inhibitors and antisecretory agents.
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PMID:Cytological transformations associated with parietal cell stimulation: critical steps in the activation cascade. 1041 72

Previously, we have shown that the soluble form of brain glutamic acid decarboxylase (GAD) is inhibited by ATP through protein phosphorylation and is activated by calcineurin-mediated protein dephosphorylation (Bao, J., Cheung, W. Y., and Wu, J. Y. (1995) J. Biol. Chem. 270, 6464-6467). Here we report that the membrane-associated form of GAD (MGAD) is greatly activated by ATP, whereas adenosine 5'-[beta,gamma-imido]triphosphate (AMP-PNP), a non-hydrolyzable ATP analog, has no effect on MGAD activity. ATP activation of MGAD is abolished by conditions that disrupt the proton gradient of synaptic vesicles, e.g. the presence of vesicular proton pump inhibitor, bafilomycin A1, the protonophore carbonyl cyanide m-chorophenylhydrazone or the ionophore gramicidin, indicating that the synaptic vesicle proton gradient is essential in ATP activation of MGAD. Furthermore, direct incorporation of (32)P from [gamma-(32)P]ATP into MGAD has been demonstrated. In addition, MGAD (presumably GAD65, since it is recognized by specific monoclonal antibody, GAD6, as well as specific anti-GAD65) has been reported to be associated with synaptic vesicles. Based on these results, a model linking gamma-aminobutyric acid (GABA) synthesis by MGAD to GABA packaging into synaptic vesicles by proton gradient-mediated GABA transport is presented. Activation of MGAD by phosphorylation appears to be mediated by a vesicular protein kinase that is controlled by the vesicular proton gradient.
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PMID:Role of synaptic vesicle proton gradient and protein phosphorylation on ATP-mediated activation of membrane-associated brain glutamate decarboxylase. 1044 15

Gastric gland stimulation triggers H(+),K(+)-ATPase translocation from cytoplasmic tubulovesicles to apical plasma membrane in parietal cells, resulting in HCl secretion. We studied the mechanisms involved in tubulovesicle translocation with a permeabilized gland system. Streptolysin O (SLO)-treated glands were permeabilized such that exogenous fluorescently labeled actin incorporated into cytoskeleton in a pattern mimicking endogenous F-actin. As shown by accumulation of the weak base aminopyrine (AP), SLO-permeabilized glands are stimulated to secrete acid by addition of cAMP and ATP and inhibited by proton pump inhibitors. Direct visualization with the fluorescent pH probe Lysosensor showed acid accumulation in glandular lumen and parietal cell canaliculi. ME-3407, an antiulcer drug with inhibitory action implicated to involve ezrin, inhibited AP uptake in and effectively released ezrin from intact and SLO-permeabilized glands. In contrast, wortmannin, an effective secretion inhibitor in intact glands, had minimal effects on ezrin or AP accumulation in SLO-permeabilized glands. The finding that SNARE protein syntaxin 3 is associated with H(+),K(+)-ATPase-containing tubulovesicles suggested that it is involved in membrane fusion. Addition of recombinant syntaxin 3, but not syntaxin 5 or heat-denatured syntaxin 3, dose-dependently inhibited acid secretion. Our studies are consistent with a membrane recycling hypothesis that activation of protein kinase cascades leads to SNARE-mediated fusion of H(+),K(+)-ATPase-containing tubulovesicles to apical plasma membrane.
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PMID:Syntaxin 3 is required for cAMP-induced acid secretion: streptolysin O-permeabilized gastric gland model. 1175 Nov 54

The cDNA of LeCPK1, a calcium-dependent protein kinase, was cloned from tomato (Lycopersicon esculentum Mill.). LeCPK1 was expressed in Escherichia coli and purified from bacterial extracts. The recombinant protein was shown to be a functional protein kinase using a synthetic peptide as the substrate (syntide-2, Km = 85 microM). Autophosphorylation of LeCPK1 was observed on threonine and serine residues, one of which was identified as serine-439. Kinase activity was shown to be Ca2+ dependent and required the C-terminal, calmodulin-like domain of LeCPK1. Two classes of high- and low-affinity Ca2+-binding sites were observed, exhibiting dissociation constants of 0.6 and 55 microM, respectively. LeCPK1 was found to phosphorylate the regulatory C-terminal domain of the plasma membrane H+-ATPase in vitro. A potential role in the regulation of proton pump activity is corroborated by the apparent colocalization of the plasma membrane H+-ATPase and LeCPK1 in vivo. Upon transient expression in suspension-cultured cells, a C-terminal fusion of LeCPK1 with the green fluorescent protein was targeted to the plasma membrane. Myristoylation of the LeCPK1 N terminus was found to be required for plasma membrane targeting.
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PMID:LeCPK1, a calcium-dependent protein kinase from tomato. Plasma membrane targeting and biochemical characterization. 1201 47

Acid secretion by the gastric parietal cell is regulated by paracrine, endocrine, and neural pathways. The physiological stimuli include histamine, acetylcholine, and gastrin via their receptors located on the basolateral plasma membranes. Stimulation of acid secretion typically involves an initial elevation of intracellular calcium and/or cAMP followed by activation of a cAMP-dependent protein kinase cascade that triggers the translocation and insertion of the proton pump enzyme, H,K-ATPase, into the apical plasma membrane of parietal cells. Whereas the H,K-ATPase contains a plasma membrane targeting motif, the stimulation-mediated relocation of the H,K-ATPase from the cytoplasmic membrane compartment to the apical plasma membrane is mediated by a SNARE protein complex and its regulatory proteins. This review summarizes the progress made toward an understanding of the cell biology of gastric acid secretion. In particular we have reviewed the early signaling events following histaminergic and cholinergic activation, the identification of multiple factors participating in the trafficking and recycling of the proton pump, and the role of the cytoskeleton in supporting the apical pole remodeling, which appears to be necessary for active acid secretion by the parietal cell. Emphasis is placed on identifying protein factors that serve as effectors for the mechanistic changes associated with cellular activation and the secretory response.
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PMID:Cell biology of acid secretion by the parietal cell. 1250 Sep 69

Although calcitonin is well known to be a potent inhibitor of bone resorption, it remains unknown how it regulates osteoclastic H(+) transport. In this study, we examined the effects of calcitonin on H(+) extrusion in cultured rat resorbing osteoclasts using an intracellular pH (pHi) indicator, BCECF [2'7'-bis-(2-carboxyethyl)- 5-carboxyfluorescein]. Resorbing osteoclasts were identified by their formation of resorbing pits on calcium phosphate-coated quartz coverslips. Both basal pHi and H(+) extrusion activity were significantly higher compared to non-resorbing osteoclasts. Two types of H(+)-extruding systems were identified by pharmacological and immunocytochemical means: a bafilomycin-A(1)-sensitive and an amiloride-sensitive system [H(+) extrusion mediated by a vacuolar type proton pump (V-ATPase) and by a Na(+)/H(+) exchanger (NHE), respectively]. Calcitonin inhibited both H(+) extrusion activities in a dose-dependent manner and this action was mimicked by protein kinase A (PKA) activators, but not by protein kinase C (PKC) activators. Pretreatment with PKA inhibitors completely suppressed calcitonin-induced inhibition, whereas neither PKC inhibitors nor calcium chelators suppressed it. These results indicate that calcitonin inhibits H(+) extrusion generated by V-ATPase and NHE via PKA activation. These inhibitory mechanisms of H(+) transport by calcitonin are important for the regulation of bone resorption.
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PMID:Calcitonin inhibits proton extrusion in resorbing rat osteoclasts via protein kinase A. 1263 84

Gastric ezrin was initially identified as a phosphoprotein associated with parietal cell activation. To explore the nature of ezrin phosphorylation, proteins from resting and secreting gastric glands were subjected to two-dimensional SDS-PAGE. Histamine triggers acid secretion and a series of acidic isoforms of ezrin on two-dimensional SDS-PAGE. Mass spectrometric analysis of these acidic ezrin spots induced by stimulation suggests that Ser66 is phosphorylated. To determine whether Ser66 is a substrate of protein kinase A (PKA), recombinant proteins of ezrin, both wild type and S66A mutant, were incubated with the catalytic subunit of PKA and [32P]ATP. Incorporation of 32P into wild type but not the mutant ezrin verified that Ser66 is a substrate of PKA. In addition, expression of S66A mutant ezrin in cultured parietal cells attenuates the dilation of apical vacuolar membrane associated with stimulation by histamine, indicating that PKA-mediated phosphorylation of ezrin is necessary for acid secretion. In fact, expression of phosphorylation-like S66D mutant in parietal cells mimics histamine-stimulated apical vacuole remodeling. Further examination of H,K-ATPase distribution revealed a blockade of stimulation-induced proton pump mobilization in S66A but not S66D ezrin-expressing parietal cells. These data suggest that PKA-mediated phosphorylation of ezrin plays an important role in mediating the remodeling of the apical membrane cytoskeleton associated with acid secretion in parietal cells.
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PMID:Characterization of protein kinase A-mediated phosphorylation of ezrin in gastric parietal cell activation. 1284 26

Syringomycin, a peptide toxin and a virulence factor produced by the bacterial phytopathogen Pseudomonas syringae pv. syringae, stimulated the phosphorylation of several plasma membrane polypeptides of red beet storage tissue. Among these was a 100-kDa polypeptide, which corresponds in size to the proton pump ATPase. The phosphorylations were insensitive to hydroxylamine, indicating that the polypeptide phosphorylated intermediates involved phosphate ester bonds characteristic of protein kinase-mediated phosphorylation. Phosphorylation of the 100-kDa polypeptide and of most of the other polypeptides was reduced or eliminated by extraction of the membranes with 0.1% (wt/vol) sodium deoxycholate, a treatment that also eliminated the ability of the toxin to stimulate ATPase activity. Phosphorylation of the 100-kDa polypeptide was highest with 10-20 mug of syringomycin; the same amounts gave the highest degree of ATPase activity stimulation. Phosphorylation of some of the polypeptides was eliminated or decreased by the Ca(2+) chelator EGTA. Addition of excess Ca(2+) restored the phosphorylation of most of these polypeptides. We conclude that syringomycin acts by stimulating an endogenous membrane protein kinase activity, which results in the phosphorylation of several membrane polypeptides. One of the phosphorylated polypeptides corresponds in size to the proton pump ATPase.
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PMID:Bacterial phytotoxin, syringomycin, induces a protein kinase-mediated phosphorylation of red beet plasma membrane polypeptides. 1657 20


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