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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The actions of parathyroid hormone (PTH) on the renal cortex are thought to be mediated primarily by cAMP-dependent protein kinase (PKA) with some suggestion of a role for protein kinase C (PKC). However, present methods for assaying PKA and PKC in subcellular fractions are insensitive and require large amounts of protein. Recently, a sensitive method for measuring the activity of protein kinases has been reported. This method uses synthetic peptides as substrates and a tandem chromatographic procedure for isolating the phosphorylated peptides. We have adapted this method to study the effect of PTH on PKA and PKC activity using thin slices of rat renal cortex. PTH (250 nM) stimulated cytosolic PKA activity four- to fivefold within 30 s, and PKA activity was sustained for at least 5 min. PTH also rapidly stimulated PKC activity in the membrane fraction and decreased PKC activity in the cytosol. These changes were maximal at 30 s, but unlike changes in PKA, they declined rapidly thereafter. PTH significantly activated PKC only at concentrations of 10 nM or greater. This study demonstrates that PTH does activate PKC in renal tissue, although the duration of activation is much less than for PKA. It also demonstrates that a combination of synthetic peptides with tandem chromatography can be used as a sensitive assay procedure for protein kinase activity in biological samples.
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PMID:Effect of parathyroid hormone on rat renal cAMP-dependent protein kinase and protein kinase C activity measured using synthetic peptide substrates. 199 Sep 75

Filtered inorganic phosphate (Pi) is largely reabsorbed in the proximal tubule. Na-Pi cotransport, with a stoichiometry of at least 2:1, mediates uphill transport at the apical membrane; at the basolateral membrane different types of transport systems can be involved in efflux and uptake of Pi from the interstitium. Regulation of transcellular Pi flux involves alteration of the apical Na-Pi cotransport; at least three different cellular control/sensing systems seem to participate in this regulation and are exemplified by parathyroid hormone (PTH)-dependent inhibition, Pi deprivation-dependent increase, and insulin-like growth factor I (IGF-I)-dependent increase in Na-Pi cotransport. For PTH inhibition, recent evidence suggests a role of the phospholipase C/protein kinase C-dependent regulatory cascade in inhibition of Na-Pi cotransport, at least at low PTH concentrations. In addition, an endocytic mechanism seems to be involved in this PTH action. Little is known of the cellular mechanisms in Pi deprivation-dependent and/or IGF-I-dependent increases in Na-Pi cotransport; they are dependent on de novo protein synthesis. Recent experiments involving an expression in Xenopus laevis oocytes led to the identification of an approximately 50 kDa membrane protein that is a good candidate for being involved in brush-border membrane Na-Pi cotransport activity.
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PMID:Cellular mechanisms in proximal tubular reabsorption of inorganic phosphate. 203 18

Chronic exposure (24 h) to parathyroid hormone (PTH) increases the intracellular proteolytic activity in cultured opossum kidney cells 2-fold at physiological PTH concentrations (10(-12) mol/l). This increase can be blocked by E-64, an inhibitor of thiol proteinases. The phorbol ester TPA mimicks the effect of PTH, whereas the calcium ionophore A23187 reduces the intracellular proteinase activity. Forskolin and dibutyrylic cAMP do not elevate proteinase activity. The protein kinase C inhibitor staurosporine is equally effective in blocking the TPA- and PTH-induced proteinase activity increase. These data indicate that PTH increases the intracellular thiol proteinase activity by an activation of protein kinase C and not by the cAMP dependent way.
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PMID:Parathyroid hormone increases thiol proteinase activity by activation of protein kinase C in cultured kidney tubule cells (OK). 211 54

In the growth plate chondrocyte, parathyroid hormone (PTH) stimulates phosphoinositol 4,5 bisphosphate (PIP2) degradation, which results in the rapid production of inositol (1,4,5) triphosphate (IP3). IP3 induced the release of calcium from an intracellular store, which caused a rapid increase in the cytosolic ionized calcium concentration. Parathyroid hormone also induced a 30-50% increase in proteoglycan synthesis. Phorbol esters, which pharmacologically activate protein kinase C, resulted in a 70-80% increase in proteoglycan synthesis. Treatment of the chondrocytes with retinoic acid (0.2 microM) inhibited the parathyroid hormone and phorbol ester-induced increase in intracellular ionized calcium and the increase in proteoglycan synthesis. From this data we postulate that the stimulation of proteoglycan synthesis in growth plate chondrocytes by PTH is mediated by the breakdown of membrane phosphoinositides, which results in the production of IP3 and an increase in ionized intracellular calcium. It is suggested that the degradation of membrane phosphoinositides also results in production of diacylglycerol and, thereby, an activation of protein kinase C, which has a large stimulatory effect on proteoglycan synthesis. The increase in cytosolic calcium most likely acts synergetically with diacylglycerol to activate protein kinase C. Retinoic acid blocks the effect of PTH and phorbol ester-induced proteoglycan synthesis and may act through the inhibition of protein kinase C. The overall effect of PTH on the growth plate chondrocyte appears to be a stimulation of proteoglycan synthesis that is mediated by the degradation products of membrane phosphoinositides.
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PMID:Mechanism of action of parathyroid hormone-induced proteoglycan synthesis in the growth plate chondrocyte. 215 1

The parathyroid hormone (PTH) receptor is coupled via a guanine nucleotide-binding regulatory protein (G protein) to phospholipase C (PLC). Binding of PTH to its receptor leads to activation of PLC with the subsequent hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 generation leads to the release of intracellular calcium stores, which produces an increase in the intracellular calcium concentration. DAG activates protein kinase C (PKC). Both IP3 metabolites and PKC may play a role in returning the intracellular calcium concentration back to base line, by stimulating the movement of calcium from the intracellular to the extracellular compartment, as well as by sequestering calcium within intracellular organelles. PKC appears to be important in the development of desensitization and downregulation of the PTH receptor to PTH. Activation of PLC may be important in modulating the well-known effects of PTH on bone and kidney and also may be relevant to recently described actions, such as the possible role of PTH as a growth factor in skeletal tissue. Important issues that need to be addressed in this field include 1) characterization of the PTH receptor, 2) the possible role of low-molecular-weight G proteins in PTH signal transduction, and 3) further description of the role of alternate pathway signal transduction in producing the effects of PTH.
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PMID:PTH receptor coupling to phospholipase C is an alternate pathway of signal transduction in bone and kidney. 215 34

The parathyroid hormone (PTH) fragment [1-34] strongly stimulated both adenylate cyclase and membrane-associated PKC activities in rat 17/2 osteosarcoma cells. By contrast, the PTH [3-34] fragment, which was unable to stimulate adenylate cyclase, remained a potent stimulator of membrane-associated PKC activity in these cells. Both PTH fragments also strongly stimulated membrane-PKC activity in cyc-S49T-lymphoma cells possessing a defective adenylate cyclase system. This ability of PTH [3-34] to stimulate membrane-associated PKC activity could explain the residual bioactivity of this fragment.
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PMID:Parathyroid hormone fragment [3-34] stimulates protein kinase C (PKC) activity in rat osteosarcoma and murine T-lymphoma cells. 217 7

Previous work demonstrated that parathyroid hormone (PTH) activates the Ca2+/protein kinase C (PKC) system in addition to cAMP production. Therefore, the authors explored the role of cAMP-dependent and Ca2(+)-dependent signals in the regulation of osteoblastic growth and bone resorption. In exponentially growing UMR 106-01 osteogenic sarcoma cells, PTH (10(-7) M) inhibited [3H] thymidine incorporation by 80%. This effect was reproduced by maximal doses of both dibutyryl-cAMP (dbcAMP) and forskolin. The Ca2+ ionophore ionomycin (10(-7) M) had no effect, whereas phorbol 12-myristate 13-acetate (PMA) was slightly mitogenic. The antimitogenic action of dbcAMP was dose-dependent, with ED0.5 at about 3 X 10(-5) M. Ionomycin enhanced this dbcAMP effect at submaximal doses of the cAMP analog. PMA used in combination with both dbcAMP and ionomycin induced further depression of cell proliferation, indicating synergism with cAMP. Both dbcAMP (10(-4) M) and ionomycin (10(-7) M) stimulated 45Ca release from fetal rat limb bones after five days in culture, although the Ca2+ ionophore was less potent. 1-Oleoyl 2-acetyl-glycerol (2 X 10(-6) M) was ineffective alone, and slightly inhibited the 45Ca release produced by the other second messenger analogs in all combinations. The combination of dbcAMP and ionomycin showed a synergistic effect, and fully reproduced PTH effect. In conclusion, PTH signal transduction for control of cell proliferation and bone resorption is mediated mainly by cAMP. Activation of the Ca2+/PKC message system is nevertheless necessary to express a full hormonal response in both cell and organ culture systems.
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PMID:Cyclic AMP-dependent and calcium-dependent signals in parathyroid hormone function. 217 68

In previous work we have shown that parathyroid hormone (PTH) inhibits Na+/H+ exchange in cellular suspensions of OK (opossum kidney) cells (an established renal epithelial cell line) in a dose-dependent manner. PTH effects could be mimicked by pharmacological activation of both protein kinase A and protein kinase C (Helmle-Kolb et al. 1990). In the present paper we extend these observations and analyze the PTH-dependent control of Na+/H+ exchange in OK cells kept in epithelial configuration (monolayer). Na+/H+ exchange activity is examined by microfluorometry using the intracellularly trapped pH-sensitive dye 2'7'-bis-(2-carboxyethyl)-5,6-carboxyfluorescein. Cells recovered from an acid load (NH4Cl prepulse) after addition of apical Na+. Ethylisopropylamiloride inhibits Na(+)-dependent pHi recovery at micromolar concentrations. PTH leads to an inhibition of apical Na+/H+ exchange activity; inhibition is observed even at a concentration of 5 pM PTH. PTH given at maximally effective concentrations (24 nM) reduces the total Na+/H+ exchange capacity by 60%-70%. Apical as well as basolateral hormone additions elicit an inhibitory response at low (5 pM) or high (24 nM) concentrations. Forskolin (activation of protein kinase A) and phorbol esters (activation of protein kinase C) lead to an inhibition of Na+/H+ exchange activity (60%-70% inhibition). These observations suggest that Na+/H+ exchange activity is preferentially located in the apical membranes of OK cells kept in monolayer configuration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Parathyroid hormone regulation of Na+/H+ exchange in opossum kidney cells: polarity and mechanisms. 217 44

Indirect evidence indicates that parathyroid hormone (PTH) interacts with pancreatic islets and modulates their insulin secretion. This property of PTH has been implicated in the genesis of impaired insulin release in chronic renal failure. We examined the direct effect of PTH-(1-84) and PTH-(1-34) on insulin release using in vitro static incubation and dynamic perifusion of pancreatic islets from normal rats. Both moieties of the hormone stimulated in a dose-dependent manner glucose-induced insulin release but higher doses inhibited glucose-induced insulin release. This action of PTH was modulated by the calcium concentration in the media. The stimulatory effect of PTH was abolished by its inactivation and blocked by its antagonist [Tyr-34]bPTH-(7-34)NH2. PTH also augmented phorbol ester (TPA)-induced insulin release, stimulated adenosine 3',5'-cyclic monophosphate (cAMP) generation by pancreatic islets, and significantly increased (+50 +/- 2.7%, P less than 0.01) their cytosolic calcium. Verapamil inhibited the stimulatory effect of PTH on insulin release. The data show that 1) pancreatic islets are a PTH target and may have PTH receptors, 2) stimulation of glucose-induced insulin release by PTH is mediated by a rise in cytosolic calcium, 3) stimulation of cAMP production by PTH and a potential indirect activation of protein kinase C by PTH may also contribute to the stimulatory effect on glucose-induced insulin release, and 4) this action of PTH requires calcium in incubation or perifusion media.
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PMID:Direct effect of parathyroid hormone on insulin secretion from pancreatic islets. 219 36

Calcitonin is a well known inhibitor of osteoclastic bone resorption, both in vivo and in vitro. However, it is also known that calcitonin has only a transient inhibitory effect on bone resorption. The mechanism for this so-called "escape from inhibition" phenomenon is not clear. In the present study, the inhibitory effect of calcitonin on phorbol ester-induced bone resorption was examined in cultured neonatal mouse calvaria. Bone resorption was assessed as the release of radioactivity from bones prelabelled in vivo with 45Ca. Two protein kinase C-activating phorbol esters, phorbol-12-myristate-13-acetate and phorbol-12,13-dibutyrate, both stimulated 45Ca release in 120-h cultures at a concentration of 10 nmol/l. Calcitonin (30 nmol/l) inhibited phorbol ester-stimulated bone resorption without any "escape from inhibition". This was in contrast to the transient inhibitory effect of calcitonin on bone resorption stimulated by parathyroid hormone (10 nmol/l), prostaglandin E2 (2 mumol/l), and bradykinin (1 mumol/l). Our results suggest that activation of protein kinase C produces a sustained inhibitory effect of calcitonin on bone resorption.
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PMID:Calcitonin causes a sustained inhibition of protein kinase c-stimulated bone resorption in contrast to the transient inhibition of parathyroid hormone-induced bone resorption. 222 Feb 63


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