Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article presents a comprehensive overview of the physiological, cellular, biochemical, and molecular actions of glucocorticoids. Emphasis is placed on the structure of the glucocorticoid receptor, the process known as receptor activation, and the function of endogenous regulators in receptor-mediated signal transduction. The role of receptor phosphorylation, and the activities of exogenous sodium molybdate, are also reviewed. In addition, recent advances in the structure and mechanism of action for the low mol wt heat-stable "modulator" of glucocorticoid receptor activity are also discussed. Modulator is a novel ether aminophosphoglyceride that appears to be the "endogenous molybdate factor." A model is presented for the interaction of modulator with the glucocorticoid receptor. This model seeks to explain the actions of sodium molybdate toward the glucocorticoid receptor, and perhaps toward other steroid-hormone receptors as well. Finally, results from an ultra-large scale purification of two new modulator isoforms, and the activities of these isoforms toward the glucocorticoid receptor, the mineralocorticoid receptor, and protein kinase C, are also summarized.
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PMID:The glucocorticoid receptor and its endogenous regulators. 215 74

Extensive tissue remodeling occurs in survivors of acute lung injury, leading to nearly normal histology and physiology in the majority of individuals, whereas others suffer significant impairment due to the development of pulmonary fibrosis. Alveolar epithelial cells play a central role in the repair process. They are strategically located to directly participate in the solubilization of intraalveolar fibrin deposits, and have the capacity to promote fibrinolysis. We have previously reported that interleukin-1 beta (IL-1 beta), an important inflammatory mediator in acute lung injury, upregulates urokinase-type plasminogen activator expression by human A549 cells (1). In this work, we show that IL-1 beta increases cell-surface plasmin generation, mediated in part by increased expression of urokinase receptor (u-PAR). Northern blot analyses demonstrated that IL-1 beta rapidly induces accumulation of u-PAR messenger RNA (mRNA) in a dose-dependent fashion, and that this effect is blocked by actinomycin. The IL-1 beta-mediated increase in u-PAR mRNA is inhibited by: (1) the relatively specific protein kinase C (PKC) inhibitors 1-(5-isoquinoline sulfonyl)-2-methylpiperazine (H7) and calphostin C; and (2) prolonged pretreatment of cells with phorbol myristate acetate (PMA), suggesting that PKC is an important component of the signaling pathway. Okadaic acid, an inhibitor of serine/threonine phosphatases, markedly potentiates the effect of IL-1 beta on u-PAR mRNA levels. In contrast, dexamethasone, in concentrations as low as 10(-8) M, completely blocks the IL-1 beta-mediated increase in u-PAR mRNA. Half-life experiments show that dexamethasone has no effect on u-PAR mRNA stability. Aldosterone, at concentrations in which it binds primarily to the mineralocorticoid receptor, has no effect on u-PAR expression, suggesting that the glucocorticoid effect is due to a transrepressive mechanism. In summary, IL-1 beta increases cell-surface plasmin generation in A549 cells by coordinately upregulating urokinase and u-PAR expression. Transcriptional activation of the u-PAR gene involves PKC-dependent mechanisms, and glucocorticoid suppression is probably due to interactions between the glucocorticoid receptor and another transcriptional activating system such as activator protein-1 (AP-1) and/or nuclear factor-kB (NF-kB).
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PMID:Induction of urokinase-type plasminogen activator receptor by IL-1 beta. 919 70

Arginine vasopressin (AVP) and corticosteroid hormones are involved in sodium reabsorption regulation in the renal collecting duct. Synergy between AVP and aldosterone has been well documented, although its mechanism remains unclear. Both aldosterone and glucocorticoid hormones bind to the mineralocorticoid receptor (MR), and mineralocorticoid selectivity depends on the MR-protecting enzyme 11 beta hydroxysteroid deshydrogenase (11-HSD), which metabolizes glucocorticoids into derivatives with low affinity for MR. We have investigated whether the activity of 11-HSD could be influenced by AVP and corticosteroid hormones. This study shows that in isolated rat renal collecting ducts, AVP increases 11-HSD catalytic activity. This effect is maximal at 10(-8) M AVP (a concentration clearly above the normal physiological range of AVP concentrations) and involves the V2 receptor pathway, while activation of protein kinase C or changes in intracellular calcium are ineffective. The stimulatory effect of AVP on 11-HSD is largely reduced after adrenalectomy, and is selectively restored by infusion of aldosterone, not glucocorticoids. We conclude that this synergy between AVP and aldosterone in controlling the activity of 11-HSD is likely to play a pivotal role in resetting mineralocorticoid selectivity, and hence sodium reabsorption capacities of the renal collecting duct.
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PMID:Vasopressin potentiates mineralocorticoid selectivity by stimulating 11 beta hydroxysteroid deshydrogenase in rat collecting duct. 936 57

The mineralocorticoid aldosterone is the most important hormone for the regulation of Na+ and K+ homeostasis in mammals and is thereby involved in the regulation of extracellular volume and blood pressure. Because aldosterone is a steroid hormone, the classical way of action involves transcription, translation, and protein synthesis. We previously reported a rapid, nongenomic, and Zn(2+)-sensitive action of aldosterone on Na+/H+ exchange in renal epithelial [Madin-Darby canine kidney (MDCK)] cells (M. Gekle, N. Golenhofen, H. Oberleithner, and S. Silbernagl. Proc. Natl. Acad. Sci. 93: 10500-10504, 1996). Here we show that, in the absence of Na+ (i.e., with inactive Na+/H+ exchange), aldosterone induces a membrane potential-dependent and Zn(2+)-sensitive cytoplasmic acidification in MDCK cells within 2-4 min. This aldosterone-induced activation of a proton conductance is insensitive to the inhibitor of the classical genomic pathway, spironolactone. Furthermore, the inhibitor of serine/threonine kinases and staurosporine, as well as the specific inhibitor of protein kinase C (PKC), calphostin C, prevented proton conductance activation. Activation of PKC by phorbol esters mimicked the effect of aldosterone. Furthermore, preincubation of the cells with pertussis toxin reduced the effect of aldosterone significantly. We propose a new nongenomic mechanism of action for aldosterone, independently of the intracellular type 1 mineralocorticoid receptor: G protein-dependent stimulation of PKC by aldosterone leads to the activation of a plasma membrane proton conductance that enhances the activity of Na+/H+ exchange. This rapid nongenomic effect could explain the observation that aldosterone may alter renal Na+ and K+ excretion within 5-10 min.
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PMID:The mineralocorticoid aldosterone activates a proton conductance in cultured kidney cells. 937 54

There is universal acceptance of the existence of rapid, non-genomic effects of aldosterone, although their physiological relevance and potential importance in hypertension are not yet clear. What has emerged over the year under review is that at least some of such rapid non-genomic effects of aldosterone may be mediated by the activation of the classical intracellular mineralocorticoid receptor, rather than a putative membrane receptor. The post-receptor mechanisms of rapid aldosterone action appear variously to involve protein kinase C, calcium, cyclic adenosine 3', 5'-monophosphate and inositol 1, 4, 5-triphosphate, with downstream effects on a variety of ion pumps and channels.
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PMID:Non-genomic actions of aldosterone: role in hypertension. 1122 98

Aldosterone increases Na(+),K(+)-adenosine triphophatase (Na(+),K(+)-ATPase) pump activity and abundance under chronic conditions in several tissues, including rat arterial vessels. The present study was undertaken to evaluate whether aldosterone has also short-term effects on the Na(+),K(+)-ATPase of rat aorta. The pump function was measured as ouabain-sensitive (86)Rb/K uptake in aortic rings. Addition of aldosterone induced a rapid inhibition of the Na(+),K(+)-ATPase (57.0 +/- 2.3% of control values; P < 0.05; n = 8), followed by a return to control values after 120 min. The aldosterone-induced decrease in ouabain-sensitive (86)Rb/K uptake was prevented by the new mineralocorticoid receptor antagonist eplerenone. The inhibition of gene transcription (actinomycin D) or protein synthesis (cycloheximide) had no effect on short-term aldosterone action on Na(+),K(+)-ATPase. The rapid aldosterone inhibition was also observed in the presence of monensin, a sodium-specific ionophore. Rapamycin, an immunosuppressive drug that stabilizes the heat shock protein-steroid receptor complex, blocked the rapid aldosterone effect. Bisindole I, an inhibitor of protein kinase C, also blocked nongenomic action of aldosterone on the Na pump. The nongenomic effect of aldosterone was inhibited by disrupters of microtubule (colchicine). Plasma membrane protein biotinylation of aortic segments and Western blot indicated a diminished presence of catalytic isoforms of Na(+),K(+)-ATPase on the cell surface. Our findings indicate that aldosterone has a nongenomic effect on the Na(+),K(+)-ATPase of vascular tissue. This effect is mediated through protein kinase C activation and implies reduced cell surface abundance of catalytic subunits. These observations together with our previous report on chronic hormone replacement suggest that aldosterone is directly involved in ionic cellular homeostasis of the vascular system through Na pump regulation.
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PMID:Nongenomic effect of aldosterone on Na+,K+-adenosine triphosphatase in arterial vessels. 1263 9

Aldosterone elevates Na+/K+/2Cl- cotransporter activity in rabbit cardiomyocytes within 15 min, an effect blocked by K-canrenoate and thus putatively mineralocorticoid receptor mediated. Increased cotransporter activity raises intracellular [Na+] sufficient to produce a secondary increase in Na+-K+ pump activity; when this increase in intracellular [Na+] is prevented, a rapid effect of aldosterone to lower pump activity is seen. Addition of transcription inhibitor actinomycin D did not change basal or aldosterone-induced lowered pump activity, indicating a direct, nongenomic action of aldosterone. We examined a possible role for protein kinase C (PKC) in the rapid nongenomic effects of aldosterone. Single ventricular myocytes and pipette solutions containing 10 mm intracellular [Na+] were used in patch clamp studies to measure Na+-K+ pump activity. Aldosterone lowered pump current, an effect abolished by epsilon PKC (epsilonPKC) inhibition but neither alphaPKC nor scrambled epsilonPKC; addition of epsilonPKC activator peptide mimicked the rapid aldosterone effect. In rabbits chronically infused with aldosterone, the lowered pump current in cardiomyocytes was acutely (< or =15 min) restored by epsilonPKC inhibition. These studies show that rapid effects of aldosterone on Na+-K+ pump activity are nongenomic and specifically epsilonPKC mediated; in addition, such effects may be prolonged (7 d) and long-lived ( approximately 4 h isolated cardiomyocyte preparation time). The rapid, prolonged, long-lived effects can be rapidly (< or =15 min) reversed by epsilonPKC blockade, suggesting a hitherto unrecognized complexity of aldosterone action in the heart and perhaps by extension other tissues.
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PMID:Rapid, nongenomic effects of aldosterone in the heart mediated by epsilon protein kinase C. 1460 11

Renal collecting ducts play a critical role in acid-base homeostasis by establishing steep transepithelial pH gradients necessary for the almost complete reabsorption of bicarbonate and the effective secretion of ammonium into the urine. The mechanisms of urine acidification in collecting ducts involve active, electrogenic hydrogen (H+) secretion and, less importantly, potassium (K+)-H+ exchange. Deranged renal acidification and the inability to lower urine pH are hallmarks of distal tubular acidosis and often result from inborn errors of metabolism involving vacuolar H+-ATPase subunits in the collecting ducts. Three factors regulate H+-ATPase activity in intercalated cells of collecting ducts: the acid-base status, angiotensin II, and aldosterone. Most effects of aldosterone involve activation of the mineralocorticoid receptor and genomic changes in transcription and protein synthesis. Here we demonstrate a nongenomic pathway of vacuolar H+-ATPase activation in intercalated cells of isolated mouse outer medullary collecting ducts (OMCD). In vitro exposure of isolated outer medullary collecting ducts to aldosterone (10 nM) for times as short as 15 min increases vacuolar H+-ATPase activity approximately 2- to 3-fold. Neither inhibition of mineralocorticoid receptors nor of transcription and protein synthesis prevented aldosterone-induced stimulation of H+-ATPase. Incubation with colchicine, however, abolished the stimulatory effect of aldosterone, suggesting a role of the microtubular network for H+-ATPase stimulation. Immunohistochemistry in kidneys from aldosterone-injected mice showed increased apical H+-ATPase staining in OMCD-intercalated cells. The stimulatory effect of aldosterone was associated with a transient rise in intracellular Ca2+ and required intact PKC. Thus, rapid nongenomic modulation of vacuolar H+-ATPase activity in OMCD-intercalated cells by aldosterone may play an additional role in hormonal control of systemic acid-base homeostasis.
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PMID:Nongenomic stimulation of vacuolar H+-ATPases in intercalated renal tubule cells by aldosterone. 1498 61

Effects of aldosterone on its target cells have long been considered to be mediated exclusively through the genomic pathway; however, evidence has been provided for rapid effects of the hormone that may involve nongenomic mechanisms. Whether an interaction exists between these two signaling pathways is not yet established. In this study, the authors show that aldosterone triggers both early nongenomic and late genomic increase in sodium transport in the RCCD(2) rat cortical collecting duct cell line. In these cells, the early (up to 2.5 h) aldosterone-induced increase in short-circuit current (Isc) is not blocked by the mineralocorticoid receptor (MR) antagonist RU26752, it does not require mRNA or protein synthesis, and it involves the PKCalpha signaling pathway. In addition, this early response is reproduced by aldosterone-BSA, which acts at the cell surface and presumably does not enter the cells (aldo-BSA is unable to trigger the late response). The authors also show that MR is rapidly phosphorylated on serine and threonine residues by aldosterone or aldosterone-BSA. In contrast, the late (4 to 24 h) aldosterone-induced increase in ion transport occurs through activation of the MR and requires mRNA and protein synthesis. Interestingly, nongenomic and genomic aldosterone actions appear to be interdependent. Blocking the PKCalpha pathway results in the inhibition of the late genomic response to aldosterone, as demonstrated by the suppression of aldosterone-induced increase in MR transactivation activity, alpha1 Na(+)/K(+)/ATPase mRNA, and Isc. These data suggest cross-talk between the nongenomic and genomic responses to aldosterone in renal cells and suggest that the aldosterone-MR mediated increase in mRNA/protein synthesis and ion transport depends, at least in part, upon PKCalpha activation. E-mail: marcel.blot-chabaud@pharmacie.univ-mrs.fr
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PMID:Early nongenomic events in aldosterone action in renal collecting duct cells: PKCalpha activation, mineralocorticoid receptor phosphorylation, and cross-talk with the genomic response. 1510 Mar 55

The steroid hormone aldosterone is important for salt and water homeostasis as well as for pathological tissue modifications in the cardiovascular system and the kidney. The mechanisms of action include a classical genomic pathway, but physiological relevant nongenotropic effects have also been described. Unlike for estrogens or progesterone, the mechanisms for these nongenotropic effects are not well understood, although pharmacological studies suggest a role for the mineralocorticoid receptor (MR). Here we investigated whether the MR contributes to nongenotropic effects. After transfection with human MR, aldosterone induced a rapid and dose-dependent phosphorylation of ERK1/2 and c-Jun NH2-terminal kinase (JNK) 1/2 kinases in Chinese hamster ovary or human embryonic kidney cells, which was reduced by the MR-antagonist spironolactone and involved cSrc kinase as well as the epidermal growth factor receptor. In primary human aortic endothelial cells, similar results were obtained for ERK1/2 and JNK1/2. Inhibition of MAPK kinase (MEK) kinase but not of protein kinase C prevented the rapid action of aldosterone and also reduced aldosterone-induced transactivation, most probably due to impaired nuclear-cytoplasmic shuttling of MR. Cytosolic Ca2+ was increased by aldosterone in mock- and in human MR-transfected cells to the same extend due to Ca2+ influx, whereas dexamethasone had virtually no effect. Spironolactone did not prevent the Ca2+ response. We conclude that some nongenotropic effects of aldosterone are MR dependent and others are MR independent (e.g. Ca2+), indicating a higher degree of complexity of rapid aldosterone signaling. According to this model, we have to distinguish three aldosterone signaling pathways: 1) genomic via MR, 2) nongenotropic via MR, and 3) nongenotropic MR independent.
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PMID:Human mineralocorticoid receptor expression renders cells responsive for nongenotropic aldosterone actions. 1576 Oct 31


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