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)

Mutations associated with sodium channel-linked inherited Long-QT syndrome often result in a gain of channel function by disrupting channel inactivation. A small fraction of channels fail to inactivate (burst) at depolarized potentials where normal (wild type) channels fully inactivate. These noninactivating channels give rise to a sustained macroscopic current. We studied the effects of protein kinase A stimulation on sustained current in wild type and three disease-linked C-terminal mutant channels (D1790G, Y1795C, and Y1795H). We show that protein kinase A stimulation differentially affects gating in the mutant channels. Wild type, Y1795C, and Y1795H channels are insensitive to protein kinase A stimulation, whereas "bursting" in the D1790G mutant is markedly enhanced by protein kinase A-dependent phosphorylation. Our results suggest that the charge at position 1790 of the C terminus of the channel modulates the response of the cardiac sodium channel to protein kinase A stimulation and that phosphorylation of residue 36 in the N terminus and residue 525 in the cytoplasmic linker joining domains I and II of the channel alpha subunit facilitate destabilization of inactivation and thereby increase sustained current.
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PMID:Modulation of cardiac sodium channel gating by protein kinase A can be altered by disease-linked mutation. 1450 Jul 10

Cross talk between the phosphatidylinositol 3-kinase (PI3-K) and mitogen-activating protein kinase (MAPK)1/2 signaling cascades in response to aldosterone-induced K-RasA was investigated in renal A6 epithelial cells. In addition, the contribution of these signaling pathways to aldosterone-stimulated Na(+) transport was investigated. Aldosterone increased active K-RasA levels in A6 cells resulting in activation of downstream effectors in both the MAPK1/2 and PI3-K cascades with K-RasA directly interacting with the catalytic p110 subunit of PI3-K in a steroid-dependent manner. Aldosterone-stimulated PI3-K signaling impinged on the MAPK1/2 cascade at the level of Akt-mediated phosphorylation of c-Raf at an established negative regulatory site. Aldosterone also increased Sgk levels as well as stimulated phosphorylation of this kinase in a PI3-K- and K-RasA-dependent manner. Blockade of MAPK1/2 signaling had little effect on Na(+) transport. Conversely, inhibition of PI3-K markedly suppressed transport. Likewise, suppression of K-RasA induction decreased transport. However, Na(+) transport was subsequently stimulated under these conditions with the PLA(2) inhibitor aristolochic acid, an established positive modulator of Na(+) transport, suggesting that K-RasA signaling through PI3-K does not directly affect epithelial sodium channel (ENaC) levels but the activity of this channel. Consistent with this possibility, activity of ENaC reconstituted in Chinese hamster ovary cells was increased by coexpression of constitutively active PI3-K. The current study demonstrates that aldosterone increases Na(+) transport, in part, by stimulating PI3-K signaling and that during aldosterone actions, there is both signaling convergence between the two aldosterone-induced proteins, K-RasA and Sgk, as well as cross talk between the PI3-K and MAPK1/2 cascades with the prior but not latter cascade enhancing ENaC activity.
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PMID:Regulation of Na+ transport by aldosterone: signaling convergence and cross talk between the PI3-K and MAPK1/2 cascades. 1503 43

VIT32, a vasopressin-induced transcript, inhibits Na(+) transport when coexpressed with the epithelial sodium channel in Xenopus laevis oocytes (EMBO J 21: 5109-5117, 2002). To understand the mechanism of VIT32 gene regulation, we examined the effect of DDAVP and cAMP stimulation on VIT32 expression in M-1 mouse collecting duct cells and in H441 human airway epithelial cells. Elevation of cAMP with forskolin and IBMX increased VIT32 gene expression with a peak effect at 2 h. The increase in gene expression was abolished by H89 and by actinomycin D, suggesting that cAMP stimulates VIT32 mRNA expression by a PKA-mediated increase in gene transcription. An approximately 1.5-kb fragment of the 5'-flanking region of VIT32 was cloned and was able to confer cAMP-stimulated reporter gene activity when transfected into M-1 and H441 cells. By deletion analysis and site-directed mutagenesis, a cAMP response element (CRE) was identified within the proximal promoter region that was sufficient to account for the increase in VIT32 gene expression seen with DDAVP and elevation of cAMP. Furthermore, DDAVP-stimulated VIT32 promoter-reporter activity was inhibited by H89 and by a dominant negative CREB construct. Finally, we were able to identify CREB as a nuclear protein that bound to the VIT32 CRE in gel mobility shift assays. In summary, DDAVP stimulates transcription of VIT32 via a CRE within the proximal promoter region of the VIT32 gene.
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PMID:AVP-induced VIT32 gene expression in collecting duct cells occurs via trans-activation of a CRE in the 5'-flanking region of the VIT32 gene. 1514 Jul 62

Long-QT syndrome is a clinically and genetically heterogeneous syndrome characterized by lengthening of the QT interval and increased dispersion of the ventricular repolarization on surface electrocardiogram and a propensity to malignant ventricular arrhythmias, torsade de pointes and ventricular fibrillation, which may lead to sudden cardiac death. Long-QT syndrome mostly affects adolescents and young adults with structurally and functionally normal hearts and is caused by aberrations in potassium and sodium ion channels. Standard therapies for long-QT syndrome include correction of the underlying cause, alleviation of the precipitating factors, magnesium sulfate, isoproterenol, antiadrenergic therapy (beta-adrenergic receptor blockers, left cervicothoracic sympathectomy), cardiac pacing, and implantable cardioverter defibrillator. The potential therapies include sodium channel blockers (mexiletine, flecainide, lidocaine, pentisomide, phenytoin), potassium, potassium channel activators (nicorandil, pinacidil, cromakalim), alpha-adrenergic receptor blockers, calcium channel blockers, atropine, and protein kinase inhibitors. The purpose of this review is to outline the established therapies and update the recent advances and potential future strategies in the treatment of long-QT syndrome and torsade de pointes.
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PMID:Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. 1515 30

The epithelial sodium channel is found in apical membranes of a variety of native epithelial tissues, where it regulates sodium and fluid balance. In vivo, a number of hormones and other endogenous factors, including polyunsaturated fatty acids (PUFAs), regulate these channels. We tested the effects of essential n-3 and n-6 PUFAs on amiloride-sensitive sodium transport in A6 epithelial cells. Eicosapentaenoic acid [EPA; C20:5(n-3)] transiently stimulated amiloride-sensitive open-circuit current (I(Na)) from 4.0 +/- 0.3 to 7.7 +/- 0.3 microA/cm2 within 30 min (P < 0.001). No activation was seen in the presence of 10 microM amiloride. In cell-attached but not in cell-excised patches, EPA acutely increased the open probability of sodium channels from 0.45 +/- 0.08 to 0.63 +/- 0.10 (P = 0.02, paired t-test). n-6 PUFAs, including linoleic acid (C18:2), eicosatetraynoic acid (C20:4), and docosapentanoic acid (C22:5) had no effect, whereas n-3 docosahexanoic acid (C22:6) activated amiloride-sensitive I(Na) in a manner similar to EPA. Activation of I(Na) by EPA was prevented by H-89, a PKA inhibitor. Similarly, PKA activity was stimulated by EPA. Nonspecific stimulation of phosphodiesterase activity by CoCl2 completely prevented the effect of EPA on sodium transport. We conclude that n-3 PUFAs activate epithelial sodium channels downstream of cAMP in a cAMP-dependent pathway also involving PKA.
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PMID:Modulation of epithelial Na+ channel activity by long-chain n-3 fatty acids. 1519 29

Effects of two small G-proteins, Rap1 and Ras, on the sodium channel activity in NG108-15 cells were studied using sindbis virus-mediated gene transfer. When an activated Rap1A mutant (Rap1-12V, the activated mutant of Rap1 carrying glycine to valine substitution at codon 12) or a dominant-negative H-Ras mutant (Ras-17N, carrying serine to asparagine substitution at codon 17) was expressed in differentiated NG108-15 cells, the proportion of cells generating action potential decreased and the amplitudes of sodium current diminished. This effect was sensitive to an inhibitor of protein kinase A. The effects of a cyclic AMP (cAMP) analog (dibutyl cAMP) on sodium current in these cells were biphasic: inhibitory at lower concentrations (<100 microM) and enhancing at higher concentrations (200-500 microM). The inhibitory phase of cAMP effect was suppressed by an activated Ras mutant (Ras-12V) while the enhancing phase was suppressed by Rap1-12V. These data are consistent with the model that Rap1 and Ras function as counteracting regulators of voltage-gated sodium current through cAMP-dependent mechanisms.
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PMID:Effects of ras and Rap1 on electrical excitability of differentiated NG108-15 cells. 1531 9

The Nav1.8 sodium channel isoform, expressed in sensory neurons and implicated in pain responses, is known to be upregulated in Xenopus oocytes by agents that activate protein kinase A. In the absence of exogenous modulators, Nav1.8 channels expressed in oocytes exhibited spontaneous downregulation, so that the amplitudes of peak sodium currents at the end of a 30-min recording period were reduced to 58% of those at the outset of recording with no change in the properties of the expressed channels. Perfusion of oocytes with either cyclosporin A or deltamethrin, considered to be diagnostic inhibitors of the protein phosphatase calcineurin, at 10 microM blocked spontaneous downregulation. These results identify endogenous calcineurin as the mediator of Nav1.8 sodium channel downregulation in oocytes. The use of a calcineurin inhibitor such as cyclosporin A provides an effective means of stabilizing the expression of Nav1.8 sodium channels in oocytes for functional and pharmacological studies.
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PMID:Cyclosporin A and deltamethrin block the downregulation of Nav1.8 sodium channels expressed in Xenopus oocytes. 1533 72

Amiloride-sensitive sodium entry, via the epithelial sodium channel (ENaC), is the rate-limiting step for Na+ absorption in kidney collecting ducts, and epidermal growth factor (EGF) inhibits Na+ transport and ENaC expression. A pathognomonic feature of polycystic kidney disease (PKD) is EGF receptor mislocalization to the apical plasma membrane and EGF/EGF receptor axis overactivity. Immunohistochemical and biochemical analysis revealed mislocalization of EGF receptor and excessive activation of the p42/44 extracellular signal-regulated protein kinase pathway (ERK1/2) in kidneys from cystic mice compared with noncystic littermates. Primary monolayer cultures of noncystic and cystic murine collecting duct principal cells were used to identify aberrant EGF-dependent ERK1/2 activation and regulation of Na+ transport associated with autosomal recessive PKD. Addition of EGF to the basolateral bathing solution of noncystic or cystic monolayers led to p42/44 phosphorylation and inhibition of Na+ transport (30-35%), whereas apical EGF was effective only in monolayers derived from cystic mice. p42/44 Phosphorylation and inhibition of Na+ transport were prevented by prior treatment of the cells with an ERK kinase inhibitor. Chronic treatment (24 h) of noncystic and cystic monolayers with basolateral EGF elicited sustained inhibition of Na+ absorption (50-55%) and a reduction in steady-state ENaC mRNA levels (50-75%). In contrast, addition of EGF to the apical bathing solution (24 h) had no effect in noncystic monolayers but led to inhibition of Na+ transport (50-60%) and decreased ENaC expression (45-60%) in cystic cells. Pretreatment of the monolayers with an ERK kinase inhibitor abolished the chronic effects of EGF on Na+ transport. The results of these studies reveal that the mislocalized apical EGF receptors are functionally coupled to the ERK pathway and that abnormal EGF-dependent regulation of ENaC function and expression may contribute to PKD pathophysiology.
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PMID:Abnormal EGF-dependent regulation of sodium absorption in ARPKD collecting duct cells. 1552 85

WNK1 (with no lysine (K) 1) is a protein-serine/threonine kinase with a unique catalytic site organization. Deletions in the first intron of the WNK1 gene were found in a group of hypertensive patients with pseudohypoaldosteronism type II. No changes in coding sequence of WNK1 were found, but its expression was increased severalfold. We have been investigating actions of WNK1 and have found that WNK1 activates the serum- and glucocorticoid-induced protein kinase SGK1, which impacts membrane expression of the epithelial sodium channel. Here we explore the role of WNK1 in SGK1 regulation. Activation of SGK1 by WNK1 is blocked by phosphatidylinositol 3-kinase inhibitors. Neither the catalytic activity nor the kinase domain of WNK1 is required; rather the N-terminal 220 residues of WNK1 are necessary and sufficient to activate SGK1. Phosphorylation of WNK1 on Thr-58 contributes to SGK1 activation. Finally, we show that WNK1 is required for the activation of SGK1 by insulin-like growth factor 1.
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PMID:WNK1 activates SGK1 by a phosphatidylinositol 3-kinase-dependent and non-catalytic mechanism. 1608 17

Regulation of cystic fibrosis transmembrane regulator (CFTR) and epithelial sodium channel (ENaC) in airway epithelia strongly influences the rate of mucociliary clearance (MCC) by determining the volume of airway surface liquid. MCC increases in response to stimuli originating on the airway surface, and CFTR and ENaC in airway epithelia appear to be regulated by local rather than systemic signaling. Although all signals that regulate CFTR and ENaC in airways have not been identified, the release of nucleotides from airway epithelial cells exposed to physical stimuli initiates a series of events that coordinately favor increased MCC. These events include activation of adenosine A2B receptors that stimulate CFTR and P2Y2 receptors that inhibit ENaC. Together these actions result in an increased volume of airway surface liquid and increased MCC rates. Stimulation of CFTR by A(2B)AR uses protein kinase (PK) A signaling elements that are localized within the apical/subapical compartment, including G proteins, adenylyl cyclase, PKA-II, A-kinase anchoring proteins, and phosphodiesterases. Inhibition of ENaC by P2Y2 receptors appears to be mediated by phospholipase C-beta3, possibly through an effect on the levels of phosphatidylinositol 4,5-bisphosphonate in the apical membrane.
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PMID:Local regulation of cystic fibrosis transmembrane regulator and epithelial sodium channel in airway epithelium. 1611 9


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