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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper summarizes a particular aspect of the stress response-the negative feedback control of anterior pituitary adrenocorticotrophin secretion with special focus on the mechanism of action of protein(s) rapidly induced by glucocorticoids. The main thesis is that the principal intracellular mechanism underlying corticosteroid inhibition of corticotroph secretory function is the opposition of cAMP-mediated activation by calcium ions. An increase of intracellular cAMP levels in corticotrophs produces a rise in intracellular free Ca2+ known to be essential for triggering hormone secretion. In parallel, calcium regulates agonist-induced cAMP accumulation through inhibition of adenylyl cyclase and the stimulation of cAMP-degrading phosphodiesterase. Furthermore, a key action of cAMP is the inhibition of a slow, sustained potassium current which is activated by calcium ions. Collectively, the actions of calcium constitute a powerful intracellular feedback inhibition of cAMP-induced cellular activation. Analysis of corticosteroid action in mouse corticotroph tumour (AtT20) cells indicates that the essence of corticosteroid feedback inhibition is the amplification of intracellular calcium feedback. A common mediator of the inhibitory actions of calcium may be the calcium receptor protein calmodulin the de novo synthesis of which is rapidly stimulated by glucocorticoid hormones. Targets of glucocorticoid-induced calmodulin may include the protein phosphatase calcineurin, calmodulin-activated phosphodiesterase(s), and BK-type potassium channels. The net result of calcium feedback inhibition is a reduction of Ca2+ available for the facilitation of secretory activity i.e. calcium-induced desensitization. It is proposed that the intracellular calcium feedback loop outlined above also operates in the CNS components of negative corticosteroid feedback. A personal note: Professor Mortyn Jones introduced me to this field of research. His open-minded and critical approach to experimental work has always remained a guiding principle for my own efforts, and I hope that this paper which is dedicated to his memory will be found worthy of its purpose.
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PMID:Mortyn Jones Memorial Lecture--1995. Calcium checks cyclic AMP--corticosteroid feedback in adenohypophysial corticotrophs. 887 15

The neurotrophins are signaling factors that are essential for survival and differentiation of distinct neuronal populations during the development and regeneration of the nervous system. The long-term effects of neurotrophins have been studied in detail, but little is known about their acute effects on neuronal activity. Here we use permeabilized whole-cell patch clamp to demonstrate that neurotrophin-3 (NT-3) and nerve growth factor activate calcium-dependent, paxilline-sensitive potassium channels (BK channels) in cortical neurons. Application of NT-3 or nerve growth factor produced a rapid and gradual rise in BK current that was sustained for 30-50 min; brain-derived neurotrophic factor, ciliary neurotrophic factor, and insulin-like growth factor-1 had no significant effect. The response to NT-3 was blocked by inhibitors of protein kinases, phospholipase C, and serine/threonine protein phosphatase 1 and 2a. Omission of Ca2+ from the extracellular medium prevented the NT-3 effect. Our results indicate that NT-3 stimulates BK channel activity in cortical neurons through a signaling pathway that involves Trk tyrosine kinase, phospholipase C, and protein dephosphorylation and is calcium-dependent. Activation of BK channels may be a major mechanism by which neurotrophins acutely regulate neuronal activity.
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PMID:Activation of calcium-dependent potassium channels in mouse [correction of rat] brain neurons by neurotrophin-3 and nerve growth factor. 902 72

Na+, K+-ATPase contributes to the high potassium concentration in the endolymph and the resulting endocochlear potential, which are both essential for the function of the sensory part of the inner ear. Na+, K+-ATPase is present in the stria vascularis and it has lately been suggested that its activity is hormonally regulated. The intracellular signalling system for hormonal short-term regulation of Na+, K+-ATPase activity by phosphorylation in renal tubular cells has been well described. In this study, the presence of the intracellular components of this phosphorylation system in the stria vascularis from guinea-pig has been investigated with immunoblotting. The concentrations found were related to those in renal medullary tissue or the corpus striatum. Protein kinase C was present with isoforms alpha, delta and zeta in the stria vascularis. Calcium- and calmodulin-dependent protein kinase II and protein phosphatase-1 isoforms alpha and gamma were found in the stria vascularis. Protein phosphatase-2B, on the other hand, could not be detected. I-1, an inhibitor of protein phosphatase activity, was present, whereas the phosphatase inhibitor dopamine- and cAMP-regulated phosphoprotein (DARPP-32), was not present in the stria vascularis. These results demonstrate that several intracellular components of the phosphorylation/dephosphorylation system are present in the stria vascularis, and suggest that hormonal short-term regulation of Na+, K+-ATPase activity is also possible in the stria vascularis.
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PMID:Protein kinase and protein phosphatase presence in the stria vascularis. 904 45

Vasodilating agents induce relaxation of mesangial cells, in part through cGMP-mediated activation of large calcium-activated potassium channels (BKCa). Normally quiescent in cell-attached patches, the response of BKCa to nitric oxide, atrial natriuretic peptide, and dibutyryl cGMP (Bt2cGMP) is characterized by a biphasic increase and then decrease ("rundown") in open probability. Using the patch-clamp method in conjunction with phosphatase inhibitors, we investigated whether the run-down phase was the result of dephosphorylation by an endogenous protein phosphatase. In cell-attached patches, cantharidic acid (500 nM), okadaic acid (100 nM), and calyculin A (100 nM), nondiscriminant inhibitors of protein phosphatases 1 (PP1) and 2A (PP2A) at these concentrations, caused a significantly greater and sustained response of BKCa to Bt2cGMP. Within 2 min, the response of BKCa to the combination of cantharidic acid and Bt2cGMP was greater than the response to these agents added separately. Incubation of mesangial cells with okadaic acid for 20 min at a concentration (5 nM) specific for PP2A increased the basal open probability of BKCa and completely inhibited rundown after activation by Bt2cGMP. Incubation with calyculin A (10 nM), a more potent inhibitor of PP1, did not affect BKCa activity. In inside-out patches, Bt2cGMP plus MgATP caused a sustained activation of BKCa that was inhibited by exogenous PP2A but not PP1. It is concluded that either BKCa or a tightly associated regulator of BKCa is a common substrate for endogenous cGMP-activated protein kinase, which activates BKCa, and PP2A, which inactivates BKCa, in human mesangial cells.
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PMID:Regulation of large calcium-activated potassium channels by protein phosphatase 2A. 909 28

1. The effects of a 4-month daily treatment with recombinant human growth hormone (GH) (150 micrograms kg-1) to aged rats were evaluated on the passive and active membrane electrical properties of extensor digitorum longus (EDL) muscle fibres in vitro by means of a two intracellular microelectrode technique. 2. Chronic GH treatment completely restored the diameter and the membrane capacitance of aged EDL muscle fibres and significantly lowered the membrane resistance towards the adult value. There was also an increase of the threshold current, a shortening of the latency and an increase of the amplitude of the action potential and a significant amelioration of the membrane firing capability. 3. The effects were almost fully attributable to a significant 50% increase of resting conductance to chloride ions (GCl), although an observed restoration of potassium conductance and a possible effect on voltage-activated sodium channels could contribute to the effects. 4. EDL muscle fibres of untreated aged rats showed a different pharmacological response to 2-(p-chlorophenoxy) propionic acid (CPP) enantiomers from that seen in adult rats; the S-(-) isomer was less potent in blocking GCl and the R-(+) isomer always increased GCl instead of producing the typical biphasic effect observed in adult fibres (an increase of GCl at 1-10 microM and a decrease at higher concentrations). The 4-month-GH-treated aged rats showed a pharmacological sensitivity to CPP enantiomers similar to that of adults. 5. The in vitro application of insulin-like growth factor I (IGF-I), the peripheral mediator of GH, produced a significant and irreversible increase of GCl of EDL muscle of EDL muscle of untreated aged rats, an effect not observed in adults. This effect was completely inhibited by preincubation with 0.5 microM okadaic acid, suggesting that the IGF-I receptor transduction pathway can act on the phosphorylation state of the chloride channel through a serine-threonine protein phosphatase. 6. The results show that the skeletal muscle chloride channel is a target of the impairment of GH/IGF-I axis occurring in aged subjects. The acute and chronic effects observed on GCl of aged muscle fibres suggest that the GH/IGF-I stimuli act through a modulation of channel phosphorylation state and through the synthesis of 'adult'-like type chloride channels.
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PMID:Effects of chronic growth hormone treatment in aged rats on the biophysical and pharmacological properties of skeletal muscle chloride channels. 917 75

Adrenal glucocorticoids exert powerful effects on cellular excitability in neuroendocrine cells and neurons, although the underlying mechanisms are poorly understood. In metabolically intact mouse anterior pituitary corticotrope (AtT20) cells glucocorticoid-induced proteins render large conductance calcium-activated potassium (BK) channels insensitive to inhibition by protein kinase A (PKA). In this study we have addressed whether this action of glucocorticoids is mediated via protein phosphatase activity at the level of single BK channels. In isolated inside-out patches from control AtT20 cells BK channels (125 pS) were inhibited by activation of closely associated PKA. Pretreatment (2 h) of cells with 1 microM dexamethasone before patch excision did not modify the intrinsic properties or expression levels of BK channel alpha-subunits in AtT20 cells. However, PKA-mediated inhibition of BK channel activity in isolated patches from steroid-treated cells was severely blunted. This effect of steroid was not observed using adenosine 5'-O-(3-thiotriphosphate) as phosphate donor or on exposure of the intracellular face of the patch with 10 nM of the protein phosphatase inhibitors okadaic acid or calyculin A but was mimicked by application of protein phosphatase 2A (PP2A) to the intracellular face of patches from control cells. Glucocorticoids did not modify total PP2A activity in AtT20 cells, suggesting that modified PP2A-like phosphatase activity closely associated with BK channels is required for glucocorticoid action.
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PMID:Glucocorticoid regulation of calcium-activated potassium channels mediated by serine/threonine protein phosphatase. 959 88

The effects of FK506, an immunosuppressant and protein phosphatase 2B (calcineurin) inhibitor, on the voltage-gated calcium channel (VGCC)-dependent long-term potentiation (LTP) were investigated in the CA1 region of mice hippocampal slices. VGCC-dependent LTP was induced either by a brief application of a potassium channel blocker tetraethyleneanmonium (TEA), or by a strong tetanic stimulation under the blockade of NMDA-receptors. FK506 (1-50 microM) produced dose-dependent inhibition on TEA-induced LTP. Cyclosporin A (CysA 50 microM), another calcineurin inhibitor, showed a similar inhibitory effect on TEA-induced LTP. FK506 (10 microM) also blocked the strong tetanus-induced LTP, but had no effect on the post-tetanic potentiation. By using a subthreshold weak tetanic stimulation protocol, we also found that low concentration of FK506 (1 microM) produced neither inhibition nor potentiation on VGCC-dependent LTP. These results showed FK506 and CysA exerted inhibitory effects on VGCC-dependent LTP, and suggest that calcineurin is involved in the processes of this kind of synaptic plasticity.
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PMID:A calcineurin inhibitor, FK506, blocks voltage-gated calcium channel-dependent LTP in the hippocampus. 967 35

We have previously shown that the mutation of the Schizosaccharomyces pombe PPZ-like protein phosphatase encoded by the gene pzh1+ results in increased tolerance to sodium and in hypersensitivity to potassium ions. A similar phenotype has also been reported for deletants in the spm1/pmk1 gene, encoding a mitogen-activated protein (MAP) kinase. We have found that the sodium tolerance phenotype of pzh1 deletants is stronger than that of spm1 mutants, and both effects are additive. Therefore, most probably both gene products mediate different pathways on sodium tolerance. In our hands, mutation of the kinase does not alter the tolerance to potassium, but it yields cells more tolerant to magnesium ions. While in budding yeast the mutations are synthetically lethal, fission yeast cells lacking both the phosphatase and the kinase genes are viable. Interestingly, their ability to export H+ to the medium is greatly impaired (although not that of pzh1 or spm1 single mutants). We have observed that, although the amount of the H+-ATPase in the plasma membrane is not altered, the activity of the enzyme is lower than normal and cannot be induced by glucose. These observations suggest that the activity of the H+-ATPase in fission yeast might be regulated by phospho-dephosphorylation mechanisms that might involve the pzh1+ and spm1+ gene products.
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PMID:The Pzh1 protein phosphatase and the Spm1 protein kinase are involved in the regulation of the plasma membrane H+-ATPase in fission yeast. 976 18

Two prominent potassium currents, termed IK and IK,n, and a cation current are found in outer hair cells (OHCs) of the guinea-pig cochlea. We report here whole-cell recordings which indicate that the currents are regulated by intracellular factors. 8-bromo-cAMP (500 microM), a membrane-permeable cAMP analogue, activated potassium currents in OHCs in both apical and basal turns of the cochlea. In OHCs from the cochlear apex, the drug effect was largest at potentials positive to -40 mV, indicating IK as the target. In short cells from the cochlear base, both IK and IK,n were affected. The effects of 8-bromo-cAMP could be blocked by the presence of 1 microM H-89 (a protein kinase A inhibitor) in the patch pipette solution. Extracellular application of 10 nM okadaic acid, a protein phosphatase inhibitor, also activated both potassium currents. Currents were also modulated by intracellular calcium. IK was activated in long cells by photorelease of calcium from the caged compound nitr5. Cation current activation required calcium release by photolysis of DM-nitrophen, a compound releasing more calcium. The results show that OHC potassium channels are regulated by background phosphorylation through protein kinase A and dephosphorylation by protein phosphatase. Cellular calcium also activates IK and the cation channel, but with different sensitivities.
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PMID:Regulation of ionic currents by protein kinase A and intracellular calcium in outer hair cells isolated from the guinea-pig cochlea. 991 97

The regulatory subunit of S. cerevisiae casein kinase II (CKII) is encoded of two genes, CKB1 and CKB2. Strains harboring deletions of either or both genes exhibit specific sensitivity to high concentrations of Na+ or Li+. Na+ tolerance in S. cerevisiae is mediated primarily by transcriptional induction of ENA1, which encodes the plasma membrane sodium pump, and by conversion of the potassium uptake system to a higher affinity form that discriminates more efficiently against Na+. To determine whether reduced ENA1 expression plays a role in the salt sensitivity of ckb mutants, we integrated an ENA1-lacZ reporter gene into isogenic wild-type, ckb1, ckb2, and ckb1 ckb2 strains and monitored beta-galactosidase activity at different salt concentrations. In all three mutants transcription from the ENA1 promoter remained salt-inducible, but both basal and salt-induced expression was depressed approximately 3- to 4-fold. The degree of reduction in ENA1 expression was comparable to that observed in an isogenic strain carrying a null mutation in protein phosphatase 2B (calcineurin), which is also required for salt tolerance. These results suggest that reduced expression ofENA1 contributes to the salt sensitivity of ckb strains. Consistent with this conclusion, overexpression of ENA1 from a heterologous promoter (GAL1) completely suppressed the salt sensitivity of ckb mutants. Induction of ENA1 expression by alkaline pH is also depressed in ckb mutants, but unlike calcineurin mutants, ckb strains are not growth inhibited by alkaline pH.
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PMID:Transcriptional regulation of the S. cerevisiae ENA1 gene by casein kinase II. 1009 5


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