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

---

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

Human UC11 astrocytoma cells were used to investigate the role of protein kinase C (PKC) and other kinases in neurokinin (NK)1 receptor desensitization. The selective NK1 receptor agonist [Sar9,Met(O2)11]-substance P stimulated a biphasic accumulation of [3H]inositol phosphates ([3H]IPs) in the presence of 10 mM LiCl in cells that had been prelabeled with [3H]inositol. An initial rapid phase of [3H]IP accumulation during the first 1 min was followed by a slower sustained phase for up to 90 min. These results demonstrate that the human NK1 receptor desensitizes rapidly but only partially. The selective PKC inhibitor Ro31-8220 did not prevent rapid NK1 receptor desensitization but after a longer incubation significantly potentiated human NK1 receptor agonist-stimulated accumulation of [3H]IPs. These results suggest that, although PKC does not mediate the process of rapid desensitization, it does have an inhibitory role at later times. This conclusion is supported by studies with staurosporine, phorbol dibutyrate, and the protein phosphatase inhibitor okadaic acid. Studies using AlF4-, an agent that can directly activate G proteins, and Ro31-8220 suggested that PKC can exert inhibitory effects 'downstream' of receptor activation, although immunoprecipitation of the G proteins alpha q/alpha 11 demonstrated that they do not undergo phosphorylation in UC11 cells and are unlikely to be the target of PKC-mediated inhibitory feedback. Delayed inhibitory feedback by PKC may be mediated by phosphorylation of phospholipase C, although an additional site of action on the NK1 receptor cannot be ruled out.
...
PMID:Protein kinase C mediates delayed inhibitory feedback regulation of human neurokinin type 1 receptor activation of phospholipase C in UC11 astrocytoma cells. 752 12

1. Exogenous arachidonic acid (AA) inhibits the protein phosphatase that dephosphorylates smooth muscle myosin, thus sensitizing the contractile response to Ca2+; it also inhibits voltage-gated Ca2+ channels in smooth muscle. The purpose of the present study was to determine whether endogenous AA is increased by agonists in a manner consistent with its role as a messenger regulating myosin phosphatase and Ca2+ channels. Both AA and diacylglycerol (DAG) were measured in [3H]AA-labelled intact and permeabilized (with staphylococcal alpha-toxin) rabbit femoral arteries stimulated with the alpha 1-adrenergic agonist phenylephrine (PE) (intact and permeabilized smooth muscles) or by guanosine-5'-O-(3-thiotriphosphate (GTP gamma S; permeabilized smooth muscles in which the [Ca2+] was maintained constant). Arachidonic acid mass was determined with gas chromatography and mass spectrometry (GC-MS). 2. In intact smooth muscle, PE increased both AA and DAG levels significantly, to 210 and 145% of baseline values, respectively. Another Ca2+-sensitizing agent, the thromboxane analogue U46619, caused a similar increase in AA and DAG levels in rabbit pulmonary artery. 3. In permeabilized smooth muscle at constant [Ca2+](pCa 6.5) GTP gamma S-induced AA and DAG release preceded force development and GTP gamma S (50 microM, 10 min) increased AA mass to 61-88 microM. 4. Phorbol-12,13-dibutyrate (PDBu), another Ca2+-sensitizing agent, also increased both AA and DAG levels in permeabilized smooth muscle at pCa 6.5, whereas the inactive analogue, 4 alpha-phorbol, did not have a Ca2+-sensitizing effect, nor did it increase AA and DAG levels. 5. In the virtual absence of Ca2+ (pCa > 8) GTP gamma S also increased AA and DAG levels by 3.5- and 1.6-fold, respectively. The effect of free Ca2+ itself on AA and DAG release was modest in the physiological range (pCa 7.0 to pCa 6.0), but pCa 4.5 caused an approximately 3- to 4-fold increase in AA and DAG levels, compared with the levels at pCa 8. In permeabilized ileum smooth muscle maintained at constant [Ca2+] (pCa 6.0), carbachol also significantly increased AA to 1.75 times its original value within 1 min of its application. 6. Our results are consistent with, although do not prove, the roles of AA and DAG as second and/or co-messenger(s) in smooth muscle, while the increases in AA and DAG levels induced by PDBu raise the possibility that they contribute to some of the cellular effects of phorbol esters.
...
PMID:Arachidonic acid and diacylglycerol release associated with inhibition of myosin light chain dephosphorylation in rabbit smooth muscle. 756 27

Degranulation of eosinophils and release of toxic granule proteins play key roles in allergic diseases such as bronchial asthma. However, the intracellular signaling mechanisms that trigger eosinophil degranulation remain unclear. In this study, we investigated protein tyrosine kinase (PTK) involvement in the degranulation of human blood eosinophils induced by immobilized Ig. Eosinophils stimulated with Sepharose beads coated with secretory IgA (slgA) or IgG showed rapid increases in the tyrosine phosphorylation of intracellular proteins with molecular masses of 50 to 56, 73, 78, 100, and 105 kDa. The Ig-induced phosphorylation response was not affected by pertussis toxin, a known inhibitor of Ig-dependent eosinophil activation. The tyrosine kinase inhibitors genistein and herbimycin A inhibited both the tyrosine phosphorylation and degranulation responses of eosinophils induced by sIgA- or IgG-coated beads. In contrast, eosinophil degranulation induced by PMA was not affected by genistein. Treatment of eosinophils with the protein phosphatase inhibitor pervanadate induced the phosphorylation of a similar set of intracellular proteins as well as cellular degranulation. Pervanadate also stimulated an increase in phosphoinositide hydrolysis, which was consistent with the activation of a phospholipase C-gamma isoform by this stimulus. Genistein pretreatment blocked the Ig-induced phospholipase C activation, providing evidence for PTK involvement in this reaction. These findings indicate that a PTK-dependent signaling pathway plays an important role in triggering the degranulation responses of human eosinophils to immobilized sIgA and IgG.
...
PMID:Tyrosine phosphorylation is required for eosinophil degranulation induced by immobilized immunoglobulins. 760 11

In bovine adrenal zona fasciculata (AZF) cells, angiotensin II (AII) may stimulate depolarization-dependent Ca2+ entry and cortisol secretion through inhibition of a novel potassium channel (IAC), which appears to set the resting potential of these cells. Aspects of the signaling pathway, which couples AII receptors to membrane depolarization and secretion, were characterized in patch clamp and membrane potential recordings and in secretion studies. AII-mediated inhibition of IAC, membrane depolarization, and cortisol secretion were all blocked by the AII type I (AT1) receptor antagonist losartan. These responses were unaffected by the AT2 antagonist PD123319. Inhibition of IAC by AII was prevented by intracellular application of guanosine 5'-O-2-(thio)-diphosphate but was not affected by pre-incubation of cells with pertussis toxin. Although mediated through an AT1 receptor, several lines of evidence indicated that AII inhibition of IAC occurred through an unusual phospholipase C (PLC)-independent pathway. Acetylcholine, which activates PLC in AZF cells, did not inhibit IAC. Neither the PLC antagonist neomycin nor PLC-generated second messengers prevented IAC expression or mimicked the inhibition of this current by AII. IAC expression and inhibition by AII were insensitive to variations in intracellular or extracellular Ca2+ concentration. AII-mediated inhibition of IAC was markedly reduced by the non-hydrolyzable ATP analog adenosine 5'-(beta, gamma-imino)triphosphate and by the non-selective protein kinase inhibitor staurosporine. The protein phosphatase antagonist okadaic acid reversibly inhibited IAC in whole cell recordings. These findings indicate that AII-stimulated effects on IAC current, membrane voltage, and cortisol secretion are linked through a common AT1 receptor. Inhibition of IAC in AZF cells appears to occur through a novel signaling pathway, which may include a losartan-sensitive AT1 receptor coupled through a pertussis-insensitive G protein to a staurosporine-sensitive protein kinase. Apparently, the mechanism linking AT1 receptors to IAC inhibition and Ca2+ influx in adrenocortical cells is separate from that involving inositol trisphosphate-stimulated Ca2+ release from intracellular stores. AII-stimulated cortisol secretion may occur through distinct parallel signaling pathways.
...
PMID:Losartan-sensitive AII receptors linked to depolarization-dependent cortisol secretion through a novel signaling pathway. 767 18

1. Cultured brain capillary endothelial cells of the rat respond to endothelin-1 (ET-1) by an increased activity of the Na+,K+,2Cl-, cotransporter and a mobilization of intracellular Ca2+ stores. 2. Calyculin A (1-30 nM), but not okadaic acid, sensitizes up to 100 fold the Na+,K+,2Cl- cotransporter to the action of ET-1. 3. Calyculin A (30 nM) does not modify the binding properties of ET-1 to ETA receptors. 4. Calyculin A (30 nM) inhibits ET-1 induced intracellular Ca2+ mobilization. 5. It is concluded that inhibition of protein phosphatase 1 selectively modifies the repertoire of intracellular actions of ET-1 and favours actions that are unrelated to the phospholipase C signalling cascade.
...
PMID:Sensitization by calyculin A of brain capillary endothelial cells to endothelin-1. 778 Jun 34

Engagement of the T cell receptor for antigen activates phospholipase C resulting in an increase in intracellular free calcium concentration ([Ca2+]i) and activation of protein kinase C (PKC). Increased [Ca2+]i activates Ca2+/calmodulin-dependent kinases including the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM-K II), as well as calcineurin, a type 2B protein phosphatase. Recent studies have identified calcineurin as a key enzyme for interleukin (IL)-2 and IL-4 promoter activation. However, the role of CaM-K II remains unknown. We have used mutants of these kinases and phosphatases (gamma B*CaM-K and delta CaM-AI, respectively) to explore their relative role in cytokine gene transcription and their interactions with PKC-dependent signaling systems. gamma B*CaM-K and delta CaM-AI, known to exhibit constitutive Ca(2+)-independent activity, were cotransfected (alone or in combination) in Jurkat T cells with a plasmid containing the intact IL-2 promoter driving the expression of the chloramphenicol acetyltransferase reporter gene. Cotransfection of gamma B*CaM-K with the IL-2 promoter construct downregulated its transcription in response to stimulation with ionomycin and phorbol myristate acetate (PMA). The inhibitory effect of CaM-K II on IL-2 promoter was associated with decreased transcription of its AP-1 and NF-AT transactivating pathways. Under the same conditions, delta CaM-AI superinduced IL-2 promoter activity (approximately twofold increase). When both mutants were used in combination, gamma B*CaM-K inhibited the induction of the IL-2 promoter by delta CaM-AI. Similar results were obtained when a construct containing the IL-4 promoter also was used. gamma B*CaM-K also downregulated the activation of AP-1 in response to transfection with a constitutively active mutant of PKC or stimulation with PMA. These results suggest that CaM-K II may exert negative influences on cytokine gene transcription in human T cells, and provide preliminary evidence for negative cross-talk with the calcineurin- and PKC-dependent signaling systems.
...
PMID:Calcium/calmodulin-dependent protein kinase II downregulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells. 786 38

CONTENTS. T-cell activation--Structure of the T-cell antigen receptor--Modular organisation of the T-cell antigen receptor--T-cell antigen receptor-coupled signaling pathways: Activation of protein-tyrosine kinase by the T-cell antigen receptor; Signal transduction in lymphoid cells involves several protein-tyrosine kinases in parallel; Regulation of T-cell antigen receptor signaling by the phosphoprotein phosphatase CD45--Consequences of T-cell antigen receptor-induced tyrosine phosphorylation: Activation of phosphoinositol-lipid-turnover pathways--Activation of phospholipase C-gamma-1: p59fyn or p56lck?--G-protein motif of CD3-gamma: relevance for signal transduction--Association of lipid kinase with the T-cell antigen receptor--Intracellular signaling by phospholipid metabolites and calcium: activation of protein kinase C--Protein kinase C isoenzymes--Heterogenity of protein kinase C and mode of activation--Phospholipid-derived mediators in activation of protein kinase C in T-cells--Role of phospholipase D metabolites in activation of protein kinase C--Polyunsaturated fatty acids and lysophosphatidylcholine as activators of protein kinase C--Potein kinase C and p21ras function in interdependent and distinct signaling pathways during T-cell activation--Raf-1 kinase: regulator or target of protein kinase C?--Summary and perspectives.
...
PMID:T-cell antigen receptor-induced signal-transduction pathways--activation and function of protein kinases C in T lymphocytes. 788 88

alpha 1-Adrenergic (alpha 1-AR) agents stimulate NaCl(K) cotransport and phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2]-specific phospholipase C in human trachea and nasal polyp epithelial cells. One second messenger generated by PtdIns(4,5)P2 degradation is inositol trisphosphate. We now show that diglycerides (DG) are also generated during alpha 1-AR stimulation. In cells prelabeled with [3H]arachidonic acid, alpha 1-AR agents produced a biphasic DG generation in normal and cystic fibrosis (CF) cells that is blocked by pertussis toxin. The early DG peak closely paralleled PtdIns(4,5)P2 degradation, stimulation of cotransport by phorbol 12-myristate 13-acetate (PMA), and inhibition of cotransport by the protein kinase C (PKC) inhibitor staurosporine. This suggests that cotransporter activation requires PKC-protein phosphorylation. This possibility was tested using the protein phosphatase inhibitor okadaic acid. Okadaic acid elevated bumetanide-sensitive Cl efflux. Staurosporine also blocked > 63% of okadaic-acid-stimulated Cl transport. The late DG peak did not support hormone-stimulated cotransport. The results demonstrate that DGs are a pivotal link between alpha 1-AR stimulation and NaCl(K) cotransport activation with a role for PKC and protein phosphorylation. alpha 1-AR intracellular signaling mechanisms apparently operate normally in CF cells.
...
PMID:The role of protein kinase C in alpha-adrenergic regulation of NaCl(K) cotransport in human airway epithelial cells. 790 Aug 23

The hypothesis that a large, possibly toxic, increase in cellular calcium accompanies photoreceptor cell degeneration in several different Drosophila mutants was tested. The calcium content of wild type and mutant photoreceptors of Drosophila was measured using rapid freezing of the eyes and energy-dispersive x-ray analysis (e.d.x.) of cryosections and semithin sections of cryosubstituted material. Light- and dark-raised mutants of the following strains were studied: retinal degeneration B (rdgB); retinal degeneration C (rdgC); neither inactivation nor afterpotential C (ninaC), and no receptor potential A (norpA). These are light-dependent retinal degeneration mutants in which the affected gene products had been previously shown as myosin-kinase (ninaC), calcium-dependent phosphoprotein phosphatase (rdgC), phosphoinositide transfer protein (rdgB), and phospholipase C (norpA). In light-raised mutants, ommatidia of variable degrees of degeneration were observed. Mass-dense globular bodies of 200-500 nm diameter in relatively large quantities were found in the degenerating photoreceptor of all the mutants tested. These subcellular globules were found to have a very high calcium content, which was not found in wild type or in nondegenerating photoreceptors of the mutants. Nondegenerating photoreceptors were found not only in dark-raised mutants, but in smaller quantities also in light-raised mutants. Usually these globular structures contained high levels of phosphorus, indicating that at least part of the calcium in the mutant photoreceptors is precipitated as calcium phosphate. The results indicate that a large increase in cellular calcium accompanies light-induced photoreceptor degeneration in degenerating Drosophila mutants even when induced by very different mutations, suggesting that the calcium accumulation is a secondary rather than a primary effect in the degeneration process.
...
PMID:Accumulation of calcium in degenerating photoreceptors of several Drosophila mutants. 791 26

Angiotensin II (AII) receptors are known to interact with two distinct guanine nucleotide binding proteins, Gq/11 and Gi, in rat adrenal glomerulosa cells to activate phospholipase C and to inhibit adenylate cyclase, respectively. However, in cultured bovine glomerulosa cells AII potentiates rather than inhibits the stimulatory effect of adrenocorticotropin (ACTH) on cAMP levels. This effect of AII was partially mimicked by phorbol 12-myristate 13-acetate (PMA) and was partially inhibited by staurosporine or depletion of protein kinase C but was unaffected by pertussis toxin treatment. No potentiation was detectable in disrupted cells or in membrane preparations. In intact glomerulosa cells, treatment with cyclosporin A or FK506 completely inhibited AII- or PMA-induced potentiation of cAMP production without affecting the response to ACTH. In COS-7 cells transfected with the rat AT1 receptor, AII caused 2-3-fold enhancement of the ACTH-induced cAMP response, an effect that was partially reproduced by PMA. These potentiating actions of AII and PMA were prevented by preincubation with cyclosporin A or FK506, and the latter effect was abolished by rapamycin. These results implicate the Ca2+- and calmodulin-dependent protein phosphatase, calcineurin, in AII-induced enhancement of adenylate cyclase activity in both adrenal glomerulosa and transfected COS-7 cells. The finding that AII enhances ACTH-stimulated production of cAMP by a second messenger-mediated mechanism that involves the participation of calcineurin reveals an additional mode of cross-talk between pathways activated by Ca(2+)-mobilizing and cAMP-generating receptors.
...
PMID:Evidence for participation of calcineurin in potentiation of agonist-stimulated cyclic AMP formation by the calcium-mobilizing hormone, angiotensin II. 792 24


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---