Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that Ph+ myeloid progenitor cells of patients with chronic myeloid leukemia (CML) can acquire characteristics of mature dendritic cells (DC) following calcium mobilization with calcium ionophore (A23187, CI). In this study we characterize the intracellular signaling pathway by which CI induces the acquisition of DC features in these leukemic cells. CI-induced activation of CML cells is attenuated by the calcineurin phosphatase inhibitor cyclosporin A (CsA) as well as the calmodulin (CaM) antagonist W-7. These cause ablation of both the CI-induced immunophenotypic expression of DC markers and immunostimulatory properties in mixed leukocyte responses (MLR). Minimal blocking effect was observed when Ca(2+)/CaM kinase II (281-301) inhibitor was added to the cultures. These findings suggest a Ca(2+)-dependent mechanism for the CI-induced activation of CML cells into antigen-presenting cells (APC), which is primarily mediated through the CaM/calcineurin pathway.
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PMID:Calcium ionophore activation of chronic myelogenous leukemia progenitor cells into dendritic cells is mediated by calcineurin phosphatase. 1099 97

We reported previously that in mouse testis calmodulin-dependent protein phosphatase (calcineurin) is localised in the nuclei of round and elongating spermatids (Cell Tissue Res. 1995; 281: 273-81). In this study, we studied the immunohistochemical localisation of calcium/calmodulin-dependent protein kinase (CaM kinase II) using antibodies against CaM kinase IIgamma from chicken gizzard and specific antibodies raised against the amino acid sequence Ileu480-Ala493 of this enzyme, and compared it with the distribution of calmodulin. Indirect immunofluorescence was most concentrated in early spermatocytes and localised in the outermost layer of seminiferous tubules where the calmodulin level was relatively low. Measurements of immuno-gold particle densities on electron micrographs revealed that CaM kinase II is transiently increased in the nucleus of zygotene spermatocytes. These observations suggest the involvement of CaM kinase II in the meiotic chromosomal pairing process. An extremely high concentration of calmodulin in spermatogenic cells undergoing meiosis may not be directly related to activation of calmodulin-dependent kinases and phosphatases.
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PMID:Immunohistochemical detection of calmodulin and calmodulin-dependent protein kinase II in the mouse testis. 1110 52

Extracellular signal-regulated kinases (ERK1/ERK2) have been shown transiently activated and involved in excitotoxicity. We searched for upstream molecules responsible for the regulation of glutamate-induced ERK1/ERK2 activation and ERK1/ERK2-mediated apototic-like death in cultured rat cortical neurons. ERK1/ERK2 activation (monitored by anti-active ERK1/ERK2 antibody) was almost completely prevented by blockage of NMDA receptor (NMDA-R) or elimination of extracellular Ca(2+), but not any other glutamate receptor or L-type voltage-gated Ca(2+) channel. It was prevented largely by inhibition of protein kinase C (PKC), protein-tyrosine kinases (PTK), respectively, but mildly by that of CaM kinase II. Combined inhibition of CaM kinase II (but not PTK) and PKC had an additive effect. Reversion of ERK1/ERK2 activation was largely prevented by inhibition of protein phosphatase (PP) 1 or protein tyrosine phosphatase (PTP). Combined inhibition of PP 1 and PTP had no additive effect. Glutamate-induced apoptotic-like death (determined by DAPI staining) was largely prevented by inhibition of NMDA-R, PKC, CaM kinase II, PTK and MEK1/MEK2 (ERK1/ERK2 kinase), respectively. Combined inhibition of CaM kinase II (but not PKC or PTK) and MEK1/MEK2 had an additive effect. Glutamate-induced apoptotic-like death was promoted by inhibition of PP1 and PTP, respectively. The above results suggested that in glutamate-induced cortical neurotoxicity ERK1/ERK2 activation be mainly mediated by NMDA-R. Subsequently, a pathway dependent on both PKC and PTK was mainly involved, which was also mainly responsible for ERK1/ERK2-mediated apoptotic-like death, and a CaM kinase II-dependent pathway was relatively mildly involved. Reversion of ERK1/ERK2 activation was mainly mediated by a pathway dependent on both PP1 and PTP, which might be involved in the restrain of glutamate-induced neurotoxicity.
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PMID:N-methyl-D-aspartate receptor activation results in regulation of extracellular signal-regulated kinases by protein kinases and phosphatases in glutamate-induced neuronal apototic-like death. 1113 17

Diisopropyl phosphorofluoridate (DFP) is a type I organophosphorus compound and produces delayed neurotoxicity (OPIDN) in adult hens. A single dose of DFP (1.7 mg/kg, s.c.) produces mild ataxia in hens in 7-14 days, which develops into severe ataxia or paralysis as the disease progresses. We have previously shown altered expression of several proteins (e.g. Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) alpha-subunit, tau, tubulin, neurofilament protein (NF), vimentin, GFAP) and an immediate early gene (e.g. c-fos) in DFP-treated hens. Here we show an increase in protein kinase A (PKA) protein level and activity in the spinal cord at 1-day and 5-days time periods after DFP administration. We also determined the protein levels of protein kinase C (PKC), CaM kinase II and several phosphatases (i.e. phosphatase 1 (PP1), phosphatase 2A (PP2A), phosphatase 2B (PP2B) in the spinal cord of DFP-treated hens after 1, 5, 10, and 20 days). There was increase in CaM kinase II alpha subunit level after 10 and 20 days of treatment, and decrease in PKC level at 1-day and 20-days time periods in spinal cord mitochondria. In contrast, the cerebrum, which is resistant to DFP-induced axonal degeneration, did not show change in PKA and CaM Kinase II levels at any time period DFP post-administration. No alteration was found in the protein levels of PP1, PP2A, and PP2B at any time period. An early induction in PKA, which is an important protein kinase in signal transduction, followed by that of CaM kinase might be contributing towards the development of OPIDN in DFP-treated hens.
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PMID:Enhanced activity and level of protein kinase A in the spinal cord supernatant of diisopropyl phosphorofluoridate (DFP)-treated hens. Distribution of protein kinases and phosphatases in spinal cord subcellular fractions. 1145 76

Since Pb(2+) substitutes for Ca(2+) in essential steps leading to exocytosis, we have investigated whether Ca(2+) and Pb(2+) induce exocytosis through similar pathways. Vesicular catecholamine release was measured from dexamethasone-differentiated PC12 cells using carbon fiber microelectrode amperometry. Effects of drugs known to modulate PKC (PMA, staurosporine), calcineurin (cyclosporin A), calmodulin (W7), and CaM kinase II (KN-62) activity were investigated in intact and in ionomycin-permeabilized PC12 cells. Activation of PKC and inhibition of calmodulin decrease the frequency of exocytotic events evoked by high K(+) stimulation in intact cells. In addition, inhibition of calmodulin enhances the frequency of basal exocytosis from intact cells. Activation of PKC and inhibition of calcineurin enhance the frequency of basal exocytosis in intact as well as in ionomycin-permeabilized cells. Inhibition of PKC and of CaM kinase II cause no significant effects. None of the treatments has a significant effect on vesicle contents. The combined results indicate that PKC and calcineurin enhance and inhibit exocytosis through direct effects on the exocytotic machinery, whereas calmodulin and CaM kinase II exert indirect effects only. Conversely, Pb(2+)-evoked exocytosis in permeabilized cells is strongly reduced by inhibition of CaM kinase II, but is not sensitive to modulation of PKC and calcineurin activity. Inhibition of calmodulin only reduces the delay to onset of Pb(2+)-evoked exocytosis. Synaptotagmin I- and II-deficient PC12-F7 cells exhibit vesicular catecholamine release following depolarization or superfusion with Pb(2+). However, the frequency of exocytosis and the contents of vesicles released are strongly reduced as compared to PC12 cells. It is concluded that Ca(2+)-evoked exocytosis is modulated mainly by PKC and calcineurin, whereas Pb(2+)-evoked exocytosis is mainly modulated by CaM kinase II.
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PMID:Signaling pathways involved in Ca2+- and Pb2+-induced vesicular catecholamine release from rat PC12 cells. 1244 76

Depolarization has been known to play an important role in the neuronal damage that occurs following cerebral ischemia. In the present study, we investigated the roles of calmodulin (CaM) and CaM-dependent enzymes in depolarization-induced neuronal cell death. Treatment of primary cortical neurons with 10 microM veratridine, a voltage sensitive Na(+) channel activator, induced cell death as indicated by lactate dehydrogenase leakage from neurons. CaM antagonists (calmidazolium, trifluoperazine, W-7, and W-5) inhibited cell death induced by veratridine in a concentration-dependent manner. CaM kinase II (CaMKII) inhibitors (KN-62, KN-93, and myristoylated autocamtide-2 related inhibitory peptide), but not inhibitors of nitric oxide synthase or calcineurin, prevented veratridine-induced neuronal cell death. Veratridine rapidly activated CaMKII in neurons, and CaM antagonists and a CaMKII inhibitor suppressed the CaMKII activation. These results suggest that the CaM-CaMKII pathway contributes to depolarization-evoked cell death in neurons.
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PMID:Calmodulin and calmodulin-dependent kinase II mediate neuronal cell death induced by depolarization. 1254 54

Reactive oxygen intermediates (ROI) have been viewed traditionally as damaging to the cell. However, a predominance of evidence has shown that ROI can also function as important activators of key cellular processes, and ROI have been shown to play a vital role in cell signaling networks. The calcium/calmodulin-dependent protein kinases (CaM kinases) are a family of related kinases that are activated in response to increased intracellular calcium concentrations. In this report we demonstrate that hydrogen peroxide treatment results in the activation of both CaM kinase II and IV in Jurkat T lymphocytes. Surprisingly, this activation occurs in the absence of any detectable calcium flux, suggesting a novel means for the activation of these kinases. Treatment of Jurkat cells with phorbol 12-myristate 13-acetate (PMA), which does not cause a calcium flux, also activated the CaM kinases. The addition of catalase to the cultures inhibited PMA-induced activation of the CaM kinases, suggesting that similar to hydrogen peroxide, PMA also activates the CaM kinases via the production of ROI. One mechanism by which this likely occurs is through oxidation and consequential inactivation of cellular phosphatases. In support of this concept, okadaic acid and microcystin-LR, which are inhibitors of protein phosphatase 2A (PP2A), induced CaM kinase II and IV activity in these cells. Overall, these results demonstrate a novel mechanism by which ROI can induce CaM kinase activation in T lymphocytes.
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PMID:Redox regulation of the calcium/calmodulin-dependent protein kinases. 1529 13

It is well known that tau is a good in vitro substrate for Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). However, it is not clear at present whether CaM kinase II phosphorylates tau in vivo or not. Serine 416, numbered according to the longest human tau isoform, has been reported to be one of the major phosphorylation sites by CaM kinase II in vitro. In this study, we produced a specific antibody against tau phosphorylated at serine 416 (PS416-tau). Immunoblot analysis revealed that the antibody reacted with tau in the rat brain extract which was prepared in the presence of protein phosphatase inhibitors. Developmental study indicated that serine 416 was strongly phosphorylated at early developmental stages in rat brain. We examined the localization of PS416-tau in primary cultured hippocampal neurons and the immortalized GnRH neurons (GT1-7 cells), which were stably transfected with CaM kinase IIalpha cDNA. Immunostaining of these cells indicated that tau was phosphorylated mainly in neuronal soma. Interestingly, tau in neuronal soma in Alzheimer's disease (AD) brain was strongly immunostained by the antibody. These results suggest that CaM kinase II is involved in the accumulation of tau in neuronal soma in AD brain.
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PMID:Phosphorylation of tau at serine 416 by Ca2+/calmodulin-dependent protein kinase II in neuronal soma in brain. 1600 Jan 44

We have previously described a Ca(2+)-permeable non-selective cation channel in freshly dispersed rabbit ear artery myocytes, which is activated by agents that deplete internal Ca(2+) stores and also by protein kinase C (PKC). In the present study, we investigated the effect of calmodulin (CaM) on store-operated channels (SOCs) with electrophysiological techniques. Bath application of the CaM inhibitor calmidazolium (CMZ) to quiescent cells produced transient activation of SOC activity in cell-attached patches. CMZ produced a dual effect on cyclopiazonic acid (CPA)-evoked SOCs by initially inducing an increase in mean open probability (NP(o)) and subsequently producing a marked inhibition of SOC activity. In contrast, SOCs activated by the cell-permeable Ca(2+) chelator 1,2-bis (2-aminophenoxy)ethane-N-N,N',N'-tetraacetic acid (BAPTA-AM) were inhibited by CMZ. In inside-out patches where SOCs were activated by CPA or the PKC activator phorbol-12,13-dibutyrate (PDBu), bath application of CaM induced an initial inhibition followed by an increase in SOC activity. In contrast, CaM only enhanced BAPTA-AM-evoked SOC activity in inside-out patches. Bath application of CaM to the cytoplasmic surface of quiescent inside-out patches evoked single channel currents with biophysical properties similar to SOCs. The inhibitory action of CaM on PDBu-induced SOC activity was inhibited by the calmodulin-dependent kinase II (CaM kinase II) inhibitor autocamtide-related inhibitory peptide (AIP) but not by inhibitors of calcineurin or myosin light chain kinase (MLCK). In addition, CaM-evoked channel currents were inhibited by coapplication of purified CaM kinase II but not by inhibitors of CaM kinase II, calcineurin or MLCK. With whole-cell and cell-attached recording, bath application of the CaM kinase II inhibitors KN93 and AIP evoked SOCs in unstimulated myocytes. These results indicate that CaM has pronounced dual inhibitory and excitatory actions on SOCs with the inhibitory effect of CaM mediated by CaM kinase II. Moreover, the present work provides strong evidence that CaM has an important role in activating SOCs, possibly through a direct action on channel/associated proteins.
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PMID:Dual effect of calmodulin on store-operated Ca2+ -permeable cation channels in rabbit portal vein myocytes. 1677 Mar 21

Insulin, in the permissive presence of nitric oxide (NO), stimulates cGMP production which inhibits autonomous calcium/calmodulin-dependent protein kinase II (CaM kinase II) thereby inhibiting cultured vascular smooth muscle cell (VSMC) migration. In the presence of angiotensin II (Ang II), insulin stimulates NAD(P)H oxidase activity leading to increased VSMC migration. We wished to see whether insulin-stimulated cGMP stimulates protein phosphatase-2A (PP-2A) thereby inhibiting autonomous CaM kinase II and migration, and whether insulin, in the presence of Ang II, inhibits PP-2A and stimulates autonomous CaM kinase II in a NAD(P)H oxidase-dependent manner. One nanomole per litre of insulin in the presence of NO, or 50 micromol/L 8-Br-cGMP stimulated PP-2A activity by 46+/-6 and 247+/-23%, respectively (both P<0.05), and 8-Br-cGMP inhibited autonomous CaM kinase II activity by 67+/-9% (P<0.05) by a 10 nmol/L okadaic acid-sensitive pathway. Insulin plus Ang II inhibited PP-2A activity by 57+/-7% (P<0.05) and stimulated autonomous CaM kinase II activity by 120+/-14% (P<0.05), both by an apocynin-sensitive pathway. 8-Br-cGMP-inhibited VSMC migration was blocked by okadaic acid. It is concluded that insulin in the presence of NO stimulates cGMP which stimulates PP-2A activity causing inhibition of autonomous CaM kinase II activity and thus VSMC migration, and that insulin in the presence of Ang II inhibits PP-2A and stimulates autonomous CaM kinase II activities by a NAD(P)H oxidase-dependent mechanism which are associated with insulin-stimulated NAD(P)H oxidase-dependent migration.
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PMID:Insulin-inhibited and stimulated cultured vascular smooth muscle cell migration are related to divergent effects on protein phosphatase-2A and autonomous calcium/calmodulin-dependent protein kinase II. 1755 5


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