Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Phosphorylation of tau at serine 416 by Ca2+/calmodulin-dependent protein kinase II in neuronal soma in brain. 1600 Jan 44

Nigrostriatal dopamine depletion disrupts striatal medium spiny neuron morphology in Parkinson's disease and modulates striatal synaptic plasticity in animal models of parkinsonism. We demonstrate that long-term nigrostriatal dopamine depletion in the rat induces evolving changes in the phosphorylation of striatal proteins critical for synaptic plasticity. Dopamine depletion increased the phosphorylation of the alpha isoform of calcium-calmodulin-dependent protein kinase II (CaMKIIalpha) at Thr286, a site associated with enhanced autonomous kinase activity, but did not alter total levels of CaMKIIalpha or other synaptic proteins. Dopamine depletion decreased CaMKIIalpha levels in postsynaptic density-enriched fractions without significant changes in other proteins. The activity of protein phosphatase 1 (PP1), a postsynaptic phosphatase that dephosphorylates CaMKII, is regulated by DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa). Dopamine depletion had no effect on DARPP-32 phosphorylation at Thr34, but increased DARPP-32 phosphorylation at Thr75. Levodopa administration reversed the increased phosphorylation of both CaMKIIalpha and DARPP-32. Normal ageing increased the levels of PP1(gamma1 isoform) but decreased levels of the PP1gamma1-targeting proteins spinophilin and neurabin. Elevated phosphorylations of CaMKIIalpha and DARPP-32 were maintained for up to 20 months after dopamine depletion. However, phosphorylation of the CaMKII-PP1 substrate, Ser831 in the glutamate receptor GluR1 subunit, was increased only after sustained (9-20 months) dopamine depletion. Interaction of ageing-related changes in PP1 with the dopamine depletion-induced changes in CaMKIIalpha may account for enhanced GluR1 phosphorylation only after long-term dopamine depletion. These evolving changes may impact striatal synaptic plasticity, Parkinson's disease progression and the changing efficacy and side-effects associated with dopamine replacement therapy.
 ...
PMID:Dopamine depletion alters phosphorylation of striatal proteins in a model of Parkinsonism. 1602 14

Acute 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") treatment induces learning deficits in different animal models. In a passive avoidance learning task in rats, previous studies suggested a role for Ca2+/calmodulin-dependent protein kinase II (CaMKII) and N-methyl-D-aspartate (NMDA) receptors in the acute learning impairment. As cognitive deficits by "ecstasy" in humans have been only reported in frequent recreational users, we examined whether a repeated MDMA treatment could induce in rats lasting molecular changes related to memory consolidation of passive avoidance. In rats with a pronounced 5-HT depletion by MDMA, the effect of another drug challenge was also examined. The surface expression in the hippocampus of NMDA receptor subunits, the scaffolding postsynaptic density protein PSD-95, phosphorylated CaMKII and protein phosphatase 1 (PP1) was measured. In rats repeatedly treated with MDMA (10 mg/kg) twice daily for 4 consecutive days, hippocampal 5-HT levels were markedly reduced 1 week later. At this time, neither learning performance was affected nor changes in membrane levels of NMDA receptor subunits, PSD-95, CaMKII and PP1 were found. In these rats, however, another drug challenge produced a rapid reduction in PSD-95 immunoreactivity and prevented the learning-specific increase in the NMDA receptor NR1 subunit and phosphorylated CaMKII. The results show no lasting change in learning-associated molecular events after a neurotoxic MDMA treatment. This drug only produces transient effects on early molecular events involved in memory consolidation, which do not appear to depend on endogenous 5-HT levels.
 ...
PMID:Acute and chronic effects of MDMA on molecular mechanisms implicated in memory formation in rat hippocampus: surface expression of CaMKII and NMDA receptor subunits. 1615 87

Cerebellar parallel fiber (PF)-Purkinje cell (PC) synapses can undergo postsynaptically expressed long-term depression (LTD) or long-term potentiation (LTP). PF-LTD induction requires the coactivity of the PF and CF (climbing fiber) inputs to PCs and a concomitant calcium transient and activation of protein kinase C (PKC). PF-LTP can be induced by PF activity alone and requires a lower calcium transient for its induction than PF-LTD. The cellular events triggering PF-LTP induction are not well characterized. At other types of synapses (e.g., in the hippocampus), bidirectional synaptic plasticity is under control of a kinase/phosphatase switch, with PKC and CaMKII (calcium/calmodulin-dependent kinase II) activity promoting LTP induction and phosphatase activity promoting LTD induction. Here, we have tested for the involvement of protein phosphatase 1 (PP1), PP2A, and PP2B (calcineurin) in cerebellar LTP induction using whole-cell patch-clamp recordings in rat cerebellar slices. LTP induction was blocked in the presence of the PP1/2A inhibitors okadaic acid and microcystin LR, the PP1 inhibitory peptide inhibitor-2, the PP2A inhibitor fostriecin, and the PP2B inhibitor cyclosporin A. LTP induction was not impaired by the PKC inhibitor chelerythrine. Conversely, LTD induction was not blocked by microcystin LR but instead was reduced when active PP2B was injected into PCs. These data indicate that a kinase/phosphatase switch controls bidirectional cerebellar plasticity, but in a manner "inverse" to the dependencies found at other types of synapses. Therefore, cerebellar LTP constitutes the only form of LTP described so far that depends on phosphatase rather than kinase activity.
 ...
PMID:A role for protein phosphatases 1, 2A, and 2B in cerebellar long-term potentiation. 1629 50

The brains of fetal alcohol syndrome patients exhibit impaired neuronal migration, but little is known about the mechanisms underlying this abnormality. Here we show that Ca2+ signaling and cyclic nucleotide signaling are the central targets of alcohol action in neuronal cell migration. Acute administration of ethanol reduced the frequency of transient Ca2+ elevations in migrating neurons and cGMP levels and increased cAMP levels. Experimental manipulations of these second-messenger pathways, through stimulating Ca2+ and cGMP signaling or inhibiting cAMP signaling, completely reversed the action of ethanol on neuronal migration in vitro as well as in vivo. Each second messenger has multiple but distinct downstream targets, including Ca2+/calmodulin-dependent protein kinase II, calcineurin, protein phosphatase 1, Rho GTPase, mitogen-activated protein kinase, and phosphoinositide 3-kinase. These results demonstrate that the aberrant migration of immature neurons in the fetal brain caused by maternal alcohol consumption may be corrected by controlling the activity of these second-messenger pathways.
 ...
PMID:Reversal of neuronal migration in a mouse model of fetal alcohol syndrome by controlling second-messenger signalings. 1642 Dec 94

Maintenance of beta1 integrin-mediated cell adhesion in quiescent human mammary epithelial (HME) cells requires protein phosphatase (PP) 2A for not only dephosphorylation of beta1 integrin but also recruitment of IQGAP1 to Rac-bound beta1 integrin. However, how PP2A-dependent regulatory machinery of cell adhesion responds to EGF remains to be elucidated. We report here that phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) at threonine 286 was involved in the beta1 integrin complex that consisted of PP2A, Rac, and IQGAP1 in quiescent HME cells. Stimulation of the cells with EGF concomitantly induced an increase in intracellular Ca2+, activation of CaMKII, and dissociation of PP2A-IQGAP1-CaMKII from beta1 integrin-Rac. Because the activation of CaMKII and dissociation of PP2A-IQGAP1-CaMKII were blocked by either Ca2+-chelator or CaMKII inhibitor, we therefore propose that EGF has the ability to abrogate the PP2A function in the maintenance of beta1 integrin-mediated cell adhesion by dissociation of PP2A-IQGAP1-CaMKII from beta1 integrin-Rac through activation of CaMKII.
 ...
PMID:Regulation of protein phosphatase 2A-mediated recruitment of IQGAP1 to beta1 integrin by EGF through activation of Ca2+/calmodulin-dependent protein kinase II. 1655 30

AMPK (AMP-activated protein kinase) is activated allosterically by AMP and by phosphorylation of Thr172 within the catalytic alpha subunit. Here we show that mutations in the regulatory gamma subunit reduce allosteric activation of the kinase by AMP. In addition to its allosteric effect, AMP significantly reduces the dephosphorylation of Thr172 by PP (protein phosphatase)2Calpha. Moreover, a mutation in the gamma subunit almost completely abolishes the inhibitory effect of AMP on dephosphorylation. We were unable to detect any effect of AMP on Thr172 phosphorylation by either LKB1 or CaMKKbeta (Ca2+/calmodulin-dependent protein kinase kinase beta) using recombinant preparations of the proteins. However, using partially purified AMPK from rat liver, there was an apparent AMP-stimulation of Thr172 phosphorylation by LKB1, but this was blocked by the addition of NaF, a PP inhibitor. Western blotting of partially purified rat liver AMPK and LKB1 revealed the presence of PP2Calpha in the preparations. We suggest that previous studies reporting that AMP promotes phosphorylation of Thr172 were misinterpreted. A plausible explanation for this effect of AMP is inhibition of dephosphorylation by PP2Calpha, present in the preparations of the kinases used in the earlier studies. Taken together, our results demonstrate that AMP activates AMPK via two mechanisms: by direct allosteric activation and by protecting Thr172 from dephosphorylation. On the basis of our new findings, we propose a simple model for the regulation of AMPK in mammalian cells by LKB1 and CaMKKbeta. This model accounts for activation of AMPK by two distinct signals: a Ca2+-dependent pathway, mediated by CaMKKbeta and an AMP-dependent pathway, mediated by LKB1.
 ...
PMID:Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. 1714 17

We investigated the subcellular localization of glycogen synthase (GS) in the adductor muscle of anesthetized rabbits injected intravenously with propranolol. Under these experimental conditions, glycogen content was about 10 mmol/kg of fresh tissue. Immunofluorescent and fractionation studies showed that GS associated with sarcoplasmic reticulum (SR) membranes. Glycogen and GS always co-sedimented, suggesting a predominant role of glycogen in targeting of GS to SR. SR-associated GS was phosphorylated in vitro by SR-bound Ca2+-calmodulin dependent protein kinase (CaMKII) and dephosphorylated by endogenous protein phosphatase 1 (PP1c). Based on measurements of GS activity ratio, in vitro phosphorylation of GS by CaMKII did not significantly affect GS activity per se. However, GS activity ratio was slightly reduced, when SR membranes were further incubated with ATP after prior phosphorylation by CaMKII, suggesting that CaMKII might act sinergistically with other protein kinases. We propose that SR-bound CaMKII plays a role in regulation of glycogen metabolism in skeletal muscle, when intracellular Ca2+ is raised.
 ...
PMID:Glycogen synthase binds to sarcoplasmic reticulum and is phosphorylated by CaMKII in fast-twitch skeletal muscle. 1717 96

The alpha-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) is an ionotropic glutamate receptor that governs most of excitatory synaptic transmission in neurons. In vitro biochemical assay has shown that calpain, a Ca2+-activated protease, can cleave AMPAR GluR1 subunits. Our physiological study found that calpain, which was activated by prolonged stimulation of the N-methyl-D-aspartate receptor (100 microM, 10 min), caused a substantial suppression of AMPAR currents in cortical neurons. Since the phosphorylation sites of GluR1 by several protein kinases are located in close proximity to the calpain cleavage sites, we investigated the effect of phosphorylation on the susceptibility of GluR1 to calpain cleavage. Interestingly, we found that the calpain regulation of AMPAR currents was diminished by inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) but was augmented by inhibition of protein phosphatase 1/2A (PP1/2A). In agreement with this, in vitro assay showed that the calpain-induced proteolytic cleavage of GluR1 C-terminal fusion protein was strongly potentiated by adding the purified active CaMKII, and GluR1 phosphorylated at Ser831 by CaMKII is much more sensitive to calpain cleavage. Taken together, our data suggest that calpain activation suppresses AMPA receptor currents via proteolytic cleavage of GluR1 subunits, and the susceptibility of AMPARs to calpain cleavage is determined by the phosphorylation state of GluR1 subunits, which is mediated by CaMKII-PP1/2A activity.
 ...
PMID:The phosphorylation state of GluR1 subunits determines the susceptibility of AMPA receptors to calpain cleavage. 1742 97

There is growing concern about long-term neurodevelopmental outcomes after neonatal corticosteroid treatment for chronic lung disease (CLD). Here, we use a protocol with tapering doses of dexamethasone (DEX) or hydrocortisone (HC) proportional to those used in preterm infants to examine the long-term consequences of these treatments on hippocampal synaptic plasticity and associative memory in later life. We found that neonatal DEX, but not HC, treatment impairs long-term potentiation (LTP) but enhances long-term depression (LTD) induction in adolescent rats. The effects of neonatal DEX treatment on LTP and LTD were prevented when the animals were given glucocorticoid receptor antagonist, RU38486, before DEX administration. We also found that neonatal DEX, but not HC, treatment induces a profound increase in the autophosphorylation of a isoform of Ca2+/calmodulin-dependent protein kinase II at threonine-286 and a decrease in the protein phosphatase 1 expression. In addition, only neonatal DEX treatment disrupts memory retention in rats subjected to passive avoidance learning tasks. These results demonstrate that only neonatal DEX treatment alters the hippocampal synaptic plasticity and associative memory formation in later life and thus suggest that HC may be a safer alternative to DEX for the treatment of CLD in the neonatal period.
 ...
PMID:Effects of neonatal corticosteroid treatment on hippocampal synaptic function. 1762 55


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