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)

Transient cerebral ischemia induces, besides delayed neurodegeneration in selected brain structures, a number of early responses which may mediate ischemic injury/repair processes. Here we report that 5 min exposure to cerebral ischemia in gerbils induces a rapid inhibition and subsequent translocation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). These changes were partially reversible during a 24 h post-ischemic recovery. Concomitantly the total amount of the enzyme protein, as revealed by Western blotting (alpha-subunit specific), remained stable. This is consistent with our previous hypothesis, that the mechanism of ischemic CaMKII down-regulation involves a reversible posttranslational modification-(auto)phosphorylation, rather than the degradation of enzyme protein. The effectiveness of known modulators of post-ischemic outcome in counteracting CaMKII inhibition was tested. Three of these drugs, namely dizocilpine (MK-801), N-nitro-L-arginine methyl ester (L-NAME) and ginkgolide (BN52021), all significantly attenuated the enzyme response to ischemia, whereas an obvious diversity in the time-course of their actions implicates different mechanisms involved.
 ...
PMID:Changes of Ca2+/calmodulin-dependent protein kinase-II after transient ischemia in gerbil hippocampus. 878 2

During transient cerebral ischemia, intracellular calcium increases initiating a cascade of events which leads to the delayed death of neurons located in the hippocampus. Coupled to this calcium disturbance is the rapid decrease of calcium/calmodulin kinase II (CaM kinase) activity, a protein kinase critical to neuronal functioning. The present study correlated the increased locomotor activity following ischemic insult with alterations in CaM kinase mRNA levels and immunocytochemical labeling of alpha and beta CaM kinase subunits in the hippocampus. The protective effect of hypothermia was also compared with CaM kinase mRNA levels and immunoreactivity. Levels of CaM kinase message for either alpha or beta subunits was not altered in ischemic gerbils compared to sham or hypothermic ischemic conditions. Immunoreactivity for both the alpha and beta subunits was markedly reduced in the vulnerable CA1 region of ischemic animals compared to sham controls. Gerbils that underwent the ischemic insult while hypothermic showed no decrement in staining. CaM kinase-like immunoreactivity in the ischemia-resistant CA3 sector was not altered following ischemia. These data suggest that the loss of hippocampal CaM kinase immunoreactivity observed at 24 h following ischemia is not associated with a reduction in CaM kinase mRNA levels and support the notion that the rapid decline in CaM kinase activity following ischemic insult is a result of a posttranslational modification and/or translocation of the enzyme.
 ...
PMID:Transient cerebral ischemia decreases calcium/calmodulin-dependent protein kinase II immunoreactivity, but not mRNA levels in the gerbil hippocampus. 882 62

We studied N-methyl-D-aspartate (NMDA) receptor-mediated synaptic potentials in CA1 pyramidal neurons using hippocampal slices of gerbils after transient forebrain ischemia. In the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and bicuculline, stimulation of Schaffer collateral/commissural fibers induced field excitatory postsynaptic potentials (fEPSP) activated by NMDA receptors. We found that in many slices after ischemia, prolonged low-frequency stimulation (0.1-10 Hz) caused repeated depression and potentiation of the NMDA-mediated fEPSP. Changes in fEPSP amplitude were dependent on stimulus frequency and the cycle frequency ranged from 0.08 to 2.5 cycles/min. These cyclic changes were blocked by application of BAPTA-AM, a membrane-permeable Ca2+ chelator, but were little affected by application of verapamil or by lowering the Ca2+ in bathing solution. Intracellular recordings from CA1 neurons revealed that low-frequency stimulation caused periodic depolarizations of membrane potential accompanied by depression of the excitatory postsynaptic potentials. The cyclic changes of fEPSPs were blocked by inhibitors of protein kinase C (PKC) but were unaffected by inhibitors of Ca2+/calmodulin-dependent protein kinase II (CaMKII) or myosin light-chain kinase (MLCK). These results suggest that stimulus-dependent NMDA-receptor activation, mediated by PKC, takes place in the postischemic CA1 neurons and that the cyclic change may reflect abnormal intracellular Ca2+ signaling processes leading to neuronal degeneration.
 ...
PMID:Cyclic changes in NMDA receptor activation in hippocampal CA1 neurons after ischemia. 952 18

The regional selectivity and mechanisms underlying the toxicity of the serine/threonine protein phosphatase inhibitor okadaic acid (OA) were investigated in hippocampal slice cultures. Image analysis of propidium iodide-labeled cultures revealed that okadaic acid caused a dose- and time-dependent injury to hippocampal neurons. Pyramidal cells in the CA3 region and granule cells in the dentate gyrus were much more sensitive to okadaic acid than the pyramidal cells in the CA1 region. Electron microscopy revealed ultrastructural changes in the pyramidal cells that were not consistent with an apoptotic process. Treatment with okadaic acid led to a rapid and sustained tyrosine phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2 (p44/42(mapk)). The phosphorylation was markedly reduced after treatment of the cultures with the microbial alkaloid K-252a (a nonselective protein kinase inhibitor) or the MAP kinase kinase (MEK1/2) inhibitor PD98059. K-252a and PD98059 also ameliorated the okadaic acid-induced cell death. Inhibitors of protein kinase C, Ca2+/calmodulin-dependent protein kinase II, or tyrosine kinase were ineffective. These results indicate that sustained activation of the MAP kinase pathway, as seen after e.g., ischemia, may selectively harm specific subsets of neurons. The susceptibility to MAP kinase activation of the CA3 pyramidal cells and dentate granule cells may provide insight into the observed relationship between cerebral ischemia and dementia in Alzheimer's disease.
 ...
PMID:Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures: evidence for a MAP kinase-dependent mechanism. 973 50

To examine the effects of ischemic preconditioning on ischemia-reperfusion-induced changes in the sarcoplasmic reticulum (SR) function, isolated rat hearts were either perfused with a control medium for 30 min or preconditioned with three episodes of 5-min ischemia and 5-min reperfusion before sustained ischemia for 30 min followed by reperfusion for 30 min was induced. Preconditioning itself depressed cardiac function (left ventricular developed pressure, peak rate of contraction, and peak rate of relaxation) and SR Ca2+-release and -uptake activities as well as protein content and Ca2+/calmodulin-dependent protein kinase (CaMK) phosphorylation of Ca2+-release channels by 25-60%. Global ischemia for 30 min produced marked depressions in SR Ca2+-release and -uptake activities as well as SR Ca2+-pump protein content in control hearts; these changes were significantly attenuated by preconditioning. Compared with the control preparations, preconditioning improved the recovery of cardiac function and SR Ca2+-release and -uptake activities as well as Ca2+-release channel and Ca2+-pump protein contents in the ischemic-reperfused hearts. Unlike the protein kinase A-mediated phosphorylation in SR membranes, the CaMK-mediated phosphorylations at Ca2+-release channels, Ca2+ pump, and phospholamban were depressed in the ischemic hearts; these changes were prevented by preconditioning. These results indicate that ischemic preconditioning may exert beneficial effects on ischemia-reperfusion-induced alterations in SR function by preventing changes in Ca2+-release channel and Ca2+-pump protein contents in the SR membrane.
 ...
PMID:Modification of ischemia-reperfusion-induced changes in cardiac sarcoplasmic reticulum by preconditioning. 984 29

This article describes the pathophysiology of, and treatment strategy for, cerebral ischemia. It is useful to think of an ischemic lesion as a densely ischemic core surrounded by better perfused "penumbra" tissue that is silent electrically but remains viable. Reperfusion plays an important role in the pathophysiology of cerebral ischemia. Magnetic resonance imaging (MRI) and histological studies in rat focal ischemia models using transient middle cerebral artery (MCA) occlusion indicate that reperfusion after an ischemic episode of 2- to 3-hour duration does not result in reduction of the size of the infarct. Brief occlusion of the MCA produces a characteristic, cell-type specific injury in the striatum where medium-sized spinous projection neurons are selectively lost; this injury is accompanied by gliosis. Transient forebrain ischemia leads to delayed death of the CA1 neurons in the hippocampus. Immunohistochemical and biochemical investigations of Ca2+/calmodulin-dependent protein kinase II(CaM kinase II) and protein phosphatase (calcineurin) after transient forebrain ischemia demonstrated that the activity of CaM kinase II was decreased in the CA1 region of the hippocampus early (6-12 hours) after ischemia. However, calcineurin was preserved in the CA1 region until 1.5 days after the ischemic insult and then lost; a subsequent increase in the morphological degeneration of neurons was observed. We hypothesized that an imbalance of Ca2+/calmodulin dependent protein phosphorylation-dephosphorylation may be involved in delayed neuronal death after ischemia. In the treatment of acute ischemic stroke, immediate recanalization of the occluded artery, using systemic or local thrombolysis, is optimal for restoring the blood flow and rescuing the ischemic brain from complete infarction. However, the window of therapeutic effectiveness is very narrow. The development of effective neuroprotection methods and the establishment of reliable imaging modalities for an early and accurate diagnosis of the extent and degree of the ischemia are imperative.
 ...
PMID:Pathophysiology and treatment of cerebral ischemia. 986 65

Considering that postsynaptic densities (PSD) are a functionally active zone involved in excitatory synaptic transmission we evaluated the influence of global, postdecapitative cerebral ischemia of 15 min duration on characteristic protein constituents of PSD in rats. Ischemia induced changes in the assembly and function of calcium, calmodulin-dependent kinase II (CaMKII), calpains and a novel, 85 kDa/RING3 kinase but to different extents. CaMKII is translocated toward the PSD very rapidly and extensively after the first seconds of ischemia. Concomitantly, the total phosphorylating potency of this kinase with endogenous, as well as exogenous, substrates was elevated but to a lower extent than suggested by the increased protein content. Of the two brain-specific isoforms of calpain (mu and m), only recently recognized in PSD, the proteolytically activated, 76 kDa subunit of mu-calpain was significantly down-regulated after 15 min of brain ischemia. However, this effect is coupled with the decline of fodrin, the only calpain substrate that has been demonstrated to be a calpain target in vivo. Together, these findings may suggest that calpains, primarily activated by calcium in ischemic PSD, are subsequently degraded. A new observation is the relatively high phosphorylating activity of a novel, 85 kDa/RING3 kinase in the PSD which independently of other kinase systems, was greatly enhanced after ischemia. These data provide evidence that the signal transduction processes could be rapidly altered by short-term (15 min) brain ischemia due to changes in the assembly and function of PSD connected proteins.
 ...
PMID:Ischemia-induced modifications of protein components of rat brain postsynaptic densities. 1037 19

Although the sarcoplasmic reticulum (SR) is known to regulate the intracellular concentration of Ca2+ and the SR function has been shown to become abnormal during ischemia-reperfusion in the heart, the mechanisms for this defect are not fully understood. Because phosphorylation of SR proteins plays a crucial role in the regulation of SR function, we investigated the status of endogenous Ca2+/calmodulin-dependent protein kinase (CaMK) and exogenous cAMP-dependent protein kinase (PKA) phosphorylation of the SR proteins in control, ischemic (I), and ischemia-reperfused (I/R) hearts treated or not treated with superoxide dismutase (SOD) plus catalase (CAT). SR and cytosolic fractions were isolated from control, I, and I/R hearts treated or not treated with SOD plus CAT, and the SR protein phosphorylation by CaMK and PKA, the CaMK- and PKA-stimulated Ca2+ uptake, and the CaMK, PKA, and phosphatase activities were studied. The SR CaMK and CaMK-stimulated Ca2+ uptake activities, as well as CaMK phosphorylation of Ca2+ pump ATPase (SERCA2a) and phospholamban (PLB), were significantly decreased in both I and I/R hearts. The PKA phosphorylation of PLB and PKA-stimulated Ca2+ uptake were reduced significantly in the I/R hearts only. Cytosolic CaMK and PKA activities were unaltered, whereas SR phosphatase activity in the I and I/R hearts was depressed. SOD plus CAT treatment prevented the observed alterations in SR CaMK and phosphatase activities, CaMK and PKA phosphorylations, and CaMK- and PKA-stimulated Ca2+ uptake. These results indicate that depressed CaMK phosphorylation and CaMK-stimulated Ca2+ uptake in I/R hearts may be due to a depression in the SR CaMK activity. Furthermore, prevention of the I/R-induced alterations in SR protein phosphorylation by SOD plus CAT treatment is consistent with the role of oxidative stress during ischemia-reperfusion injury in the heart.
 ...
PMID:Status of Ca2+/calmodulin protein kinase phosphorylation of cardiac SR proteins in ischemia-reperfusion. 1048 25

Brief ischemic episode, which in itself is not lethal, confers tolerance to subsequent ischemic insults. Since intracellular signal transduction system has been implicated in ischemic cell death, we studied the effect of pre-conditioning on the changes in the subcellular distribution of protein kinase Cgamma (PKCgamma) as well as CaM kinase II (CaMKII). Gerbils were pre-conditioned by a sublethal 2 min cerebral ischemia 24 h prior to lethal 5 min ischemia. The pre-conditioning generally downregulated PKCgamma and CaMKII in the CA1 hippocampus. Especially at the starting point of the second lethal ischemia, the cytosolic PKCgamma level was about 40% lower in the pre-conditioned group. Also, the crude synaptosomal CaMKII level at 24 h reperfusion following the second ischemia was significantly lower in the pre-conditioned group, showing enhanced recovery of CaMKII translocation. Present results suggest that ischemic pre-conditioning may downregulate calcium-mediated cell signaling system, enhancing normalization of calcium homeostasis, perturbed by the second ischemia of lethal duration.
 ...
PMID:Ischemic pre-conditioning affects the subcellular distribution of protein kinase C and calcium/calmodulin-dependent protein kinase II in the gerbil hippocampal CA1 neurons. 1168 May 16

Sarcoplasmic reticulum (SR) dysfunction is one of the multiple alterations that occurs in ischemia-reperfused hearts. Because SR function is regulated by phosphorylation of phospholamban (PLB), a SR protein phosphorylated by cAMP-dependent protein kinase (PKA) at Ser(16)and Ca(2+)-calmodulin-dependent protein kinase (CaMKII) at Thr(17), the phosphorylation of these residues during ischemia and reperfusion was examined in Langendorff-perfused rat hearts. Ser(16)phosphorylation increased significantly after 20 min of ischemia from 2.5+/-0.6% to 99.8+/-25.5% of maximal isoproterenol-induced site-specific phosphorylation and decreased to control values immediately after reperfusion. Thr(17)phosphorylation transiently increased at 2-5 min of ischemia and at 1 min of reperfusion (R1, 166.2+/-28.2%). The ischemia-induced increase in Ser(16)phosphorylation was significantly diminished in hearts from catecholamine-depleted animals and/or after beta-blockade and abolished in the presence of the PKA-inhibitor, H-89. Thr(17)phosphorylation at the beginning of ischemia was blunted by nifedipine, whereas at R1 it was significantly diminished by perfusion with 0 m m Ca(2+)in the presence of EGTA and by the Na(+)/Ca(2+)exchanger inhibitor KB-R7943. KN-93, used to specifically inhibit CaMKII, decreased Thr(17)phosphorylation at R1 and significantly prolonged half relaxation time. The results demonstrated a dissociation between the phosphorylation of PLB sites, being phosphorylation of Ser(16)dependent on the beta-adrenergic cascade during ischemia and phosphorylation of Thr(17)on Ca(2+)influx both, at the beginning of ischemia and reperfusion. Phosphorylation of Thr(17)at the onset of reflow may provide the cell a mechanism to cope with Ca(2+)overload, transiently favoring the recovery of relaxation during early reperfusion.
 ...
PMID:Time course and mechanisms of phosphorylation of phospholamban residues in ischemia-reperfused rat hearts. Dissociation of phospholamban phosphorylation pathways. 1181 63


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