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

Purified pig brain Ca(2+)-calmodulin (CaM)-dependent protein kinase Ia kinase (Lee, J. C., and Edelman, A. M. (1994) J. Biol. Chem. 269, 2158-2164) enhances, by up to 24-fold, the activity of recombinant CaM kinase IV in a reaction also requiring Ca(2+)-CaM and MgATP. The addition of brain extract, although capable of activating CaM kinase IV by itself, provides no further activation beyond that induced by purified CaM kinase Ia kinase, consistent with the lack of a requirement of additional components for activation. Activation is accompanied by the development of significant (38%) Ca(2+)-CaM-independent CaM kinase IV activity. In parallel fashion to its activation, CaM kinase IV is phosphorylated in a CaM kinase Ia kinase-, Ca(2+)-CaM-, and MgATP-dependent manner. Phosphorylation occurs on multiple serine and threonine residues with a Ser-P:Thr-P ratio of approximately 3:1. The identical requirements for phosphorylation and activation and a linear relationship between extent of phosphorylation of CaM kinase IV and its activation state indicate that CaM kinase IV activation is induced by its phosphorylation. Replacement of Thr-196 of CaM kinase IV with a nonphosphorylatable alanine by site-directed mutagenesis abolishes both the phosphorylation and activation of CaM kinase IV, demonstrating that Thr-196 phosphorylation is essential for activation.
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PMID:Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation. 761 69

Endogenous calcium-activated proteases, the calpains, are thought to play a role in the regulation of postsynaptic function. Here we characterize some biochemical and morphological effects of calpain on isolated postsynaptic densities (PSDs). When a PSD preparation from rat forebrain was treated with exogenous calpain, many proteins, including spectrin, tubulin and the alpha-subunit of calcium calmodulin-dependent protein kinase (alpha-CaM kinase), were proteolyzed at varying rates, while another major protein, actin, remained intact. The selectivity of calpain action became more apparent in experiments designed to achieve limited proteolysis by using a lower calpain-to-protein ratio; it was possible to obtain extensive breakdown of spectrin with no decrease in the levels of either tubulin, alpha-CaM kinase, or actin. Electron microscopy of freeze-substituted preparations showed that limited calpain action caused a partial unraveling of the PSD, in which the characteristic central dense lamina became wider and less dense. We interpret these changes as due to calpain-mediated breakdown of cross-bridging elements, leading to a partial unraveling of the central PSD lamina. Opening up of the PSD structure following limited calpain action could facilitate exposure of previously occluded functional sites within the PSD and contribute to the modification of the synaptic function.
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PMID:Effect of calpain on the composition and structure of postsynaptic densities. 762 34

Glucocorticoid hormones (GC) have profound effects on the development and homeostasis of the immune system. In this communication we present evidence that GC regulate Ca(2+)-mediated pathways of T cell activation by a mechanism that involves abrogation of the autophosphorylation of the multifunctional Ca2+/calmodulin kinase (CaM kinase II) and induction of protein phosphatase activity. Primary human T cells were stimulated with the combination of ionomycin and phorbol ester in the presence or absence of dexamethasone (Dex) (10(-6)-10(-12) M). Stimulation of T cells resulted in a rapid activation of CaM kinase II and protein kinase C (PKC) activity as determined by the phosphorylation of synthetic peptide substrates recognized by these enzymes. Dex inhibited the activity of CaM kinase II but not PKC activity in a dose-dependent fashion (minimum effective dose 10(-10) M). Stimulation of 32P-labeled T cells induced a rapid increase in the phosphorylation level of CaM kinase II which was inhibited by Dex. The inhibitory effect of Dex on this enzyme was fully reversed in the presence of the phosphatase inhibitor okadaic acid (250 nM) or RU 486, a glucocorticoid antagonist. These results suggest that GC inhibit the activation of CaM kinase during T cell activation through a mechanism that involves both the GC receptor and protein phosphatases 2A and/or 1. Inhibition of protein phosphorylation through the induction of protein phosphatase activity may represent a novel mechanism for the diverse effects of GC on eukaryotic cells.
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PMID:Glucocorticoid-mediated regulation of protein phosphorylation in primary human T cells. Evidence for induction of phosphatase activity. 763 35

Human Ca(2+)-calmodulin (CaM) dependent protein kinase I (CaMKI) encodes a 370 amino acid protein with a calculated M(r) of 41,337. The 1.5 kb CaMKI mRNA is expressed in many different human tissues and is the product of a single gene located on human chromosome 3. CaMKI 1-306, was unable to bind Ca(2+)-CaM and was completely inactive thereby defining an essential component of the CaM-binding domain to residues C-terminal to 306. CaMKI 1-294 did not bind CaM but was fully active in the absence of Ca(2+)-CaM, indicating that residues 295-306 are sufficient to maintain CaMKI in an auto-inhibited state. CaMKI was phosphorylated on Thr177 and its activity enhanced approximately 25-fold by CaMKI kinase in a Ca(2+)-CaM dependent manner. Replacement of Thr177 with Ala or Asp prevented both phosphorylation and activation by CaMKI kinase and the latter replacement also led to partial activation in the absence of CaMKI kinase. Whereas CaMKI 1-306 was unresponsive to CaMKI kinase, the 1-294 mutant was phosphorylated and activated by CaMKI kinase in both the presence and absence of Ca(2+)-CaM although at a faster rate in its presence. These results indicate that the auto-inhibitory domain in CaMKI gates, in a Ca(2+)-CaM dependent fashion, accessibility of both substrates to the substrate binding cleft and CaMKI kinase to Thr177. Additionally, CaMKI kinase responds directly to Ca(2+)-CaM with increased activity.
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PMID:Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase. 764 87

CA2+-regulated protein kinases play critical roles in long-term potentiation (LTP). To understand the role of Ca2+/calmodulin (CaM) signaling pathways in synaptic transmission better, Ca2+/CaM was injected into hippocampal CA1 neurons. Ca2+/CaM induced significant potentiation of excitatory synaptic responses, which was blocked by coinjection of a CaM-binding peptide and was not induced by injections of Ca2+ or CaM alone. Reciprocal experiments demonstrated that Ca2+/CaM-induced synaptic potentiation and tetanus-induced LTP occluded one another. Pseudosubstrate inhibitors or high-affinity substrates of CaMKII or PKC blocked Ca2/CaM-induced potentiation, indicating the requirement of CaMKII and PKC activities in synaptic potentiation. We suggest that postsynaptic levels of free Ca2+/CaM is a rate limiting factor and that functional cross-talk between Ca2+/CaM and PKC pathways occurs during the induction of LTP.
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PMID:Postsynaptic injection of CA2+/CaM induces synaptic potentiation requiring CaMKII and PKC activity. 764 96

Neuronal activity is required for normal neural development. Excessive activity can cause abnormal growth of neural processes and may contribute to formation of epileptic foci. Using PC12 cells, we investigated mechanisms by which depolarization regulates neurite growth. Depolarization with 45 mM KCl induced neurite outgrowth only if NGF receptors were partly activated by overexpression of p140trkA or by treatment with a low concentration of NGF that alone was insufficient to stimulate neurite formation. Depolarization-induced neurite growth was reduced by inhibitors of L-type Ca2+ channels, Ca2+/calmodulin-dependent protein (CaM) kinases II and IV, and transcription. These results identify a novel mechanism by which depolarizing stimuli synergize with subthreshold activation of NGF receptors to induce neurite growth through a Ca2+ and CaM kinase-dependent signal transduction pathway.
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PMID:Depolarization-induced neurite outgrowth in PC12 cells requires permissive, low level NGF receptor stimulation and activation of calcium/calmodulin-dependent protein kinase. 766 81

KN-62, an inhibitor of CaM kinase II, attenuated phase shifts induced by low intensity light pulses and reduced light-induced phosphorylation of the transcription factor, CREB, in the suprachiasmatic nucleus. The calmodulin inhibitor, W-7, had similar effects: neither drug produced a complete block of photic responses. The results support the hypothesis that circadian responses to light are mediated in part by CaM kinase activity and CREB, and suggest that other signal transduction pathways also take part.
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PMID:Circadian responses to light: the calmodulin connection. 767 13

Inorganic lead inhibits neurite initiation in cultured rat hippocampal neurons at concentrations as low as 100 nM. Conflicting reports suggest that Pb2+ may stimulate or inhibit protein kinase C, adenylyl cyclase, phosphodiesterase, and calmodulin, or increase intracellular free Ca2+ concentrations. Therefore, Pb2+ may alter the activities of Ca2+/calmodulin-dependent protein kinase (CaM kinase) or protein kinases C or A. We cultured rat hippocampal neurons in 100 nM PbCI2 alone or in combination with kinase or calmodulin inhibitors. Inhibiting protein kinase C with calphostin C exacerbated the inhibition of neurite initiation caused by PbCI2, but inhibiting protein kinase A with KT5720, CaM kinase with KN62, or calmodulin with calmidazolium completely reversed the effects of PbCI2. These results indicate that Pb2+ may inhibit neurite initiation by inappropriately stimulating protein phosphorylation by CaM kinase or cyclic AMP-dependent protein kinase (PKA), possibly by stimulating calmodulin. This hypothesis is supported by findings that other treatments that should increase protein phosphorylation (okadaic acid, a protein phosphatase inhibitor, and Sp-cAMPS, a PKA activator) also reduced neurite initiation. Whole-cell intracellular free Ca2+ ion concentrations were not significantly altered by 100 nM PbCI2 at 4, 12, 24, or 48 hr. Therefore, the hypothesized stimulatory effects of Pb2+ exposure on calmodulin, CaM kinase, or PKA are probably not caused by increases in whole-cell intracellular free Ca2+, but may be attributable either to intracellular Pb2+ or to localized increases in [Ca2+]in that are not reflected in whole-cell measurements.
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PMID:Inorganic lead may inhibit neurite development in cultured rat hippocampal neurons through hyperphosphorylation. 767 45

The alpha-Ca2+/calmodulin kinase II (alpha CaMKII) is required for long-term potentiation in the CA1 region of the hippocampus. Here, we report that this kinase also has a crucial role in presynaptic plasticity. Paired-pulse facilitation is blunted in the CA1 region of mice heterozygous for a targeted mutation of alpha CaMKII, confirming that this kinase can promote neurotransmitter release. Unexpectedly, field and whole-cell recordings of posttetanic potentiation show that the synaptic responses of mutants are larger than those of controls, indicating that alpha CaMKII can also inhibit transmitter release immediately after tetanic stimulation. Thus, alpha CaMKII has the capacity either to potentiate or to depress excitatory synaptic transmission depending on the pattern of presynaptic activation.
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PMID:The alpha-Ca2+/calmodulin kinase II: a bidirectional modulator of presynaptic plasticity. 769 5

The effects of cerebral ischemia on calcium/calmodulin-dependent kinase II (CaM kinase II) were investigated using the rat four-vessel occlusion model. In agreement with previous results using rat or gerbil models of cerebral ischemia or a rabbit model of spinal cord ischemia, this report demonstrates that transient forebrain ischemia leads to a reduction in CaM kinase II activity within 5 min of occlusion onset. Loss of activity from the cytosol fractions of homogenates from the neocortex, striatum, and hippocampus correlated with a decrease in the amount of CaM kinase alpha and beta isoforms detected by immunoblotting. In contrast, there was an apparent increase in the amount of CaM kinase alpha and beta in the particulate fractions. The decrease in the amount of CaM kinase isoforms from the cytosol but not the particulate fractions was confirmed by autophosphorylation of CaM kinase II after denaturation and renaturation in situ of the blotted proteins. These results indicate that ischemia causes a rapid inhibition of CaM kinase II activity and a change in the partitioning of the enzyme between the cytosol and particulate fractions. CaM kinase II is a multifunctional protein kinase, and the loss of activity may play a critical role in initiating the changes leading to ischemia-induced cell death. To identify a structural basis for the decrease in enzyme activity, tryptic peptide maps of CaM kinase II phosphorylated in vitro were compared. Phosphopeptide maps of CaM kinase alpha from particulate fractions of control and ischemic samples revealed not only reduced incorporation of phosphate into the protein but also the absence of a limited number of peptides in the ischemic samples. This suggested that certain sites are inaccessible, possibly due to a conformational change, a covalent modification of CaM kinase II, or steric hindrance by an associated molecule. Verifying one of these possibilities should help to elucidate the mechanism of ischemia-induced modulation of CaM kinase II.
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PMID:Effect of cerebral ischemia on calcium/calmodulin-dependent protein kinase II activity and phosphorylation. 771 3


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