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)

Glucose induces an increase in the intracellular Ca2+ concentration in pancreatic beta-cells to secrete insulin. CD38 occurs in beta-cells and has both ADP-ribosyl cyclase, which catalyzes the formation of cyclic ADP-ribose (cADPR) from NAD+, and cADPR hydrolase, which converts cADPR to ADP-ribose. ATP, produced by glucose metabolism, competes with cADPR for the binding site, Lys-129, of CD38, resulting in the inhibition of the hydrolysis of cADPR and thereby causing cADPR accumulation in beta-cells. Cyclic ADP-ribose then binds to FK506-binding protein 12.6 in the ryanodine receptor Ca2+ channel (RyR), dissociating the binding protein from RyR to induce the release of Ca2+ from the endoplasmic reticulum. Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) phosphorylates RyR to sensitize and activate the Ca2+ channel. Ca2+, released from the RyR, further activates CaM kinase II and amplifies the process. Thus, cADPR acts as a second messenger for Ca2+ mobilization to secrete insulin. The novel mechanism of insulin secretion described above is different from the conventional hypothesis in which Ca2+ influx from extracellular sources plays a role in insulin secretion by glucose.
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PMID:The CD38-cyclic ADP-ribose signaling system in insulin secretion. 1033 47

Glucose induces an increase in the intracellular Ca2+ concentration in pancreatic beta-cells to secrete insulin. CD38 exists in beta-cells and has both ADP-ribosyl cyclase, which catalyzes the formation of cyclic ADP-ribose (cADPR) from NAD+, and cADPR hydrolase, which converts cADPR to ADP-ribose. ATP, produced by glucose metabolism, competes with cADPR for the binding site, Lys-129, of CD38, resulting in the inhibition of the hydrolysis of cADPR and thereby causing cADPR accumulation in beta-cells. cADPR then binds to FK506-binding protein 12.6 (FKBP 12.6) in the islet type of the ryanodine receptor (RyR), dissociating the binding protein from RyR to induce the release of Ca2+ from the endoplasmic reticulum. Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) phosphorylates RyR to sensitize and activate the Ca2+ channel. Ca2+, released from the RyR, further activates CaM kinase II and amplifies this process. Thus, cADPR acts as a second messenger for Ca2+ mobilization to secrete insulin. The novel mechanism of insulin secretion described above is different from the conventional hypothesis in which Ca2+ influx from extracellular sources plays a role in insulin secretion by glucose. Furthermore, many physiological and pathological phenomena in various tissues and cells such as cardiac muscles, cerebellum, neuronal cells, pancreatic acinar cells, alveolar macrophages and immune B-cells become understandable in terms of "the CD38-cADPR signaling system" that sometimes acts in cooperation with other signal systems.
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PMID:["The CD38-cyclic ADP-ribose signal system": molecular mechanism and biological significance]. 1055 76

The relation between CaM kinase II activity and high Ca2+-mediated stress responses was studied in cultured vascular smooth muscle cells. Treatment with ionomycin (1 microM) for 5 min caused a significant loss of CaM kinase II activity in whole cell homegenates and prominent vesiculation of the endoplasmic reticulum (ER). Similar losses of CaM kinase II activity were observed in the soluble lysate as assessed by activity measurements and Western blotting. Examination of the post-lysate particulate fraction showed that the loss of CaM kinase II from the soluble lysate was accompanied by a redistribution of CaM kinase II to this fraction. The ionomycin-mediated response was limited to this concentration (1 microM); lower concentrations of ionomycin as well as stimulation with angiotensin II (1 microM) orATP (100 microM) did not cause a shift in CaM kinase II distribution. Treatment with neither the CaM kinase II inhibitor KN-93 nor the phosphatase inhibitor okadaic acid altered the ionomycin-induced redistribution indicating that CaM kinase II activation and/or phosphorylation was not part of the mechanism. The response, however, was eliminated when the cells were treated in Ca2+-free medium. Washout of ionomycin led to only a partial restoration of the kinase activity in the soluble fraction after 10 min. Immunofluorescence microscopy of resting cells indicated colocalization of antibodies to CaM kinase II and an ER protein marker. ER vesiculation induced by ionomycin coincided with a parallel redistribution of CaM kinase II and ER marker proteins. These data link ionomycin-induced ER restructuring to a progressive redistribution of CaM kinase II protein to an insoluble particulate fraction and loss of cellular CaM kinase II activity. We propose that redistribution of CaM kinase II and loss of cellular activity are components of a common Ca2+-overload induced cellular stress response in cells.
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PMID:Ca2+-induced redistribution of Ca2+/calmodulin-dependent protein kinase II associated with an endoplasmic reticulum stress response in vascular smooth muscle. 1112 62

Vascular smooth muscle cells (VSMC) express three isoforms of the sarcoplasmic or endoplasmic reticulum Ca2+-ATPase (SERCA) pump; SERCA2b predominates (91%), whereas SERCA2a (6%) and SERCA3 (3%) are present in much smaller amounts. Treatment with thapsigargin (Tg) or A-23187 increased the level of mRNA encoding SERCA2b four- to fivefold; SERCA3 increased about 10-fold, whereas SERCA2a was unchanged. Ca2+ chelation prevented the Tg-induced SERCA2b increase, whereas Ca2+ elevation itself increased SERCA2b expression. These responses were discordant with those of 78-kDa glucose-regulated protein/immunoglobulin-binding protein (grp78/BiP), an endoplasmic reticulum stress-response protein. SERCA2b mRNA elevation was much larger than could be accounted for by the observed increase in message stability. The induction of SERCA2b by Tg did not require protein synthesis, nor was it affected by inhibitors of calcineurin, protein kinase C, Ca2+/calmodulin-dependent protein kinase, or tyrosine protein kinases. Treatment with the nonselective protein kinase inhibitor H-7 prevented Tg-induced SERCA2b expression from occurring, whereas another nonselective inhibitor, staurosporine, was without effect. We conclude that changes in cytosolic Ca2+ control the expression of SERCA2b in VSMC via a mechanism involving a currently uncharacterized, H-7-sensitive but staurosporine-insensitive, protein kinase.
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PMID:Regulation of SERCA Ca2+ pump expression by cytoplasmic Ca2+ in vascular smooth muscle cells. 1124 1

The PSD-95 protein family organizes the glutamatergic postsynaptic density and it is involved in the regulation of the excitatory signal at central nervous system synapses. We show here that PSD-95 deficiency by means of antisense oligonucleotides induces significant neuronal cell death within 24 h both in primary hippocampal cultures and in organotypic hippocampal slices. On the other hand, cultured cortical neurons are spared by PSD-95 antisense toxicity until they reach a NR2A detectable protein level (24 days in vitro). The neurotoxic event is characterized by increased alpha CaMKII association to NR2 regulatory subunits of NMDA receptor complex. As a direct consequence of alpha CaMKII association, we found increased GluR1 delivery to cell surface in cultured hippocampal neurons paralleled by AMPA-dependent increase in [Na+]I levels. In addition, both CaMKII specific inhibitor KN-93 and AMPA receptor antagonists CNQX and NBQX rescued neuronal survival to control values. On the other hand, both the NMDA channel blocker MK-801 and Dantrolene, an inhibitor of calcium release from ryanodine-sensitive endoplasmic reticulum stores, failed to have any effect on neuronal survival in PSD-95 deficient neurons. Thus, our data provide clues that PSD-95 reduced expression in neurons is responsible for neuronal vulnerability mediated by direct activation of alpha CaMKII transduction pathway in the postsynaptic compartment.
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PMID:Lack of PSD-95 drives hippocampal neuronal cell death through activation of an alpha CaMKII transduction pathway. 1237 13

The sarcoplasmic reticulum (SR) plays a key role in excitation/contraction coupling of skeletal muscle. The SR is composed of two continuous yet heterogeneous membrane compartments, the free or longitudinal SR and cisternal SR. Cisternal SR is made up of free SR membrane, enriched in Ca(2+) pumps, and junctional SR (jSR) membrane, enriched in ryanodine-sensitive Ca(2+)-release channels, and contains calsequestrin within its lumen. Protein phosphorylation mediated by the Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II) has significant, distinct regulatory roles in both Ca(2+) uptake and Ca(2+) release. Kinase-anchoring proteins (KAPs) constitute a novel mechanism for achieving cell compartmentalization of effectors in phosphorylation pathways. Here, targeting of alpha KAP, a CaM kinase II-anchoring protein encoded within the alpha-CaM kinase II gene, was studied in transgenic skeletal muscle fibres of the adult rat soleus. The transgenes were epitope-tagged versions of alpha KAP and of a deletion mutant, allowing their specific immunodetection against the wild-type background. Our results show that alpha KAP is largely localized at the free SR and thus near the Ca(2+) pump, a protein that can be modulated by CaM kinase II phosphorylation. Only minor co-localization was observed with the jSR ryanodine-sensitive Ca(2+)-release channel, which is a potential CaM kinase II target. In non-muscle cells, recombinant alpha KAP is targeted to endoplasmic reticulum (ER). Both ER and SR targeting requires the N-terminal hydrophobic region of alpha KAP. An unexpected additional specific localization that does not require the N-terminus was found in the nucleus, providing a first clue of how CaM kinase II can fulfil its nuclear functions in skeletal muscle.
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PMID:Targeting of alpha-kinase-anchoring protein (alpha KAP) to sarcoplasmic reticulum and nuclei of skeletal muscle. 1247 Feb 97

Localized mRNAs are thought to be transported in defined particles to their final destination. These particles represent large protein complexes that may be involved in recognizing, transporting, and anchoring localized messages. Few components of these ribonucleoparticles, however, have been identified yet. We chose the strategy to biochemically enrich native RNA-protein complexes involved in RNA transport to identify the associated RNAs and proteins. Because Staufen proteins were implicated in intracellular RNA transport, we chose mammalian Staufen proteins as markers for the purification of RNA transport particles. Here, we present evidence that Staufen proteins exist in two different complexes: (i) distinct large, ribosome- and endoplasmic reticulum-containing granules preferentially found in the membrane pellets during differential centrifugation and (ii) smaller particles in the S100 from rat brain homogenates. On gel filtration of the S100, we identified soluble 670-kDa Staufen1-containing and 440-kDa Staufen2-containing particles. They do not cofractionate with ribosomes and endoplasmic reticulum but rather coenrich with kinesin heavy chain. Furthermore, the fractions containing the Staufen1 particles show a 15-fold enrichment of mRNAs compared with control fractions. Most importantly, these fractions are highly enriched in BC1, and, to a lesser extent, in the alpha-subunit of the Ca(2+)/calmodulin-dependent kinase II, two dendritically localized RNAs. Finally, both RNAs colocalize with Staufen1-hemagglutinin in particles in dendrites of transfected hippocampal neurons. We therefore propose that these Staufen1-containing particles may represent RNA transport intermediates that are in transit to their final destination within neurons.
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PMID:Isolation and characterization of Staufen-containing ribonucleoprotein particles from rat brain. 1257 67

The thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) ligands that promote increased insulin sensitivity in type II diabetic patients. In addition to their ability to improve glucose homeostasis, TZDs also exert anti-proliferative effects by a mechanism that is unclear. Our laboratory has shown that two TZDs, ciglitazone and troglitazone, rapidly induce calcium-dependent p38 mitogen-activated protein kinase (MAPK) phosphorylation in liver epithelial cells. Here, we further characterize the mechanism responsible for p38 MAPK activation by PPARgamma ligands and correlate this with the induction of endoplasmic reticulum (ER) stress. Specifically, we show that TZDs rapidly activate the ER stress-responsive pancreatic eukaryotic initiation factor 2alpha (eIF2alpha) kinase or PKR (double-stranded RNA-activated protein kinase)-like endoplasmic reticulum kinase/pancreatic eIF2alpha kinase, and that activation of these kinases is correlated with subsequent eIF2alpha phosphorylation. Interestingly, PPARgamma ligands not only activated calcium/calmodulin-dependent kinase II (CaMKII) 2-fold over control, but the selective CaMKII inhibitor, KN-93, attenuated MKK3/6 and p38 as well as PKR and eIF2alpha phosphorylation. Although CaMKII was not affected by inhibition of PKR with 2-aminopurine, phosphorylation of MKK3/6 and p38 as well as eIF2alpha were significantly reduced. Collectively, these data provide evidence that CaMKII is a regulator of PKR-dependent p38 and eIF2alpha phosphorylation in response to ER calcium depletion by TZDs. Furthermore, using structural derivatives of TZDs that lack PPARgamma ligand-binding activity as well as a PPARgamma antagonist, we show that activation of these kinase signaling pathways is PPARgamma-independent.
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PMID:Peroxisome proliferator-activated receptor gamma-independent activation of p38 MAPK by thiazolidinediones involves calcium/calmodulin-dependent protein kinase II and protein kinase R: correlation with endoplasmic reticulum stress. 1564 92

The effects of inhibitors of CaMKII on intracellular Ca2+ signaling were examined in single calf pulmonary artery endothelial (CPAE) cells using indo-1 microfluorometry to measure cytoplasmic Ca2+ concentration ([Ca2+]i). The three CaMKII inhibitors, KN-93, KN-62, and autocamtide-2-related inhibitory peptide (AIP), all reduced the plateau phase of the [Ca2+]i transient evoked by stimulation with extracellular ATP. Exposure to KN-93 or AIP alone in the presence of 2 mM extracellular Ca2+ resulted in a dose-dependent increase of [Ca2+]i consisting of a rapid and transient Ca2+ spike followed by a small sustained plateau phase of elevated [Ca2+]i. Exposure to KN-93 in the absence of extracellular Ca2+ caused a transient rise of [Ca2+]i, suggesting that exposure to CaMKII inhibitors directly triggered release of Ca2+ from intracellular endoplasmic reticulum (ER) Ca2+ stores. Repetitive stimulation with KN-93 and ATP, respectively, revealed that both components released Ca2+ largely from the same store. Pretreatment of CPAE cells with the membrane-permeable inositol 1,4,5-trisphosphate (IP3) receptor blocker 2-aminoethoxydiphenyl borate caused a significant inhibition of the KN-93-induced Ca2+ response, suggesting that exposure to KN-93 affects Ca2+ release from an IP3-sensitive store. Depletion of Ca2+ stores by exposure to ATP or to the ER Ca2+ pump inhibitor thapsigargin triggered robust capacitative Ca2+ entry (CCE) signals in CPAE cells that could be blocked effectively with KN-93. The data suggest that in CPAE cells, CaMKII modulates Ca2+ handling at different levels. The use of CaMKII inhibitors revealed that in CPAE cells, the most profound effects of CaMKII are inhibition of release of Ca2+ from intracellular stores and activation of CCE.
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PMID:Modulation of intracellular Ca2+ release and capacitative Ca2+ entry by CaMKII inhibitors in bovine vascular endothelial cells. 1609 79

A dramatic increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) occurs in eggs at fertilization common to all animal species examined to date, and this serves as a pivotal signal for egg activation characterized by resumption of meiotic cell division and formation of the pronuclei. In mammalian eggs, repetitive [Ca(2+)](i) rises (Ca(2+) oscillations) each of which accompanies a propagating wave across the egg occur due to release of Ca(2+) from the endoplasmic reticulum mainly through type 1 inositol 1,4,5-trisphosphate (IP(3)) receptor. Ca(2+) oscillations are induced by a cytosolic sperm factor driven into the egg cytoplasm upon sperm-egg fusion. A current strong candidate of the sperm factor is a novel sperm-specific isozyme of phospholipase C (IP(3)-producing enzyme), PLCzeta. Recent extensive research has reveled characteristics of PLCzeta such as the Ca(2+) oscillation-inducing activity after injection of PLCzeta-encoding RNA or recombinant PLCzeta into mouse eggs, extremely high Ca(2+)-sensitivity of the enzymatic activity in vitro, and nuclear translocation ability possibly related to cell-cycle-dependent regulation of Ca(2+) oscillations. [Ca(2+)](i) rises cause successive activation of calmodulin-dependent kinase II and E3 ubiquitin ligase, lead to proteolysis of ubiquitinated cyclin B1 and inactivation of metaphase-promoting factor (Cdk1/cyclin B1 complex), and result in the release of eggs from meiotic arrest.
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PMID:Calcium signals for egg activation in mammals. 1679 64


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