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)

Phosphorylation-dependent events have been shown to modulate the activity of several members of the mammalian CLC Cl- channel gene family, including the inward rectifier ClC-2. In the present study we investigated the regulation of rat ClC-2 expressed in the TSA-201 cell line (a transformed HEK293 cell line that stably expresses the SV40 T-antigen) by protein kinases. Protein kinase A activation phosphorylated ClC-2 in vivo, whereas stimulation of protein kinase C with phorbol 12-myristate 13-acetate did not. In vitro labeling studies confirmed that protein kinase A could directly phosphorylate ClC-2, and that protein kinase C and Ca2+/calmodulin-dependent protein kinase II did not. Nevertheless, protein kinase A-dependent phosphorylation of CLC-2 failed to regulate either the magnitude or the kinetics of the hyperpolarization-activated Cl- currents. Considered together, we demonstrate that protein kinase A activation results in the phosphorylation of rat ClC-2 in vivo, but this event is independent of Cl- channel activity.
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PMID:Protein kinase A activation phosphorylates the rat ClC-2 Cl- channel but does not change activity. 1142 97

Protein targeting is increasingly being recognized as a mechanism to ensure speed and specificity of intracellular signal transduction in a variety of biological systems. Conceptually, this is of particular importance for second-messenger-regulated protein kinases with a broad spectrum of substrates, such as the serine/threonine protein kinases PKA, PKC, and CaMKII (cyclic-AMP-dependent protein kinase, Ca(2+)-phospholipid-dependent protein kinase, and Ca(2+)/calmodulin-dependent protein kinase II). The activating second messengers of these enzymes can be produced or released in response to a large variety of "upstream" signals, and they can, in turn, regulate a large variety of "downstream" proteins. Targeting, e.g., via anchoring proteins, can link certain incoming stimuli with specific outgoing signals by restricting the subcellular compartment at which activation and/or action of a signaling molecule can take place. Elegant research on PKA and PKC reinforced the biological importance of such mechanisms. We will focus here on CaMKII, as recent advances in the understanding of its targeting have some significant general implications for signal transduction. The interaction of CaMKII with the NMDA receptor, for instance, shows that a targeting protein can not only specify the subcellular localization of a signaling effector, but can also directly influence its regulation.
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PMID:Regulation of signal transduction by protein targeting: the case for CaMKII. 1174 Dec 77

Skin wound healing requires epithelial cell migration for re-epithelialization, wound closure, and re-establishment of normal function. We believe that one of the earliest signals to initiate wound healing is the lateral electric field generated by the wound current. Normal human epidermal keratinocytes migrate towards the negative pole, representing the center of the wound, in direct currents of a physiological strength, 100 mV/mm. Virtually nothing is known about the signal transduction mechanisms used by these cells to sense the endogenous electric field. To elucidate possible protein kinase (PK) involvement in the process, PK inhibitors were utilized. Two important findings have been described. Firstly, addition of 50 nM KT5720, an inhibitor of PKA, resulted in a 53% percent reduction in the directional response of keratinocytes in the electric field, while not significantly affecting general cell motility. The reduction was dose-dependent, there was a gradual decrease in the directional response from 5 to 50 nM. Secondly, addition of 1 microM ML-7, a myosin light chain kinase inhibitor, resulted in an approximate 31% decrease in the distance the cells migrated without affecting directional migration. The PKC inhibitors GF109203X at 4 microM and H-7 at 20 microM and W-7, a CaM kinase inhibitor, did not significantly alter either directed migration or cell migration, although they all resulted in a slight reduction in directional migration. D-erythro-sphingosine at 15 microM, a PKC inhibitor, had virtually no effect on either migration distance or directed migration. These findings demonstrate that divergent kinase signaling pathways regulate general cell motility and sustained directional migration and highlight the complexity of the signal transduction mechanisms involved. The inhibitor studies described in this paper implicate a role for PKA in the regulation of the directional migratory response to applied electric fields, galvanotaxis.
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PMID:Cyclic AMP-dependent protein kinase A plays a role in the directed migration of human keratinocytes in a DC electric field. 1180 41

Phospholamban (PLB) plays a primary role in regulating cardiac sarcoplasmic reticulum (SR) Ca(2+)-ATPase activity. Dephosphorylated PLB suppresses the SR Ca(2+) pump activity, whereas phosphorylation of PLB leads to deinhibition. A widely accepted sequential model of dual site PLB phosphorylation states that PKA-dependent phosphorylation of Ser(16) is obligatory to phosphorylation of Thr(17) by Ca(2+)/calmodulin-dependent kinase II, and mainly accounts for beta-adrenergic receptor mediated cardiac relaxation. However, emerging evidence supports independent phosphorylation of Ser(16) and Thr(17) and their independent contributions to cardiac relaxation. Furthermore, concurrent activation of PKA and CaMKII signaling pathways exhibits a robust synergistic effect on phosphorylation of Thr(17), but not of Ser(16). Thus, the synergistic interaction may masquerade as a sequential phosphorylation of Ser(16) and Thr(17) under certain circumstances. Further studies are required to determine the exact process of dual site PLB phosphorylation and its functional roles in healthy and diseased hearts.
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PMID:Dual site phospholamban phosphorylation and its physiological relevance in the heart. 1185 50

Neuronal nicotinic acetylcholine receptors (nAChR) can modulate many cellular mechanisms, such as cell survival and memory processing, which are also influenced by the serine/threonine protein kinases ERK1/2. In SH-SY5Y cells and hippocampal neurones, nicotine (100 microM) increased the activity of ERK1/2. This effect was Ca2+ dependent, and prevented by the alpha7 nAChR antagonist alpha-bungarotoxin (alpha-Bgt) and an inhibitor (PD98059) of the upstream kinase MEK. To determine the intervening steps linking Ca2+ entry to MEK-ERK1/2 activation, inhibitors of Ca2+-dependent kinases were deployed. In SH-SY5Y cells, selective blockers for PKC (Ro 31-8220), CaM kinase II (KN-62) or PI3 kinase (LY 294002) failed to inhibit the nicotine-evoked increase in ERK1/2 activity. In contrast, two structurally different inhibitors of PKA (KT 5720 and H-89) completely prevented the nicotine-dependent increase in ERK1/2 activity. Inhibition of the nicotine-evoked increase in ERK1/2 activity by H-89 was also observed in hippocampal cultures. Down stream of PKA, the activity of B-Raf was significantly decreased by nicotine in SH-SY5Y cells, as determined by direct measurement of MEK1 phosphorylation or in vitro kinase assays, whereas the modulation of MEK1 phosphorylation by Raf-1 tended to increase. Thus, this study provides evidence for a novel signalling route coupling the stimulation of alpha7 nAChR to the activation of ERK1/2, in a Ca2+ and PKA dependent manner.
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PMID:Nicotine activates the extracellular signal-regulated kinase 1/2 via the alpha7 nicotinic acetylcholine receptor and protein kinase A, in SH-SY5Y cells and hippocampal neurones. 1190 97

Injection of capsaicin into the skin results in pain, primary heat and mechanical hyperalgesia, and secondary mechanical allodynia and hyperalgesia. Sensory receptors in the area of secondary mechanical allodynia and hyperalgesia are unaffected, and so the sensory changes must be due to central actions of the initial intense nociceptive discharge that follows the capsaicin injection. Central sensitization of the responses of spinothalamic tract neurons lasts several hours, but can be prevented by spinal cord administration of non-NMDA and NMDA glutamate receptor antagonists or NK1 substance P receptor antagonists. The long-lasting increase in excitability of spinothalamic tract cells depends on the activation of several second messenger cascades (PKC, PKA, and NO/PKG signal transduction pathways). The excitability change also depends on activation of calcium/calmodulin-dependent kinase II, which is consistent with the proposal that this central sensitization response is a form of long-term potentiation.
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PMID:Role of neurotransmitters in sensitization of pain responses. 1200 17

Functions attributed to phospholipase (PL) D include the regulation of intracellular trafficking of Golgi-derived vesicles and secretion of granules from mast cells. We have reported that activation of PLD and secretion in a rat mast cell (RBL-2H3) line is substantially enhanced by cholera toxin, a known activator of protein kinase (PK) A. Here we review the evidence that (1) the synergistic interactions of cholera toxin and other pharmacological agents on mast cell secretion are attributable to the synergistic activation of PLD via PKA, CaM kinase II, and PKC and (2) both PLD1 and PLD2 participate in this process. For example, treatment with cholera toxin, thapsigargin, and phorbol 12-myristate 13-acetate (which activate PKA, CaM kinase II, and PKC, respectively) exhibit synergy in the stimulation of both PLD and secretion. These kinases and PLD are likely confined to membrane components, as similar synergistic interactions could be demonstrated in permeabilized cells. The regulation of PLD and secretion by these kinases is also apparent from studies of inhibitors of PKA and other kinases. Also, by overexpression of either PLD1 or PLD2 it is apparent that both isoforms respond to the same stimuli as endogenous PLD, although PLD1 is largely associated with secretory granules and PLD2 with plasma membrane. The studies reveal interesting differences in the regulation of the translocation of granules (regulated by PKA) and the fusion of these granules with the plasma membrane (regulated by Ca(2+) and PKC). The pathological/physiological implications of the regulation of PLD by PKA require further evaluation in other cell systems.
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PMID:Regulation of phospholipase D and secretion in mast cells by protein kinase A and other protein kinases. 1211 77

The modulatory effect of oxytocin (OT) on ATP-activated currents (I(ATP)) was studied in freshly isolated dorsal root ganglion (DRG) neurons of rats using whole cell clamp technique. In most of the neurons examined (50/70, 71.4%) extracellular application of OT (10(-9)-10(-5) mol/L) suppressed I(ATP) while in the rest (20/70, 28.6%) no modulatory effect was observed. OT shifted the ATP concentration-response curve downwards with a decrease of 39.8+/-4.2% in the maximal current response and with no significant change of Kd value. This OT-induced inhibition of I(ATP) showed no voltage dependence, and could be blocked by [d(CH(2))(5),Tyr(Me)(2),Thr(4),Tyr-NH(2)(9)]-OVT (d(CH(2))(5)-OVT) (10(-8) mol/L), a specific OT receptor antagonist. Intracellular application of H-9 (4 x 10(-5) mol/L, an inhibitor of protein kinase A) (n=12), BAPTA (10(-2) mol/L, a chelator of calcium ions) (n=4) could reverse the inhibitory effect of extracellular OT (10(-7) mol), while inclusion of H-7 (2 x 10(-5) mol/L, a protein kinase C inhibitior) (n=8) and KN-93 (10(-5) mol/L, an inhibitor of CaMKII) (n=9) in the recording pipette did not affect this effect. The results suggested that OT inhibition on ATP-activated currents was mediated by OT receptors in the membrane of DRG neurons; and this inhibitory effect involved the transduction of intracellular cAMP-PKA and Ca(2+).
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PMID:Modulation by oxytocin of ATP-activated currents in rat dorsal root ganglion neurons. 1238 76

Recent studies have demonstrated that transgenic (TG) expression of either Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) or CaMKIIdeltaB, both of which localize to the nucleus, induces cardiac hypertrophy. However, CaMKIV is not present in heart, and cardiomyocytes express not only the nuclear CaMKIIdeltaB but also a cytoplasmic isoform, CaMKIIdeltaC. In the present study, we demonstrate that expression of the deltaC isoform of CaMKII is selectively increased and its phosphorylation elevated as early as 2 days and continuously for up to 7 days after pressure overload. To determine whether enhanced activity of this cytoplasmic deltaC isoform of CaMKII can lead to phosphorylation of Ca2+ regulatory proteins and induce hypertrophy, we generated TG mice that expressed the deltaC isoform of CaMKII. Immunocytochemical staining demonstrated that the expressed transgene is confined to the cytoplasm of cardiomyocytes isolated from these mice. These mice develop a dilated cardiomyopathy with up to a 65% decrease in fractional shortening and die prematurely. Isolated myocytes are enlarged and exhibit reduced contractility and altered Ca2+ handling. Phosphorylation of the ryanodine receptor (RyR) at a CaMKII site is increased even before development of heart failure, and CaMKII is found associated with the RyR in immunoprecipitates from the CaMKII TG mice. Phosphorylation of phospholamban is also increased specifically at the CaMKII but not at the PKA phosphorylation site. These findings are the first to demonstrate that CaMKIIdeltaC can mediate phosphorylation of Ca2+ regulatory proteins in vivo and provide evidence for the involvement of CaMKIIdeltaC activation in the pathogenesis of dilated cardiomyopathy and heart failure.
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PMID:The deltaC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure. 1267 14

In the present study, possible mechanisms involved in fluoride-induced apoptosis in a human epithelial lung cell line (A549) were examined. Sodium fluoride (NaF) induced apoptosis in the A549 cells, with a maximum at 5-7.5 mM after 20 hours of exposure. The number of cells with plasma membrane damage (PI-positive cells) increased moderately up to 5 mM, but markedly at 7.5 mM. Deferoxamine (an Al3+ chelator) almost completely prevented these NaF-induced responses, which may suggest a role for G protein activation. The apoptotic effect was partially reduced by the PKA inhibitor H89. NaF induced a weak but sustained increase in PKC activity, whereas the PKC activator TPA induced a transient effect. TPA, which enhanced the NaF-induced PKC activity, was not apoptotic when added alone, but facilitated the NaF-induced apoptosis and the increase in PI-positive cells. PKC downregulation induced by TPA pretreatment almost completely prevented the NaF-induced apoptosis and the increase in PI-positive cells. Pretreatment with the PKC inhibitor GF109203X, which abolished the PKC activity after 3 hours, enhanced the NaF-induced apoptosis. KN93 (a CaM kinase II inhibitor) and W7 (a calmodulin inhibitor) seem to reduce the apoptotic effect of NaF, whereas BAPTA-AM (a Ca2+ chelator) was without effect. The tyrosine kinase inhibitor genistein also markedly reduced the NaF-induced apoptosis, whereas the PI-3 kinase inhibitor wortmannin augmented the response. In conclusion, the present results suggest that NaF induces an apoptotic effect and an increase in PI-positive A549 cells via similar mechanisms, involving PKC, PKA, tyrosine kinase and Ca2+-linked enzymes, whereas PI-3 kinase seems to exert a counteracting effect.
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PMID:Fluoride-induced apoptosis in human epithelial lung cells (A549 cells): role of different G protein-linked signal systems. 1272 91


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