Differential Role of Protein Kinase Cδ Isoform in Agonist-induced Dense Granule Secretion in Human Platelets

Murugappan, Swaminathan; Tuluc, Florin; Dorsam, Robert T.; Shankar, Haripriya; Kunapuli, Satya P.

doi:10.1074/jbc.m306960200

Cited by 97 publications

(144 citation statements)

References 65 publications

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“…6A). On the other hand, there were no significant attenuations by 1 M Gö6976, an inhibitor of PKC-␣ and PKC-␤ (Ma et al, 2002), or 1 M rottlerin, an inhibitor of novel types of PKCs, including the PKC-␦ isoform (Murugappan et al, 2004). These results suggest that PKC-␥ is more likely to be involved in insulin-induced necrosis inhibition.…”

Section: Pkc-␥ Activation In Insulin Signaling Prevents Necrosis 1029mentioning

confidence: 49%

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Insulin Receptor-Protein Kinase C-γ Signaling Mediates Inhibition of Hypoxia-Induced Necrosis of Cortical Neurons

Hamabe

Fujita²,

Ueda³

2005

J Pharmacol Exp Ther

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Ischemic stress causes neuronal death and functional impairment. Evidence has suggested that cells in the ischemic core first lose viability due to the decline in blood flow and cellular energy metabolism and then die by necrosis. Although inhibition of necrosis could be a potent therapeutic target for brain ischemia, known neurotrophic factors are ineffective for neuronal necrosis. We previously reported that insulin, but not brainderived neurotrophic factor or insulin like-growth factor-1, inhibited neuronal necrosis under serum-free starvation stress. Although insulin receptors are abundant in the central nervous system as well as in peripheral tissues, neurons are not dependent upon insulin for their glucose supply, indicating that insulin receptors have other roles in the central nervous system. In the present study, by using hypoxia-reperfusion stress, we showed that cortical neurons rapidly died by necrosis as evaluated by propidium iodide staining and transmission electron microscopic analysis. As expected, insulin treatment significantly inhibited neuronal necrosis, although this effect was blocked by pretreatment with an antisense oligonucleotide for the insulin receptor. Furthermore, an inhibitor of protein kinase C (PKC) eliminated the insulin-induced antinecrotic effect. The addition of insulin induced significant translocation of only the PKC-␥ isoform, whereas antisense oligonucleotide treatment for this isoform abolished the insulin-induced inhibition of necrosis. Together, these results suggest that insulin mediates inhibition of neuronal necrosis through a novel mechanism involving PKC-␥ activation.

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Section: Pkc-␥ Activation In Insulin Signaling Prevents Necrosis 1029mentioning

confidence: 49%

“…To clarify the PKC isoform that plays an important role in necrosis inhibition, we performed pharmacological analysis using a panel of different PKC inhibitors (Ma et al, 2002;Murugappan et al, 2004). As shown in Fig.…”

Section: Pkc-␥ Activation In Insulin Signaling Prevents Necrosis 1031mentioning

confidence: 99%

Insulin Receptor-Protein Kinase C-γ Signaling Mediates Inhibition of Hypoxia-Induced Necrosis of Cortical Neurons

Hamabe

Fujita²,

Ueda³

2005

J Pharmacol Exp Ther

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“…Interestingly, previous work has demonstrated that collagen-evoked Ca 2+ signalling in human platelets is negatively regulated by novel PKC isoforms and positively regulated by conventional PKC isoforms [44]. An agonist-specific effect of isoform-selective PKC inhibition has also been reported for platelet dense granule secretion [45]. These results beg the question as to whether novel PKC isoforms are potentiating collagen-evoked signalling by triggering the same effects on SERCA and Na + /K + -ATPase activity elicited by the conventional isoforms upon thrombin-or ADP-stimulation, or whether there are distinct molecular targets for PKC that modulate collagen-evoked Ca 2+ signals.…”

Section: Discussionmentioning

confidence: 99%

Conventional protein kinase C isoforms differentially regulate ADP- and thrombin-evoked Ca2+ signalling in human platelets

et al. 2015

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Rises in cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ) are central in platelet activation, yet many aspects of the underlying mechanisms are poorly understood. Most studies examine how experimental manipulations affect agonist-evoked rises in [Ca 2+ ] cyt , but these only monitor the net effect of manipulations on the processes controlling [Ca 2+ ] cyt (Ca 2+ buffering, sequestration, release, entry and removal), and cannot resolve the source of the Ca 2+ or the transporters or channels affected. To investigate the effects of protein kinase C (PKC) on platelet Ca 2+ signalling, we here monitor Ca 2+ flux around the platelet by measuring net Ca 2+ fluxes to or from the extracellular space and the intracellular Ca 2+ stores, which act as the major sources and sinks for Ca 2+ influx into and efflux from the cytosol, as well as monitoring the cytosolic Na + concentration ([Na + ] cyt ), which influences platelet Ca 2+ fluxes via Na + /Ca 2+ exchange. The intracellular store Ca 2+ concentration ([Ca 2+ ] st ) was monitored using Fluo-5N, the extracellular Ca 2+ concentration ([Ca 2+ ] ext ) was monitored using Fluo-4 whilst [Ca 2+ ] cyt and [Na + ] cyt were monitored using Fura-2 and SFBI respectively. PKC inhibition using Ro-31-8220 or bisindolaemide I potentiated ADP-and thrombin-evoked rises in [Ca 2+ ] cyt in the absence of extracellular Ca 2+ . PKC inhibition potentiated ADP-evoked but reduced thrombin-evoked intracellular Ca 2+ release and Ca 2+ removal into the extracellular medium. SERCA inhibition using thapsigargin and 2,5-di(tert-butyl) l,4-benzohydroquinone abolished the effect of PKC inhibitors on ADP-evoked changes in [Ca 2+ ] cyt but only reduced the effect on thrombin-evoked responses. Thrombin evokes substantial rises in [Na + ] cyt which would be expected to reduce Ca 2+ removal via the Na + /Ca 2+ exchanger (NCX). Thrombinevoked rises in [Na + ] cyt were potentiated by PKC inhibition, an effect which was not due to altered changes in non-selective cation permeability of the plasma membrane as assessed by Mn 2+ quench of Fura-2 fluorescence. PKC inhibition was without effect on thrombin-evoked rises in [Ca 2+ ] cyt following SERCA inhibition and either removal of extracellular Na + or inhibition of Na + /K + -ATPase activity by removal of extracellular K + or treatment with digoxin. These data suggest that PKC limits ADP-evoked rises in [Ca 2+ ] cyt by acceleration of SERCA activity, whilst rises in [Ca 2+ ] cyt evoked by the stronger platelet activator thrombin are limited by PKC through acceleration of both SERCA and Na + /K + -ATPase activity, with the latter limiting the effect of thrombin on rises in [Na + ] cyt and so forward mode NCX activity. The use of selective PKC inhibitors indicated that conventional and not novel PKC isoforms are responsible for the inhibition of agonist-evoked Ca 2+ signalling.

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“…In contrast, positive regulation by PKC␦ of stimulus-induced granule secretion has been described in nonimmune cell types. PKC␦ was proposed to have a role in the induction of dense granule and insulin secretion in platelets and pancreatic ␤ cells, respectively (38,39). Interestingly, depending on the type of stimulus, PKC serves either as a positive or as a negative regulator of dense granule secretion in platelets.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Cδ Regulates Antigen Receptor-Induced Lytic Granule Polarization in Mouse CD8+ CTL

Jennifer

Monu

Shen

et al. 2007

The Journal of Immunology

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T cell receptor (TCR)‐induced activation of protein kinase C (PKC) has long been known to be critical for regulation of granule exocytosis mediated cytotoxicity in CD8+ T cells. However, the mechanism by which PKC regulates this effector function is not clear. In addition, it is not known which PKC family members are involved in the regulation of this process. By combining the use of pharmacological inhibitors and mice with targeted gene deletions, we showed that Protein Kinase C □elta is required for granule exocytosis mediated lytic function in mouse CD8+T cells. We studied lysosomal/lytic granule movements in CD8+ T cells responding to target cell recognition by confocal microscopy and live imaging and demonstrated that PKC □elta regulates TCR induced lytic granule polarization. In summary, our studies identified Protein Kinase C □elta, a member of the family of diacylglycerol dependent, calcium independent PKC isoforms, as a novel regulator of TCR mediated lytic granule release in mouse CD8+CTL. This work was supported by the NIH grants RO1AI48837 and RO1AI41573 to SV and by NIH, NCI F32CA101449‐02 and Research Advisory Council grant to SR.

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Differential Role of Protein Kinase Cδ Isoform in Agonist-induced Dense Granule Secretion in Human Platelets

Cited by 97 publications

References 65 publications

Insulin Receptor-Protein Kinase C-γ Signaling Mediates Inhibition of Hypoxia-Induced Necrosis of Cortical Neurons

Insulin Receptor-Protein Kinase C-γ Signaling Mediates Inhibition of Hypoxia-Induced Necrosis of Cortical Neurons

Conventional protein kinase C isoforms differentially regulate ADP- and thrombin-evoked Ca2+ signalling in human platelets

Protein Kinase Cδ Regulates Antigen Receptor-Induced Lytic Granule Polarization in Mouse CD8+ CTL

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