Ionomycin causes activation of p38 and p42/44 mitogen-activated protein kinases in human neutrophils

Elzi, David J.; Bjornsen, A. Jason; MacKenzie, Todd A.; Wyman, Travis H.; Silliman, Christopher C.

doi:10.1152/ajpcell.2001.281.1.c350

Cited by 55 publications

(47 citation statements)

References 57 publications

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“…This type of Ca 2+ -dependent activation of p38-MAPK has been reported in a number of cell types (Blanquet, 2000;Dehez et al, 2001;Elzi et al, 2001;Kreideweiss et al, 1999;Shigemoto-Mogami et al, 2001), including peripheral macrophages which express functional P2X4 receptor (Brone et al, 2007;Qureshi et al, 2007;Ulmann et al, 2010). In macrophages, P2X4 receptor activation of p38 MAPK is upstream from the production and release of prostaglandin E2 (Ulmann et al, 2010), a principal substrate for inflammation that sensitizes peripheral nociceptors (Portanova et al, 1996;Samad et al, 2002).…”

Section: Role Of Microglial P2x4 Receptors In Neuropathic Painmentioning

confidence: 76%

ATP receptors gate microglia signaling in neuropathic pain

Trang

Beggs

Salter

2012

Experimental Neurology

136

104

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Microglia were described by Pio del Rio-Hortega (1932) as being the 'third element' distinct from neurons and astrocytes. Decades after this observation, the function and even the very existence of microglia as a distinct cell type was a topic of intense debate and conjecture. However, considerable advances have been made towards understanding the neurobiology of microglia resulting in a radical shift in our view of them as being passive bystanders that have solely immune and supportive roles, to being active principal players that contribute to central nervous system pathologies caused by disease or following injury. Converging lines of evidence implicate microglia as being essential in the pathogenesis of neuropathic pain, a debilitating chronic pain condition that can occur after peripheral nerve damage caused by disease, infection, or physical injury. A key molecule that modulates microglial activity is ATP, an endogenous ligand of the P2-purinoceptor family consisting of P2X ionotropic and P2Y metabotropic receptors. Microglia express several P2 receptor subtypes, and of these the P2X4, P2X7, and P2Y12 receptor subtypes have been implicated in neuropathic pain. The P2X4 receptor has emerged as the core microglianeuron signaling pathway: activation of this receptor causes release of brain-derived neurotrophic factor (BDNF) which causes disinhibition of pain-transmission neurons in spinal lamina I. The present review highlights recent advances in understanding the signaling and regulation of P2 receptors expressed in microglia and the implications for microglia-neuron interactions for the management of neuropathic pain. KeywordsMicroglia; P2 purinoceptors; Neuropathic pain; Nerve injury; ATP; BDNF; spinal cord Pain is a double-edged sword that can be protective or cause considerable suffering. Acute nociceptive pain warns against imminent or existing tissue damage, whereas chronic pain has no known defensive or beneficial function and is unremitting for those who suffer from this condition. Acute pain is produced by physiological functioning of the normal peripheral and central nervous systems. However, the processes initiated during acute pain can sometimes progress to chronic pain that is characterized as persisting long after the initiating event has healed. This transition to chronicity is highly variable between individuals and the degree of injury is not necessarily predictive of the severity or chronicity of the pain. There is mounting evidence that the transition from acute to chronic pain involves discrete CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript pathophysiological steps that alter the cellular, molecular, and anatomical organization of nociceptive neural networks in the spinal dorsal horn (Latremoliere and Woolf, 2009;Scholz and Woolf, 2002;Voscopoulos and Lema, 2010;Woolf and Salter, 2000). In this pathologically altered system, the balance of inhibitory and excitatory control is shifted such that inhibitory mechanisms are weakened while excitatory mechanisms ar...

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Section: Role Of Microglial P2x4 Receptors In Neuropathic Painmentioning

confidence: 76%

ATP receptors gate microglia signaling in neuropathic pain

Trang

Beggs

Salter

2012

Experimental Neurology

136

104

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“…This finding implies that activation of p38-MAPK by ATP is necessary for the release of BDNF from the pre-existing pool, and together with the Ca 2ϩ dependence of the early phase release, a mechanistically simple explanation is that Ca 2ϩ induces activation of p38-MAPK, which in turn stimulates BDNF release. Ca 2ϩ -dependent activation of p38-MAPK has been demonstrated in a number of cell types (Blanquet, 2000;Dehez et al, 2001) including immune cells (Kreideweiss et al, 1999;Elzi et al, 2001;Shigemoto-Mogami et al, 2001). There is, however, no evidence in the literature for involvement of p38-MAPK in the process of release of peptides from cells, and therefore, an alternative possibility is that activation of p38-MAPK is permissive for Ca 2ϩ -dependent BDNF release.…”

Section: Discussionmentioning

confidence: 99%

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

Trang¹,

Beggs²,

Wan³

et al. 2009

J. Neurosci.

420

378

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Microglia in the dorsal horn of the spinal cord are increasingly recognized as being crucial in the pathogenesis of pain hypersensitivity after injury to a peripheral nerve. It is known that P2X4 purinoceptors (P2X4Rs) cause the release of brain-derived neurotrophic factor (BDNF) from microglia, which is necessary for maintaining pain hypersensitivity after nerve injury. However, there is a critical gap in understanding how activation of microglial P2X4Rs leads to the release of BDNF. Here, we show that stimulating P2X4Rs with ATP evokes a biphasic release of BDNF from microglia: an early phase occurs within 5 min, whereas a late phase peaks 60 min after ATP stimulation. Concomitant with the late phase of release is an increased level of BDNF within the microglia. Both phases of BDNF release and the accumulation within the microglia are dependent on extracellular Ca 2ϩ . The late phase of BDNF release and accumulation, but not the early phase of release, are suppressed by inhibiting transcription and translation, indicating that activation of P2X4R causes an initial release of a pre-existing pool of BDNF followed by an increase in de novo synthesis of BDNF. The release of BDNF is abolished by inhibiting SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-mediated exocytosis. Furthermore, we find that the P2X4R-evoked release and synthesis of BDNF are dependent on activation of p38-mitogen-activated protein kinase (MAPK). Together, our findings provide a unifying mechanism for pain hypersensitivity after peripheral nerve injury through P2X4R-evoked increase in Ca 2ϩ and activation of p38-MAPK leading to the synthesis and exocytotic release of BDNF from microglia.

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“…Previous reports showed that Ca 2ϩ influx activates p38 MAPK and Erk1/2 in human neutrophils or PC12 cells. 35,36 Recently, it was reported that Y568 of human KIT (corresponding to murine Y567) is important of SFK activation and Shc phosphorylation resulting in Ras/Erk2 activation, 37 and p38 MAPK was involved in SCF-mediated cell migration. 22 In this report, for the first time, we showed that not only p38 MAPK but also Erk1/2 was involved in SCF-mediated cell migration, and that both MAPKs differentially transduce the signaling from Y567-induced SFK activation to Ca 2ϩ influx and cell migration.…”

Section: Discussionmentioning

confidence: 99%

Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor–induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration

Ueda

Mizuki

Ikeda

et al. 2002

Blood

105

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Introduction c-Kit is a receptor tyrosine kinase (RTK), which constitutes a type III RTK subfamily with the receptors for platelet-derived growth factor (PDGF), colony-stimulating factor 1 (CSF-1), and flt-3 ligand. 1,2 The type III RTKs are characterized by an extracellular domain with 5 immunoglobulinlike domains and a cytoplasmic domain consisting of a kinase domain that is interrupted by a kinase insert. c-Kit (KIT) and its ligand stem cell factor (SCF) play an important role in hematopoiesis, melanogenesis, and gametogenesis, 3 as has been clearly shown by loss of function mutations of c-kit gene. In addition, c-kit gene product has been associated with various forms of neoplasms. Activating mutants of KIT, either in the juxtamembrane domain or the catalytic domain, were identified as the cause for transformation of hematopoietic stem cells, mast cells, and gastrointestinal stromal cells. [4][5][6][7][8][9][10] Thus, KIT/SCF has pleiotropic functions such as proliferation, survival, differentiation, and transformation. In this report, we focus on SCF/KITmediated cell migration, which is also a characteristic function of SCF in hematopoietic stem cells and mast cells, [11][12][13] and has critical roles in immunity, metastasis, and development.On ligand stimulation, KIT receptors dimerize, activate its intrinsic tyrosine kinase, and autophosphorylate. The phosphorylated KIT receptor generates binding sites for SH2 domaincontaining proteins, which include proteins of the p21Ras-mitogenactivated protein kinase (MAPK) pathway, 14 the p85 subunit of phosphatidylinositol 3Ј kinase (PI3K), 15 phospholipase C-␥ 1 , the Grb2 adaptor protein, 16 the Src family kinases (SFKs), 17 Cbl, CRKL, 19 SHP1, and SHP2. 20 Those proteins are subsequently activated or phosphorylated and further transduce signaling cascades that lead to various cellular responses. However, little is known about which signaling is essential for SCF-mediated migration. Recently, a few reports indicated that Lyn or p38 MAPK plays an important role, 21,22 but no comprehensive investigation has been done in which the tyrosine residue of KIT is involved in signal transduction, which is required for cell migration. In this study, we have converted all possible tyrosine (Y) residues on KIT cytoplasmic domain to phenylalanine (F) and introduced these YF substitute mutants on 293T cells or murine interleukin 3 (IL-3)-dependent BAF3 cells. We used these cell lines to elucidate signaling cascades that are important for SCF-mediated cell Supported in part by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology, the Japanese Ministry of Health, Labor and Welfare, and the Japan Society for Promotion of Science.Reprints: Yuzuru Kanakura, Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan; e-mail: kanakura@bldon.med.osaka-u.ac.jp.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate thi...

show abstract

Ionomycin causes activation of p38 and p42/44 mitogen-activated protein kinases in human neutrophils

Cited by 55 publications

References 57 publications

ATP receptors gate microglia signaling in neuropathic pain

ATP receptors gate microglia signaling in neuropathic pain

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor–induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration

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