Expression of P2X4 receptor by lesional activated microglia during formalin-induced inflammatory pain

Guo, Liang-Hao; Trautmann, Katrin; Schluesener, Hermann J.

doi:10.1016/j.jneuroim.2005.03.007

Cited by 67 publications

(40 citation statements)

References 38 publications

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“…Peripheral nerve injury induces the upregulation of a variety of molecules in spinal microglia; it includes the expression of microglial markers (CD11b, CD14, tolllike receptor 4, and others), the chemokine (C-C motif) receptor 2 and chemokine (C-X3-C) receptor 1 chemokine receptors, the CB 2 cannabinoid receptor, and ATP receptor P2X 4 ion channel (Abbadie et al, 2003;Tsuda et al, 2003;Zhang et al, 2003;DeLeo et al, 2004;Verge et al, 2004). P2X 4 was reported to increase the expression in microglia after peripheral nerve injury (Tsuda et al, 2003) and after peripheral inflammation (Guo et al, 2005). The time course of upregulation of P2X 4 in spinal microglia was different in these two models; it increased at 2 weeks after nerve injury but no information was available after that, and it peaked at 7 d after Formalin injection and returned to normal at 2 weeks.…”

Section: Discussionmentioning

confidence: 99%

P2Y₁₂Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain

Kobayashi¹,

Yamanaka²,

Fukuoka³

et al. 2008

J. Neurosci.

257

238

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Microglia in the spinal cord may play an important role in the development and maintenance of neuropathic pain. A metabotropic ATP receptor, P2Y 12 , has been shown to be expressed in spinal microglia constitutively and be involved in chemotaxis. Activation of p38 mitogen-activated protein kinase (MAPK) occurs in spinal microglia after nerve injury and may be related to the production of cytokines and other mediators, resulting in neuropathic pain. However, it remains unknown whether any type of P2Y receptor in microglia is involved in the activation of p38 MAPK and the pain behaviors after nerve injury.Using the partial sciatic nerve ligation (PSNL) model in the rat, we found that P2Y 12 mRNA and protein increased in the spinal cord and peaked at 3 d after PSNL. Double labeling studies revealed that cells expressing increased P2Y 12 mRNA and protein after nerve injury were exclusively microglia. Both pharmacological blockades by intrathecal administration of P2Y 12 antagonist and antisense knockdown of P2Y 12 expression suppressed the development of pain behaviors and the phosphorylation of p38 MAPK in spinal microglia after PSNL. The intrathecal infusion of the P2Y 12 agonist 2-(methythio) adenosine 5Ј-diphosphate trisodium salt into naive rats mimicked the nerve injury-induced activation of p38 in microglia and elevated pain behaviors.These data suggest a new mechanism of neuropathic pain, in which the increased P2Y 12 works as a gateway of the following events in microglia after nerve injury. Activation of this receptor by released ATP or the hydrolyzed products activate p38 MAPK pathway and may play a crucial role in the generation of neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

P2Y₁₂Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain

Kobayashi¹,

Yamanaka²,

Fukuoka³

et al. 2008

J. Neurosci.

257

238

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“…After stimulating lysosome exocytosis, P2X 4 receptor-mediated currents were enhanced, indicating that lysosome-resident receptors retain their function and provide a pool that can be mobilized to upregulate the responsiveness of the cells to extracellular ATP. P2X 4 receptors are one of the predominant subtypes expressed in vascular endothelial cells, microglia, macrophages and monocytes, and their regulation at the plasma membrane will therefore be an important determinant of the responsiveness of these cells to extracellular ATP (Bowler et al, 2003;Coull et al, 2005;Guo et al, 2004;Guo et al, 2005;Tsuda et al, 2003;Wang et al, 2004;Wang et al, 2002;Yamamoto et al, 2000b;Zhang et al, 2006). In vascular endothelial cells, the receptors play a central role in the response to changes in blood flow, and their expression is also regulated by blood flow (Korenaga et al, 2001;Yamamoto et al, 2000a).…”

Section: Discussionmentioning

confidence: 99%

Regulation of P2X4 receptors by lysosomal targeting, glycan protection and exocytosis

Qureshi

Paramasivam

et al. 2007

Journal of Cell Science

197

225

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The P2X4 receptor has a widespread distribution in the central nervous system and the periphery, and plays an important role in the function of immune cells and the vascular system. Its upregulation in microglia contributes to neuropathic pain following nerve injury. The mechanisms involved in its regulation are not well understood, although we have previously shown that it is constitutively retrieved from the plasma membrane and resides predominantly within intracellular compartments. Here, we show that the endogenous P2X4 receptors in cultured rat microglia, vascular endothelial cells and freshly isolated peritoneal macrophages are localized predominantly to lysosomes. Lysosomal targeting was mediated through a dileucine-type motif within the N-terminus, together with a previously characterized tyrosine-based endocytic motif within the C-terminus. P2X4 receptors remained stable within the proteolytic environment of the lysosome and resisted degradation by virtue of their N-linked glycans. Stimulation of phagocytosis triggered the accumulation of P2X4 receptors at the phagosome membrane. Stimulating lysosome exocytosis, either by incubating with the Ca2+ ionophore ionomycin, for normal rat kidney (NRK) cells and cultured rat microglia, or the weak base methylamine, for peritoneal macrophages, caused an upregulation of both P2X4 receptors and the lysosomal protein LAMP-1 at the cell surface. Lysosome exocytosis in macrophages potentiated ATP-evoked P2X4 receptor currents across the plasma membrane. Taken together, our data suggest that the P2X4 receptor retains its function within the degradative environment of the lysosome and can subsequently traffic out of lysosomes to upregulate its exposure at the cell surface and phagosome.

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“…The microglial P2X 4 expression was considerably increased following formalin injection into the spinal cord (a common inflammatory pain model); maximal levels of P2X 4 immunoreactivity were observed 7 days after lesion (339). Incidentally, the formalin-induced activation of microglia and hyperalgesia was blocked by the broad P2 antagonist suramin (1006).…”

Section: P2x 4 Receptors and Neuropathic Painmentioning

confidence: 99%

Physiology of Microglia

Kettenmann

Hanisch

Нода

et al. 2011

Physiological Reviews

3,134

2,981

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Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

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Expression of P2X4 receptor by lesional activated microglia during formalin-induced inflammatory pain

Cited by 67 publications

References 38 publications

P2Y₁₂Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain

P2Y₁₂Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain

Regulation of P2X4 receptors by lysosomal targeting, glycan protection and exocytosis

Physiology of Microglia

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Expression of P2X4 receptor by lesional activated microglia during formalin-induced inflammatory pain

Cited by 67 publications

References 38 publications

P2Y12Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain

P2Y12Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain

Regulation of P2X4 receptors by lysosomal targeting, glycan protection and exocytosis

Physiology of Microglia

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P2Y₁₂Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain

P2Y₁₂Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain