Fibronectin/integrin system is involved in P2X(4) receptor upregulation in the spinal cord and neuropathic pain after nerve injury.
ABSTRACT We have previously shown that activation of the ATP-gated ion channel subtype P2X(4) receptors (P2X(4)Rs) in the spinal cord, the expression of which is upregulated in microglia after nerve injury, is necessary for producing neuropathic pain. The upregulation of P2X(4)Rs in microglia is, therefore, a key process in neuropathic pain, but the mechanism remains unknown. Here, we find a fibronectin/integrin-dependent mechanism in the upregulation of P2X(4)Rs. Microglia cultured on dishes coated with fibronectin, an extracellular matrix molecule, expressed a higher level of P2X(4)R protein when compared with those cultured on control dishes. The increase was suppressed by echistatin, a peptide that selectively blocks beta(1) and beta(3)-containing integrins, and with a function-blocking antibody of beta(1) integrin. In in vivo studies, the upregulation of P2X(4)Rs in the spinal cord after spinal nerve injury was significantly suppressed by intrathecal administration of echistatin. Tactile allodynia in response to nerve injury and intrathecal administration of ATP- and fibronectin-stimulated microglia was inhibited by echistatin. Furthermore, intrathecal administration of fibronectin in normal rats increased the level of P2X(4)R protein in the spinal cord and produced tactile allodynia. Moreover, the fibronectin-induced allodynia was not observed in mice lacking P2X(4)R. Taken together with the results of our previous study showing an increase in the spinal fibronectin level after nerve injury, the present results suggest that the fibronectin/integrin system participates in the upregulation of P2X(4)R expression after nerve injury and subsequent neuropathic pain.
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ABSTRACT: Most hypotheses concerning the mechanisms underlying Parkinson's disease are based on altered synaptic transmission of the nigrostriatal system. However, extrasynaptic transmission was recently found to affect dopamine neurotransmitter delivery by anisotropic diffusion in the extracellular matrix, which is modulated by various extracellular matrix components such as fibronectin. The present study reviewed the neuroprotective effect of fibronectin in extrasynaptic transmission. Fibronectin can regulate neuroactive substance diffusion and receptor activation, and exert anti- neuroinflammatory, adhesive and neuroprotective roles. Fibronectin can bind to integrin and growth factor receptors to transactivate intracellular signaling events such as the phosphatidylinositol 3-kinase/protein kinase B pathway to regulate or amplify growth factor-like neuroprotective actions. Fibronectin is assembled into a fibrillar network around cells to facilitate cell migration, molecule and ion diffusion, and even drug delivery and treatment. In addition, the present study analyzed the neuroprotective mechanism of fibronectin in the pathogenesis of Parkinson's disease, involving integrin and growth factor receptor interactions, and discussed the possible therapeutic and diagnostic significance of fibronectin in Parkinson's disease.Neural Regeneration Research 02/2013; 8(4):376-82. · 0.14 Impact Factor
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ABSTRACT: It is now well established that glial cells not only provide mechanical and trophic support to neurons but can directly contribute to neurotransmission, for example, by release and uptake of neurotransmitters and by secreting pro- and anti-inflammatory mediators. This has greatly changed our attitude towards acute and chronic disorders, paving the way for new therapeutic approaches targeting activated glial cells to indirectly modulate and/or restore neuronal functions. A deeper understanding of the molecular mechanisms and signaling pathways involved in neuron-to-glia and glia-to-glia communication that can be pharmacologically targeted is therefore a mandatory step toward the success of this new healing strategy. This holds true also in the field of pain transmission, where the key involvement of astrocytes and microglia in the central nervous system and satellite glial cells in peripheral ganglia has been clearly demonstrated, and literally hundreds of signaling molecules have been identified. Here, we shall focus on one emerging signaling system involved in the cross talk between neurons and glial cells, the purinergic system, consisting of extracellular nucleotides and nucleosides and their membrane receptors. Specifically, we shall summarize existing evidence of novel “druggable” glial purinergic targets, which could help in the development of innovative analgesic approaches to chronic pain states.BioMed Research International 09/2014; 2014. · 2.71 Impact Factor
Article: P2X4R and P2X7R in neuropathic pain[Show abstract] [Hide abstract]
ABSTRACT: Neuropathic pain is often a consequence of nerve injury or of diseases such as diabetes, infection, autoimmune disease, or cancer. Neuropathic pain can be agonizing, can persist over long periods, and, unfortunately, is often resistant to known painkillers. There is a rapidly growing body of evidence indicating that signaling by extracellular nucleotides through purinergic P2 receptors [ionotropic P2X receptors (P2XRs) and metabotropic P2Y receptors (P2YRs)] play crucial roles in neuropathic pain. Following peripheral nerve injury, the expression of purinergic receptors (e.g., P2X4R) is markedly upregulated specifically in microglia, a type of glial cells known as resident macrophages in the central nervous system. Activation of P2X4R and P2X7R in microglia causes release of diffusible factors (such as brain-derived neurotrophic factor, interleukin-1β, interleukin-6, and tumor necrosis factor-α) involved in nerve-injury-induced pain behaviors and hyperexcitability of dorsal horn neurons. Suppression of the function or expression of these purinergic receptors strongly suppresses neuropathic pain. Recent advances further our understanding of mechanisms by which microglial purinergic receptors contribute to the pathogenesis of neuropathic pain. WIREs Membr Transp Signal 2012, 1:513–521. doi: 10.1002/wmts.47 For further resources related to this article, please visit the WIREs website.Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 07/2012; 1(4).