title: Signaling pathways of ATP-induced PGE2 release in spinal cord astrocytes are EGFR transactivation-dependent.
abstract: Traumatic spinal cord injury is characterized by an immediate, irreversible loss of tissue at the lesion site, as well as a secondary expansion of tissue damage over time. Although secondary injury should, in principle, be preventable, no effective treatment options currently exist for patients with acute spinal cord injury (SCI). Excessive release of ATP by the traumatized tissue, triggers the rapid release of arachidonic acid (AA) and prostaglandin E2 (PGE2), and has beenimplicated in acute and chronic neuropathic pain and inflammation. But the intracellular pathways between ATP and PGE2 remain largely unknown. We have explored the signaling events involved in this synthesis by primarily culturing spinal cord astrocytes: (1) we determined significant PGE2 production increased by ATP is mainly via Subtype 1 of P2 purinoceptors (P2Y1) but not P2Y2; (2) we found that ATP strongly increased the level of intracellular Ca(2+) via P2Y1 receptor; (3) we indicated that ATP stimulates the definitely release of AA and PGE2 which involved the transactivation of epidermal growth factor (EGF) receptor, the phosphorylation of extracellular-regulated protein kinases 1 and 2 (ERK(1/2) ) and the activation of cytosolic phospholipase A(2) (cPLA(2) ); (4) we examined ATP could increase the phosphorylation of Akt via P2Y1 receptor which also depend on the transactivation of EGFR, but the activation of Akt has no effect on the downstream of cPLA(2) phosphorylation. ATP induced by SCI could mobilize the release of AA and PGE2. And inhibition of PGE2 release reduces behavioral signs of pain after SCI and peripheral nerve injury.
authors.affiliation: Department of Orthopaedics, The First Hospital of China Medical University, Heping District, Shenyang, People's Republic of China.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Xia
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D015232:Dinoprostone / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058470:Receptors, Purinergic P2Y / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: D058470:Receptors, Purinergic P2Y; D000255:Adenosine Triphosphate; D066246:ErbB Receptors; D015232:Dinoprostone