title: Indomethacin activates protein kinase C and potentiates α7 ACh receptor responses.
abstract: OBJECTIVE
  We have earlier found that indomethacin activates CaMKII, as a novel action distinct from COX inhibition. To explore further indomethacin actions, the present study focused upon PKC and examined the effect of indomethacin on α7 ACh receptor responses and hippocampal synaptic transmission through PKC.
  
  
  METHODS
  We recorded currents through α7 ACh receptors expressed in Xenopus oocytes, quantified PKC activity in the in situ and cell-free PKC assay, and monitored field excitatory postsynaptic potentials (fEPSPs) and miniature excitatory postsynaptic currents (mEPSCs) from the CA1 region of rat hippocampal slices.
  
  
  RESULTS
  Indomethacin potentiated α7 ACh receptor currents in a bell-shaped concentration (100 nM-1 mM)-dependent manner, and the potentiating effect was inhibited by the PKC inhibitor GF109203X. Indomethacin activated PKC in a concentration (1-100 μM)-dependent manner for cultured rat hippocampal neurons. Additionally, indomethacin (100 μM) significantly activated PKC-ε under the cell-free conditions. Indomethacin (100 μM) induced a transient huge increase in the fEPSP slope followed by persistent increase, and the former effect was attenuated by the α7 ACh receptor antagonist α-bungarotoxin or GF109203X. Indomethacin (100 μM) also increased the rate of nicotine-evoked mEPSCs, and the effect was prevented by α-bungarotoxin or GF109203X.
  
  
  CONCLUSIONS
  The results of the present study show that indomethacin activates PKC, possibly PKC-e in the brain, thereby potentiating α7 ACh receptor responses to stimulate presynaptic glutamate release, which in part contributes to facilitation of hippocampal transmission. This extends our knowledge about diverse indomethacin actions.
authors.affiliation: Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yaguchi
authors.forename: Tetsu
authors.initials: T
authors.lastname: Nagata
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishizaki
mesh_terms: D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D014981:Xenopus / Q000254:growth & development / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D007211:Indoles; D008301:Maleimides; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D007213:Indomethacin