title: Modulation of ACh receptor currents by arachidonic acid.
abstract: The present study investigated the effects of arachidonic acid on Torpedo (alpha beta gamma delta) and neuronal nicotinic acetylcholine (ACh) receptors (chick alpha7; rat alpha7, alpha3 beta2, alpha3 beta4, alpha4 beta2, and alpha4 beta4). Arachidonic acid (10 microM) depressed currents through normal Torpedo ACh receptors during treatment and afterward, persistently (>/=30 min) potentiated the currents. The potentiation was blocked by the selective protein kinase C (PKC) inhibitor, GF109203X or PKC inhibitor peptide (PKCI). The depression was not inhibited by any protein kinase inhibitor examined here, but greater in Ca2+-free extracellular solution. Arachidonic acid also potentiated currents through mutant Torpedo ACh receptors lacking PKC phosphorylation sites at Ser333 on the alpha subunit and Ser377 on the delta subunit without depression, but otherwise, it depressed currents through mutant receptors replacing of each Ser by negatively charged amino acid residue, possibly that mimics PKC phosphorylation of the receptors. These results suggest that the depression was due to the direct blocking effect on Ca2+-modulatory sites, which was accelerated under conditions of the receptors phosphorylated by PKC, and that the potentiation was caused by PKC activation, independently of PKC phosphorylation of the receptors. Arachidonic acid reduced currents through chick alpha7 receptors by a mechanism independent of protein kinase activation. In contrast, arachidonic acid potentiated currents through rat alpha7, alpha3 beta2, alpha4 beta2, and alpha4 beta4 receptors, perhaps by the same mechanism as the potentiation observed in Torpedo ACh receptors, although it had no effect on rat alpha3 beta4 receptors. The results of the present study thus demonstrate that arachidonic acid exerts diverse actions on nicotinic ACh receptors by different mechanisms.
authors.affiliation: Department of Physiology, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. tomo@med.kobe-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Nishizaki
authors.forename: T
authors.initials: T
authors.lastname: Matsuoka
authors.forename: T
authors.initials: T
authors.lastname: Nomura
authors.forename: K
authors.initials: K
authors.lastname: Sumikawa
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D001923:Brain Chemistry / Q000502:physiology; D002642:Chick Embryo; D003513:Cycloheximide / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000201:enzymology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism*; D013449:Sulfonamides; D014101:Torpedo; D014981:Xenopus
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D007546:Isoquinolines; D008301:Maleimides; D011500:Protein Synthesis Inhibitors; D011978:Receptors, Nicotinic; D013449:Sulfonamides; D016718:Arachidonic Acid; D009637:Masoprocol; D003513:Cycloheximide; D019833:Genistein; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D000109:Acetylcholine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D007213:Indomethacin