The aniracetam metabolite 2-pyrrolidinone induces a long-term enhancement in AMPA receptor responses via a CaMKII pathway.
The present study was conducted to assess the effect of aniracetam and its metabolites, such as 2-pyrrolidinone, p-anisic acid, and anisamide butyrate, on the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, heteromerically formed of GluR1,2 (GluR1 and GluR2), GluR1,3 (GluR1 and GluR3), and GluR1,2,3 (GluR1, GluR2, and GluR3), expressed in Xenopus oocytes. 2-Pyrrolidinone potentiated kainate-evoked currents through GluR1,2,3 channels in a bell-shaped dose-dependent manner at concentrations ranged from 1 nM to 300 microM, with a maximal effect at 100 microM. The potentiation was long-lasting, reaching approximately 180% of basal levels 60 min after 5-min treatment with 2-pyrrolidinone at 100 microM. 2-Pyrrolidinone (100 microM) potentiated GluR1,3 channel currents as observed in GluR1,2,3, but instead it depressed GluR1,2 currents. Aniracetam and p-anisic acid potentiated GluR1,2,3 channel currents, but to a lesser extent, each about 130 and 103% of basal levels 60 min after treatment at 100 microM. In contrast, anisamide butyrate had no potentiating effect on the currents. Potentiation of GluR1,2,3 channel currents obtained with 2-pyrrolidinone was inhibited by KN-93, a selective inhibitor of calcium/calmodulin-dependent protein kinase (CaMKII), while it was not affected by GF109203X, a selective inhibitor of protein kinase C or H-89, a selective inhibitor of cAMP-dependent protein kinase. The results of the present study suggest that 2-pyrrolidinone persistently enhances activity of the Ca2+-permeable AMPA receptors, GluR1,3 and GluR1,2,3, by interacting with CaMKII.
Nishizaki
Tomoyuki
T
Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, 663-8501, Nishinomiya, Japan. tomoyuki@hyo-med.ac.jp
Matsumura
Takuro
T
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects; D008301:Maleimides / Q000494:pharmacology; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011760:Pyrrolidinones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D014982:Xenopus laevis; D000096926:Benzenesulfonamides
D001596:Benzylamines; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D007211:Indoles; D007546:Isoquinolines; D007608:Kainic Acid; D008301:Maleimides; D011493:Protein Kinase C; D011760:Pyrrolidinones; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; C104723:glutamate receptor ionotropic, AMPA 3; C072105:KN 93; D000096926:Benzenesulfonamides; C036466:aniracetam; C028537:2-pyrrolidone; C070515:bisindolylmaleimide I; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C104722:glutamate receptor ionotropic, AMPA 2