2-pyrrolidinone induces a long-lasting facilitation of hippocampal synaptic transmission by enhancing alpha7 ACh receptor responses via a PKC pathway.
2-Pyrrolidinone, a metabolite of aniracetam, potentiated currents through alpha7 receptors expressed in Xenopus oocytes, in a bell-shaped dose-dependent manner at concentrations ranged from 1 nM to 10 microM, with a maximum at 100 nM (189% of original levels 60 min after 20-min treatment). The potentiation was inhibited by GF109203X, a selective inhibitor of protein kinase C (PKC), but not by KN-93, a selective inhibitor of CaMKII, or H-89, a selective inhibitor of protein kinase A (PKA). In the PKC assay using reversed-phase high-performance liquid chromatography, 2-pyrrolidinone enhanced activity of PKC-epsilon activated by linoleic acid to about 1.8-times greater than that in the absence of 2-pyrrolidinone, although it did not directly activate PKC-epsilon. In the Western immunoblot analysis, rat hippocampal slices treated with 2-pyrrolidinone (100 nM) was more reactive to an antibody against phosphorylated myristoylated alanine-rich C kinase substrate (MARCKS) than untreated slices. 2-Pyrrolidinone (100 nM) induced a long-lasting facilitation of hippocampal synaptic transmission in the CA1 region of rat hippocampal slices, and the facilitation was inhibited by GF109203X or alpha-bungarotoxin, an inhibitor of alpha7 receptors. The results of the present study suggest that 2-pyrrolidinone enhances activity of activated PKC, thereby potentiating alpha7 receptor responses, and then leading to a facilitation of hippocampal synaptic transmission.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002038:Bungarotoxins / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000295:instrumentation / Q000379:methods; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D004791:Enzyme Inhibitors; D011760:Pyrrolidinones; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C028537:2-pyrrolidone; D000109:Acetylcholine