Differential modulation of the GYKI 53784-induced inhibition of AMPA currents by various AMPA-positive modulators in cerebellar Purkinje cells.
The effects of various (S)-alpha-amino-3-hydroxy-5-methyl-4-izoxazole-propionate (AMPA) receptor modulators on AMPA-induced whole-cell currents were compared in isolated rat cerebellar Purkinje cells. The positive modulators, aniracetam, cyclothiazide, 1-(1, 3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP), and 1-(quinoxaline-6-ylcarbonyl)-piperidine (BDP-12), dose-dependently potentiated the steady-state component of AMPA currents. The negative modulator, (-)1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine (GYKI 53784), dose-dependently suppressed AMPA responses. Its concentration-response curve was shifted to the right in a parallel fashion by all positive modulators, indicating a competitive type of interaction. However, the relative potencies of the positive modulators were different with regard to the enhancement of AMPA responses and the reversal of GYKI 53784-induced inhibition, respectively. It is supposed that positive modulators act at multiple allosteric sites and that they interact with GYKI 53784 at only one of these sites.
Kapus
G
G
Institute for Drug Research, P.O. Box 82, H-1325, Budapest, Hungary. sipka@freemail.hu
Bódi
I
I
Pataki
A
A
Gueritaud
J
J
Székely
J I
JI
Tarnawa
I
I
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001581:Benzothiadiazines / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004149:Dioxoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D011689:Purkinje Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects* / Q000502:physiology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
C097396:1-(quinoxalin-6-ylcarbonyl)piperidine; D001581:Benzothiadiazines; D004149:Dioxoles; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011760:Pyrrolidinones; D018091:Receptors, AMPA; D001569:Benzodiazepines; C085415:1-(1,3-benzodioxol-5-ylcarbonyl)piperidine; C036466:aniracetam; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C118651:GYKI 53784; C004639:cyclothiazide