title: Inhibition of delayed rectifier K+ conductance in cultured rat cerebellar granule neurons by activation of calcium-permeable AMPA receptors.
abstract: Activation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors in cerebellar granule cells during perforated-patch whole-cell recordings activated an inward current at negative voltages which was followed, after a delay, by the inhibition of an outward potassium current at voltages positive to -20 mV. The activated inward current was inwardly rectifying suggesting that the AMPA receptors were Ca2+-permeable. This was confirmed by direct measurements of intracellular calcium where Ca2+ rises were seen following AMPA receptor activation in Na+-free external solution. Ca2+ rises were equally large in the presence of 100 microM Cd2+ to block voltage-gated Ca2+ channels. Specific voltage-protocols, allowing selective activation of the delayed rectifier potassium current (KV) and the transient A current (KA), showed that kainate inhibited KV, but not to any great extent KA. The inhibition of KV was blocked by the AMPA receptor antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) and was no longer observed when the KV current was abolished with high concentrations of Ba2+. The responses to kainate were not altered by pre-treating the cells with pertussis toxin, suggesting that the AMPA receptor stimulation of the G-protein Gi cannot account for the effects observed. Replacing extracellular Na+ with choline did not alter the inhibition of KV by kainate, however, removing extracellular Ca2+ reduced the kainate response. The inhibition of KV by kainate was unaffected by the presence of 100 microM Cd2+. The guanylyl cyclase inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), did not alter kainate inhibition of KV. It is concluded that ion influx (particularly Ca2+ ions) through AMPA receptor channels following receptor activation leads to an inhibition of KV currents in cerebellar granule neurons.
authors.affiliation: Department of Pharmacology, Medawar Building, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: G
authors.initials: G
authors.lastname: Jones
authors.forename: D F
authors.initials: DF
authors.lastname: Boyd
authors.forename: S Y
authors.initials: SY
authors.lastname: Yeung
authors.forename: A
authors.initials: A
authors.lastname: Mathie
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000648:ultrastructure; D051668:Delayed Rectifier Potassium Channels; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005260:Female; D005456:Fluorescent Dyes; D016257:Fura-2; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists*; D012964:Sodium / Q000502:physiology
chemical_list: D051668:Delayed Rectifier Potassium Channels; D018690:Excitatory Amino Acid Agonists; D005456:Fluorescent Dyes; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D018091:Receptors, AMPA; D012964:Sodium; D007608:Kainic Acid; D002118:Calcium; D016257:Fura-2