Kainate down-regulates a subset of GABAA receptor subunits expressed in cultured mouse cerebellar granule cells.
The effect of kainate, an agonist selective for ionotropic AMPA/kainate type of glutamate receptors, on GABAA receptor subunit expression in cultured mouse cerebellar granule cells was studied using quantitative RT-PCR, ligand binding and electrophysiology. Chronic kainate treatment, without producing excitotoxicity, resulted in preferential, dose- and time-dependent down-regulation of alpha1, alpha6 and beta2 subunit mRNA expression, the expression of beta3, gamma2 and delta subunit mRNAs being less affected. The down-regulation was reversed by DNQX, an AMPA/kainate-selective glutamate receptor antagonist. A 14-day kainate treatment resulted in 46% decrease of total [3H]Ro 15-4513 binding to the benzodiazepine sites. Diazepam-insensitive [3H]Ro 15-4513 binding was decreased by 89% in accordance with very low amount of alpha6 subunit mRNA present. Diazepam-sensitive [3H]Ro 154513 binding was decreased only by 40%, contrasting >90% decrease in alpha1 subunit mRNA expression. However, this was consistent with lower potentiation of GABA-evoked currents in kainate-treated than control cells by the alpha1-selective benzodiazepine site ligand zolpidem, suggesting compensatory expression of alpha5 (and/or alpha2 or alpha3) subunits producing diazepam-sensitive but zolpidem-insensitive receptor subtypes. In conclusion, chronic kainate treatment of cerebellar granule cells selectively down-regulates oil, alpha6 and beta2 subunits resulting in altered GABAA receptor pharmacology.
Martikainen
Ilkka K
IK
Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland.
Lauk
Kadri
K
Möykkynen
Tommi
T
Holopainen
Irma E
IE
Korpi
Esa R
ER
Uusi-Oukari
Mikko
M
D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D058787:GABA-A Receptor Antagonists; D007608:Kainic Acid / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D018092:Kainic Acid Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism
D058787:GABA-A Receptor Antagonists; D007608:Kainic Acid; D011963:Receptors, GABA-A; D018092:Kainic Acid Receptors; C546172:Gabra6 protein, mouse