Kainate-induced excitotoxicity is dependent upon extracellular potassium concentrations that regulate the activity of AMPA/KA type glutamate receptors Byeong Keun Ha,* Stefano Vicini, Richard C. Rogers,* ,1 Jacqueline C. Bresnahan,* Richard W. Burry* and Michael S. Beattie* *Department of Neuroscience, Ohio State University, Columbus, Ohio, USA  Department of Physiology and Biophysics, Georgetown University, Washington DC, USA Abstract In addition to well-known N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity, recent studies suggest that non-NMDA type ionotropic glutamate receptors are also important mediators of excitotoxic neuronal death, and that their functional expression can be regulated by the cellular environment. In this study, we used cerebellar granule cells (CGCs) in culture to investigate kainate (KA)-induced excito- toxicity. Although previous reports indicated that KA induces apoptosis of CGCs in culture, no KA-induced excitotoxic cell death was observed in CGCs treated with KA when cells were maintained in high potassium media (24 mM K + ). In contrast, when mature CGCs were shifted into low potassium media (3 mM K + ), KA produced significant excitotoxicity. In electro- physiological studies, the KA-induced inward current density was significantly elevated in CGCs shifted into low K + media compared with those maintained in high K + media. Non- desensitizing aspects of KA currents observed in this study suggest that these responses were mediated by AMPA rather than KA receptors. In immunofluorescence studies, the sur- face expression of GluR1 subunits increased when mature CGCs were shifted into a low K + environment. This study suggests that KA-induced excitotoxicity in mature CGCs is dependent upon the extracellular potassium concentration, which modulates functional expression and excitability of AMPA/KA receptors. Keywords: AMPA/KA receptors, cerebellar granule cell, excitotoxicity, GluR1, potassium. J. Neurochem. (2002) 83, 934–945. IonotropicglutamatereceptorsintheCNSmediateexcitatory neurotransmission, and participate in synaptogenesis and synapticplasticityincludinglong-termpotentiationandlong- term depression (Lynch and Baudry 1984; Kleinschmidt et al. 1987; Bliss and Collingridge 1993; Bear and Abraham 1996; Malenka and Nicoll 1999; Luscher et al. 2000). In contrast, excessive activation of ionotropic glutamate recep- tors contributes to neuronal death, which is referred to as excitotoxicity (Frandsen et al. 1989; Choi 1992b). Excito- toxic neuronal death is associated with a variety of neuro- pathological and neurodegenerative disease states such as traumatic and hypoxic–ischemic injuries to the CNS, epilepsy, Alzheimer’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis (Choi 1992a; Lipton and Rosenberg 1994; Shaw 1994). Ionotropic glutamate receptors are classified into three subtypes based on their binding of selective agonists and electrophysiological responses to their agonists: N-methyl- D-aspartate (NMDA) receptors, a-amino-3-hydroxy-5- methyl-4-isoxazole propionate (AMPA) receptors, and kai- nate(KA)receptors.Molecularcloningofthesereceptorshas revealed that each subtype of ionotropic glutamate receptors is a hetero-oligomeric receptor complex that is composed of Received June 24, 2002; revised manuscript received August 20, 2002; accepted August 28, 2002. Address correspondence and reprint requests to Michael S. Beattie, Department of Neuroscience, The Ohio State University College of Medicine, 333 W 10th Avenue, Columbus, OH 43210, USA. E-mail: beattie.2@osu.edu 1 Present address: Department of Neuroscience, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. Abbreviations used: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxaz- ole propionate; CGC, cerebellar granule cell; CNQX, 6-cyano-7-nitro- quinoxaline-2,3-dione; KA, kainate; K24, 24 mM potassium; K3, 3 mM potassium; MTT, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide; NBQX, 6-nitro-7-sulfamoyl-(f)-quinoxaline-2,3-dione. Journal of Neurochemistry , 2002, 83, 934–945 934 Ó 2002 International Society for Neurochemistry, Journal of Neurochemistry , 83, 934–945