Q/R editing of the rat GluR5 and GluR6 kainate receptors in vivo and in vitro: evidence for independent developmental, pathological and cellular regulation

Kainate (KA) is a potent neuroexcitatory agent in several areas of the adul t brain, with convulsant and excitotoxic properties that increase as ontoge ny proceeds. Besides its depolarizing actions, KA may enhance intracellular accumulation of Ca2+ to promote selective neuronal damage. The effects of KA are mediated by specific receptors recently considered to be involved in fast neurotransmission and that can be activated synaptically. KA receptor s, e.g. GluR5 and GluR6 have been characterized by molecular cloning. Struc ture-function relationships indicate that in the MII domain of these KB rec eptors, a glutamine (Q) or arginine (R) residue determines ion selectivity. The arginine stems from post-transcriptional editing of the GluR5 and GluR 6 pre-RNAs, and the unedited and edited versions of GluR6 elicit distinct C a2+ permeability Using a PCR-based approach, we show that in vivo, Q/R edit ing in the GluR5 and GluR6 mRNAs is modulated during ontogeny and differs s ubstantially in a variety of nervous tissues. GluR5 editing is highest in p eripheral nervous tissue, e.g. the dorsal root ganglia, where GluR6 express ion is barely detectable. In contrast, GluR6 editing is maximal in forebrai n and cerebellar structures where GluR5 editing is lower. Intra-amygdaloid injections or KA provide a model of temporal lobe epilepsy, and we show tha t following seizures, the extent of GluR5 and GluR6 editing is altered in t he hippocampus. However, in vitro, high levels of glutamate and potassium-i nduced depolarizations have no effect on GluR5 and GluR6 Q/R editing. GluR6 editing is rapidly enhanced to maximal levels in primary cultures of cereb ellar granule neurons but not in cultured hippocampal pyramidal neurons. Fi nally, we show that cultured glial cells express partially edited GluR6 mRN As, Our results indicate that Q/R editing of GluR5 and GluR6 mRNAs is struc ture; cell type- and time-dependent, and suggest that editing of these mRNA s is not co-regulated.