Regulation of kainate-type glutamate receptors by auxiliary subunits

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 DESCRIPTION (provided by applicant): The ionotropic glutamate receptors are responsible for fast excitatory neurotransmission in the mammalian brain. There are three types of ionotropic glutamate receptors, named the AMPA, NMDA and kainate receptors. Kainate-type glutamate receptors are found in both pre- and post-synaptic locations, where they regulate neurotransmitter release and increase neuronal excitability. Dysregulation of kainate receptors has been linked to a variety of neurological disorders. In particular, abnormal expression patterns of these receptors may contribute to hyperexcitability of the hippocampus in temporal lobe epilepsy. The kainate receptors are tetrameric in structure, composed from a combination of five different pore-forming subunits (GluK1-GluK5). In addition, the kainate receptors can be regulated by co-assembly with the auxiliary subunits Neto1 and Neto2. Both the pore-forming and auxiliary subunits show distinct patterns of expression throughout the brain and may be regulated throughout development and in response to pathological conditions. The goal of this work is to determine the functional impact of subunit-specific interactions between pore-forming and auxiliary subunits, in order to predict the characteristics of neuronal receptors. In addition, we will use chimeric subunits and site-directed mutagenesis to determine the structural differences between the Neto1 and Neto2 subunits that give rise to their distinct functional effects. The results of this work will illuminate the roles that auxiliary subunits play in the regulation of excitatory neurotransmission and will suggest novel approaches for the treatment of neurological disorders through the targeted regulation of specific receptor populations.