Kainate receptors are glutamate-gated ion channels that mediate synaptic transmission and regulate cellular excitability in the central nervous system. They contribute to cognitive processing by participating in the generation of rhythmic oscillations of hippocampal neurons at behaviorally relevant frequencies. Kainate receptors have also been implicated in a number of neurological disorders including temporal lobe epilepsy, schizophrenia, autism, and neuropathic pain. Rational development of novel therapies targeting these receptors depends upon a better understanding of their function. Kainate receptors are tetrameric and comprised of low affinity GluR5-7 and high affinity KA1 and KA2 subunits. Functional properties of kainite receptors depend upon their subunit composition. In particular, KA2-containing kainate receptors play a distinctive role in neuronal excitation. Current at KA2-containing kainate receptors exhibits a higher conductance and slower decay than that at KA2-lacking kainate receptors. In addition, KA2-containing kainate receptors enhance intrinsic neuronal excitability through a noncanonical metabotropic action. Perhaps because of their importance in neuronal excitation, receptors containing the KA2 subunit exhibit significantly increased sensitivity to modulation by a variety of endogenous agents, including protons, polyamines and zinc. While recent studies have shed light on the roles of KA2-containing kainate receptors in physiological conditions, little is known about how the expression of kainate receptor subunits or the functional role of these receptors changes in disease. Kainate receptors have long been implicated in mechanisms underlying temporal lobe epilepsy. A better understanding of how the properties and regulation of kainate receptors change in temporal lobe epilepsy would provide valuable information in the design of novel therapies for this disease. This project will examine the role of the KA2 subunit in kainate receptors in physiological conditions and in epilepsy.
Aim 1 will use recombinant receptors to define the functional contribution of KA2 subunits to kainate receptors.
Aim 2 will use lentiviral vectors and pharmacological agents to determine the effect of changes in KA2 subunit expression on KAR-mediated neurotransmission.
Aim 3 will use quantitative real time qRT-PCR and immunohistochemistry to determine the time course of changes in KAR subunit RNA and protein in the hippocampus during the development of epilepsy after pilocarpine-induced status epilepticus (SE). Hippocampal slice electrophysiology combined with pharmacological agents and lentiviral vectors will then define how SE-induced alterations in subunit expression change functional properties of kainate receptors at these same time points.
Kainate receptors are glutamate-gated ion channels that are critical for synaptic transmission and can contribute to neurological diseases, such as temporal lobe epilepsy, schizophrenia, autism, and neuropathic pain. The goals of this study are to examine subunit dependent properties of these receptors and the impact of changes in subunit composition on hippocampal function. A better understanding of kainate receptor properties is essential in the rational development of novel therapeutic agents targeted at these receptors.
|Fisher, Janet L (2015) The auxiliary subunits Neto1 and Neto2 have distinct, subunit-dependent effects at recombinant GluK1- and GluK2-containing kainate receptors. Neuropharmacology 99:471-80|
|Fisher, Janet L (2014) The neurotoxin domoate causes long-lasting inhibition of the kainate receptor GluK5 subunit. Neuropharmacology 85:9-17|
|Fisher, M T; Fisher, J L (2014) Contributions of different kainate receptor subunits to the properties of recombinant homomeric and heteromeric receptors. Neuroscience 278:70-80|
|Fisher, Janet L; Mott, David D (2013) Modulation of homomeric and heteromeric kainate receptors by the auxiliary subunit Neto1. J Physiol 591:4711-24|
|Fisher, Janet L; Housley, Paul R (2013) Agonist binding to the GluK5 subunit is sufficient for functional surface expression of heteromeric GluK2/GluK5 kainate receptors. Cell Mol Neurobiol 33:1099-108|
|Fisher, Janet L; Mott, David D (2012) The auxiliary subunits Neto1 and Neto2 reduce voltage-dependent inhibition of recombinant kainate receptors. J Neurosci 32:12928-33|
|Mott, David D; Dingledine, Raymond (2011) Unraveling the role of zinc in memory. Proc Natl Acad Sci U S A 108:3103-4|
|Fisher, Janet L; Mott, David D (2011) Distinct functional roles of subunits within the heteromeric kainate receptor. J Neurosci 31:17113-22|
|Benveniste, Morris; Wilhelm, Jennifer; Dingledine, Raymond J et al. (2010) Subunit-dependent modulation of kainate receptors by muscarinic acetylcholine receptors. Brain Res 1352:61-9|
|Mott, David D; Rojas, Asheebo; Fisher, Janet L et al. (2010) Subunit-specific desensitization of heteromeric kainate receptors. J Physiol 588:683-700|