AMPA-type glutamate receptors are expressed throughout the mammalian central nervous system and represent the principal means of fast excitatory signaling at central synapses. Functional AMPA receptors are homo- or hetero-oligomeric complexes generated by assembly of four individual subunits, GIuRI -4, each of which exists in at least two alternatively spliced isoforms. The molecular diversity that arises from varying subunit and splice-variant composition imparts unique functional properties to the receptors that can differ in their ionic permeabilities, unitary conductances, ligand binding affinities, and kinetics of activation, deactivation, desensitization, and recovery from desensitization. All of these properties are important to synaptic signaling. Particularly intriguing is the very rapid desensitization of AMPA receptor currents within a few milliseconds upon exposure to glutamate. The impact of such rapid desensitization on the synaptic response is yet unresolved, however the recent description of several non-desensitizing AMPA receptor mutants presents a unique opportunity to study how desensitization controls receptor and synaptic function. The proposed studies will compare the functional properties of the fast-desensitizing wild type and non-desensitizing mutant AMPA receptors by whole-cell and outside-out patch clamp recording in conjunction with ultra fast solution exchange techniques. Experiments will seek to determine the extent to which desensitization governs the receptor affinity for peak activation by glutamate and the rate of deactivation following removal of glutamate. These properties in turn limit the magnitude and duration of the postsynaptic response. Studies will also examine the mechanism of allosteric drug actions that target desensitization and seek to elucidate some of the amino acid residues that are important for desensitization. Results of these investigations should facilitate our understanding of the functional and pharmacological properties of AMPA receptors, their regulation by subunit composition, and the structural elements that are involved in this regulation.
| Mitchell, Nicholas A; Fleck, Mark W (2007) Targeting AMPA receptor gating processes with allosteric modulators and mutations. Biophys J 92:2392-402 |
| Kistler, Tara; Fleck, Mark W (2007) Functional consequences of natural substitutions in the GluR6 kainate receptor subunit ligand-binding site. Channels (Austin) 1:417-28 |
| Fleck, Mark W (2006) Glutamate receptors and endoplasmic reticulum quality control: looking beneath the surface. Neuroscientist 12:232-44 |
| Mah, Stephanie J; Cornell, Elizabeth; Mitchell, Nicholas A et al. (2005) Glutamate receptor trafficking: endoplasmic reticulum quality control involves ligand binding and receptor function. J Neurosci 25:2215-25 |
| Fleck, Mark W; Cornell, Elizabeth; Mah, Stephanie J (2003) Amino-acid residues involved in glutamate receptor 6 kainate receptor gating and desensitization. J Neurosci 23:1219-27 |
