Ionotropic glutamate receptors (iGluRs) are oligomeric ligand-gated ion channels responsible for mediating fast excitatory neurotransmission in the brain. The large extracellular domain is composed of an amino terminal domain (ATD) and a ligand-binding domain (S1S2). The overall goal of this proposal is to understand the role of the ATD in assembly, agonist/antagonist binding, channel gating, and subsequent desensitization in iGluRs. To achieve this objective, a multifaceted approach is proposed. Once an ATD or ATD-S1S2 construct is purified, its aggregation state and ligand-binding properties will be examined. Initial hypotheses derived from subsequent structural analysis of either a dimeric ATD or tetrameric ATD-S1S2 will be tested by site-directed mutagenesis and electrophysiological measurements of ion conductance in the intact receptor. iGluR dysfunction has been implicated in disease states such as epilepsy, stroke, and schizophrenia and, thus, knowledge of the structure/function relationships obtained from this study may assist in the development of novel therapeutics.