The long-term objective of this research is to identify and understand the molecular events that occur when synaptic glutamate receptors are activated. The majority of excitatory information that is transmitted in the central nervous system (CNS) is mediated by the activation of glutamate receptors. Consequently, glutamate receptors are pivotal for numerous neurological functions including learning and memory but are also associated with acute and chronic nervous disorders such as epilepsy and ischemia-induced neuronal injury. Within the last decade, glutamate receptors have been identified as targets for the development of therapeutically relevant compounds. However, despite the considerable time, effort and financial cost that have been exacted in recent years, few drugs show promise for clinical use. Recently, the first crystal structure of the agonist-binding domain of the AMPA receptor, a glutamate receptor subtype, has been obtained. Although, future drug development will benefit from the atomic resolution of crystal structures, a dynamic, three-dimensional model of the AMPA receptor will also require further insight into the events that lead to and control the opening and closing of the AMPA receptor ion-channel. The research in this proposal will focus on the observation that ion flow through the pore region (permeation) of AMPA receptors interacts with the transduction events that are initiated by agonist binding (gating). This finding has not been documented previously and suggests that permeation and gating of AMPA receptors are coupled. Single channel and macroscopic measurements of recombinant and genetically modified AMPA receptors will be studied in different ionic conditions to characterize this observation. The proposed research will provide basic operational information on two gating modes of AMPA receptors; deactivation and desensitization that shape the time course of excitatory signals in the CNS. Memory- and cognition-enhancing drugs that may be used in the treatment of Alzheimer's disease are believed to prolong deactivation and desensitization of AMPA receptors. Experiments will investigate if changes in the properties of the pore reflect the slowing of each gating mode of the AMPA receptor.
