A cDNA clone, GluR Kl, coding for a kainate subtype of the glutamate receptor family has been isolated in the laboratory. The GluR KI cDNA codes for a protein which forms a functional glutamate receptor when expressed in Xenopus oocytes. The fast kinetics of the glutamate response and the preliminary structural data that has been obtained suggest that the GluR Kl gene product is a member of the ligand-gated channel superfamily. A major goal of the work proposed in this application is to clone the genes coding for the remaining members of the family of glutamate receptors, including the NMDA receptor subtype. The long term aim of this research is to understand the mammalian glutamate receptor family at the molecular level. The glutamate receptor system is a major excitatory receptor in the brain and one glutamate receptor subtype, the NMDA receptor is thought to be involved in a number of important brain mechanisms and brain disorders. The NMDA receptor has been implicated in the early steps of memory and learning as well as developmental plasticity. The NMDA receptors are also thought to contribute to the uncontrolled electrical activity in epilepsy and to mediate the neurotoxic effects seen after brain ischaemia. Physiological experiments have demonstrated that the NMDA receptor is a complex molecule with numerous ligands and binding sites that can modulate function. Thus, it important to understand in molecular detail how the glutamate receptors and in particular the NMDA receptors work. It will then be possible to relate the structural differences between the receptor subtypes to the operations that the receptors carry out in the nervous system. Site-- directed mutagenesis will be used to generate mutant receptors which will be analyzed in functional assays and in transgenic mice. The availability of cloned genes makes it possible to use the techniques of molecular biology and physiology to begin to understand the role that the glutamate receptor family plays in normal brain function, especially in learning and memory, and in the many disorders of the brain, including epilepsy and the neurotoxic effects that occur after stroke and brain ischaemia.