Research Summary

Molecular Mechanisms for Regulation of Ionotropic Glutamate Receptors by their Auxiliary Subunits

Ionotropic glutamate receptors (iGluRs) form the cornerstones of fast excitatory neurotransmission in the mammalian central nervous system. They are essential for many basic nervous system functions, including learning and development, and are involved in a remarkable range of neuronal diseases. Despite their physiological importance, our understanding of these receptors is hampered by a lack of insight into their complex structures and working mechanisms. Recombinant iGluRs on their own form functional channels and are capable of eliciting glutamate-evoked currents in heterologous expression systems, but recent evidence indicates that rather than existing as independent units, native iGluRs are part of a signaling complex that involves transmembrane auxiliary proteins. Till date several of these transmembrane auxiliary subunits have been discovered, which regulate the native iGluRs gating properties, pharmacology, distribution and trafficking to synapses. However, there has been essentially no progress towards understanding the structural basis of how this expanding family of glutamate receptor auxiliary membrane proteins modulates receptor function.

To address this, I propose to undertake structure-function analysis of the iGluR auxiliary subunits targeting both the isolated extracellular domains as well as intact full-length proteins to elucidate their mechanisms of action. The experimental plan combines a multipronged approach including X-ray crystallography, electrophysiology, and a variety of biophysical and biochemical techniques. Structure based functional and mutational analysis will also be carried out to test the veracity of the structural findings. Completion of my aims will not only provide structural and mechanistic details but also provide crucial molecular blueprints to guide the development of new drugs targeting these receptors.