Understanding the activation-deactivation mechanism of glutamate receptor proteins at the single molecule level

Ionotropic glutamate receptor proteins form ion channels at the neuronal membrane and mediate excitatory synaptic neurotransmission in the mammalian central nervous system. These receptor proteins, such as NMDA and AMPA receptors, are structurally diverse and house multiple extracellular and intracellular binding sites, which can modulate activated (open) or deactivated (closed) states of the ion channel. The gating action (activation and deactivation) of the ion channels are controlled by a number of molecules (ligands) interacting with specific binding sites. Hence, these binding sites can serve as potential drug targets for controlling the aberrant activation of the ion channel that leads to a number of neurological disorders. In this research, we have utilized single molecule Förster Resonance Energy Transfer (smFRET) spectroscopy to provide a mechanistic understanding of the activation processes that the receptors undergo. We have probed, at a single molecule level, the structural changes explored by the NMDA receptor proteins, upon binding with several ligands that induce different modes of activation and have provided a comprehensive mechanism for their gating action. Furthermore, we have reported the conformational behavior induced by phosphorylation, at the structurally unresolved C-terminal domain of the AMPA receptors. We have demonstrated the capability of single molecule spectroscopy for studying such complex protein structures and deciphering mechanisms that would otherwise remain unresolved by ensemble measurements. The results from this study are expected to contribute to the ever-expanding research of targeted neuro-therapy.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Natural Sciences

Grantor

Rice University

Year dc:date.issued

2019

Author dc:creator

• Chatterjee, Sudeshna

Advisor dc:contributor.advisor

• Landes, Christy F.

• Glutamate receptors
• NMDA
• AMPA
• smFRET

Statement dc:rights

• Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1911/105998

OAI identifier oai:identifier

oai:repository.rice.edu:1911/105998