Figure 1. a, An example cryo-EM micrograph showing GluA2-STZ particles bound to the neurotransmitter, with some example particles circled in red. b, Cryo-EM density of the activated GluA2-STZ complex bound to glutamate. The A/C subunits are colored purple, B/D green and STZ in teal. Example molecules of glutamate, which would be diffusing through synaptic space in tissue, are illustrated as pink polygons.
AMPA-subtype glutamate receptors (AMPARs) are the major receptors in the brain that regulate excitatory neurotransmission in response to the neurotransmitter glutamate. In neurons, AMPARs are tightly regulated by transmembrane AMPAR regulatory proteins (TARPs). Aberrancies in the formation of these AMPAR complexes lead to disruption of excitatory neurotransmission, resulting in a wide-range of acute and chronic neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases, epilepsy, stroke-induced cell death and schizophrenia. Using cryo-electron microscopy (cryo-EM), we investigated how the AMPAR GluA2 assembles with the prototypical TARP protein, stargazin (STZ) and the subunit GSG1L. We provided the first evidence of how these regulatory units structurally assemble with receptors to regulate brain signaling, and how the proteins respond structurally to the neurotransmitter glutamate to impact neurotransmission. Our findings provide new understandings for the molecular basis of neuronal signaling and neurodegeneration.
- Twomey, et al. Science 2016.
- Twomey, et al. Neuron 2017.
- Twomey, et al. Nature 2017.
- Twomey, et al. Biochemistry 2018.
Relevant news stories:
- “New Images of Brain Receptor Could Lead to MS Therapy Breakthroughs” – MD Magazine
- “Scientists Capture First Image of Major Brain Receptor in Action“ – CUMC Newsroom
- “Detailed Images Reveal Interactions that Affect Signaling In The Brain” – CUMC Newsroom
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