AMPA receptor biogenesis, structure and function
Personal group site
Information transfer in the nervous system occurs at synapses, where presynaptic signals are interpreted by postsynaptic receptors. We study this process with a focus on AMPA-type glutamate receptors.
AMPA-Rs are glutamate-gated cation channel tetramers. They are the prime mediators of excitatory neurotransmission and are regulators of synaptic plasticity, which underlies higher-order cognitive processes. Our ultimate aim is to understand how AMPA-R signalling contributes to learning at synapses at various levels of complexity.
First, we study fundamental mechanisms underlying AMPA-R signalling with a specific focus on receptor biogenesis and allosteric modulation by interacting proteins. This aspect includes structural approaches such as X-ray crystallography, electron cryo-microscopy (cryo-EM), complemented by simulations of receptor dynamics and high-resolution electrophysiological recordings.
Secondly, we build on this information to unravel AMPA-R operation at synapses. We ask how AMPA-Rs of different subunit compositions are selectively targeted to and anchored at potentiated synapses, and how structural dynamics of AMPA-R tetramers contribute to functional and structural synaptic plasticity. Towards this aim we utilize a combination of brain slice electrophysiology and super-resolution light microscopy approaches.
- Zhang, D., Ivica, J., Krieger, J.M., Ho, H., Yamashita, K., Stockwell, I., Baradaran, R., Cais, O., Greger, I.H. (2023)
Structural mobility tunes signalling of the GluA1 AMPA glutamate receptor
Nature 621(7980): 877-882
- Zhang, D., Watson, J.F., Matthews, P.M., Cais, O. and Greger, I.H. (2021)
Gating and modulation of a hetero-octameric AMPA glutamate receptor
Nature 594(7863): 454-458. https://doi.org/10.1038/s41586-021-03613-0
- Herguedas, B., Watson, J.F., Ho, H., Cais, O., García-Nafría, J., Greger, I.H. (2019)
Architecture of the heteromeric GluA1/2 AMPA receptor in complex with the auxiliary subunit TARP γ8
Science 364(6438): pii: eaav9011. doi: 10.1126/science.aav9011.
- Watson JF, Ho H, Greger IH. (2017)
Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain
Elife 14;6: pii: e23024.
- Greger, I.H., Watson, J.F., Cull-Candy, S.G. (2017)
Structural and Functional Architecture of AMPA-Type Glutamate Receptors and Their Auxiliary Proteins
Neuron 94: (4):713-730.
- Herguedas, B., García-Nafría, J., Cais, O., Fernández-Leiro, R., Krieger, J., Ho, H. and Greger, I.H. (2016)
Structure and organization of heteromeric AMPA-type glutamate receptors
Science 352: (6285):aad3873.
- Cais, O., Herguedas, B., Krol, K., Cull-Candy, S.G., Farrant, M. and Greger, I.H. (2014)
Mapping the interaction sites between AMPA receptors and TARPs reveals a role for the receptor N-terminal domain in channel gating.
Cell Rep. 9: 728-40
- Penn, A.C., Balik, A., Wozny, C., Cais, O. and Greger I.H. (2012)
Activity-mediated AMPA receptor remodeling, driven by alternative splicing in the ligand-binding domain.
Neuron 76: 530-10
- Ondrej Cais
- Joseph Gehler
- Josip Ivica
- Terunaga Nakagawa
- Mikel Perez Rodriguez
- Aditya Pokharna
- Alex Scrutton
- Imogen Stockwell