AMPA receptor biogenesis, structure and function
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, cryo-electron 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.
- 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
- Sukumaran, M., Rossmann, M., Dutta, A., Shrivstava, I., Bahar, I. and Greger, I.H. (2011)
Dynamics and allosteric potential of the AMPA receptor N-terminal domain.
EMBO J 30: 972-82.
- Rossmann, M., Sukumaran, M., Penn, A.C., Veprintsev, D., Madan Babu, M. and Greger, I.H. (2011)
Subunit-selective N-terminal domain associations organize the formation of AMPA receptor heteromers.
EMBO J 30: 959-71.
- Ondrej Cais
- Maria Carvalho
- Beatriz Herguedas
- Sui Hin (Hinze) Ho
- Bianka Kohegyi
- Peter Matthews
- Alexandra Pinggera
- Matti Pronker
- Jake Watson