MRC Laboratory of Molecular Biology

Glutamate-gated ion channels: biogenesis and trafficking

Greger IH, Akamine P, Khatri L, Ziff EB.(2006)
Developmentally regulated, combinatorial RNA processing modulates AMPA receptor biogenesis.
Neuron 51(1):85-97.

Greger IH, Esteban JA.(2007)
AMPA receptor biogenesis and trafficking.
Curr Opin Neurobiol. 17(3):289-97.

Penn, A.C., Williams, S.R. & Greger, I.H. (2008)
Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum.
EMBO J. 27, 3056-68.

Rossmann, M., Sukumaran, M., Penn, A.C., Veprintsev, D., Madan Babu, M. & Greger, I.H. (2011)
Subunit-selective N-terminal domain associations organize the formation of AMPA receptor heteromers.
EMBO J. 30, 959-71.

Sukumaran, M., Rossmann, M., Dutta, A., Shrivstava, I., Bahar, I. & Greger, I.H. (2011)
Dynamics and allosteric potential of the AMPA receptor N-terminal domain.
EMBO J. 30, 972-82.

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Glutamate-gated ion channels (iGluRs) mediate the majority of fast excitatory neurotransmission in vertebrate brains. These receptors are instrumental for the formation of neuronal circuits, and are key regulators of synaptic function and plasticity, which underlies higher-order cognitive processes. They comprise three functionally distinct subtypes: AMPA, NMDA and kainate receptors.

iGluRs are heterotetramers, the subunit composition determines receptor function at synapses and their trafficking to synapses, and is therefore central for information transfer in neuronal networks.
The rules underlying iGluR subunit assembly in the endoplasmic reticulum (ER) are largely elusive. Alternative RNA processing, including alternative (flip/flop) splicing and RNA editing modulates assembly properties of AMPA-type receptors. These genetic elements lie at strategic subunit interfaces in the ligand-binding domain and channel pore where they affect interface contacts and the quarternary conformation of the receptor, parameters which are sensed during biogenesis in the ER.
We are utilising cell biological, x-ray structural, and electrophysiological approaches to unravel, 1) the signatures that facilitate subunit assembly only within but not between iGluR families and drive preferential formation of receptor heteromers, 2) how recoding by RNA processing modulates the assembly process 3) the dynamics of receptor biogenesis in hippocampal model circuits, which is aimed at understanding the nature of iGluR remodelling in response to altered input.

Another key focus is the large extracellular portion of the iGluR, which in AMPA receptors encodes ~70% of primary polypeptide sequence. Using a combination of electrophysiology and x-ray crystallography we aim to elucidate allosteric signal propagation in this region in physiological and pathological settings.