AMPA Receptor Assembly: Atomic Determinants and Built-In Modulators
Glutamate-gated ion channels (iGluRs) predominantly operate as heterotetramers to mediate excitatory neurotransmission at glutamatergic synapses. The subunit composition of the receptors determines their targeting to synaptic sites and signalling properti
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AMPA Receptor Assembly: Atomic Determinants and Built-In Modulators Madhav Sukumaran, Andrew C. Penn, and Ingo H. Greger
Abstract Glutamate-gated ion channels (iGluRs) predominantly operate as heterotetramers to mediate excitatory neurotransmission at glutamatergic synapses. The subunit composition of the receptors determines their targeting to synaptic sites and signalling properties and is therefore a fundamental parameter for neuronal computations. iGluRs assemble as obligatory or preferential heteromers; the mechanisms underlying this selective assembly are only starting to emerge. Here we review recent work in the field and provide an in-depth update on atomic determinants in the assembly domains, which have been facilitated by recent advances in iGluR structural biology. We also discuss the role of alternative RNA processing in the ligand-binding domain, which modulates a central subunit interface and has the capacity to modulate receptor formation in response to external cues. Finally, we review the emerging physiological significance of signalling via distinct iGluR heterotetramers and provide examples of how recruitment of functionally diverse receptors modulates excitatory neurotransmission under physiological and pathological conditions.
M. Sukumaran Laboratory of Cellular and Synaptic MRC LMB and Neurophysiology, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA A.C. Penn Univ. de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000, Bordeaux, France CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France I.H. Greger (*) Neurobiology Division, MRC Laboratory of Molecular Biology, Hills Road, CB2 0QH Cambridge, UK e-mail: [email protected] M.R. Kreutz and C. Sala (eds.), Synaptic Plasticity, Advances in Experimental Medicine and Biology 970, DOI 10.1007/978-3-7091-0932-8_11, # Springer-Verlag/Wien 2012
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Keywords Alternative splicing • AMPA receptor biosynthesis • Endoplasmic reticulum • Ligand binding domain • N-(amino) terminal domain • RNA editing • Synaptic plasticity
11.1
From Polysome to Receptor Oligomer
Cell surface receptors, such as ion channels and G-protein-coupled receptors, prominently operate as hetero-oligomers. Assembly from a pool of different subunits increases the versatility and plasticity of signal transmission and is under complex cellular control. Ionotropic glutamate receptors (iGluRs) provide a dramatic example of how functionally diverse receptor stoichiometries shape an essential cellular process. iGluRs mediate excitatory neurotransmission in vertebrate nervous systems. This process involves three distinct iGluR subfamilies (AMPA-, NMDA- and kainate types), differentially expressed and regulated subunits within each subfamily, and a multitude of accessory subunits (Hollmann and Heinemann 1994; Traynelis et al. 2010). The result of this rich variety of assembly substituents is a combinatorial diversity
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