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Genetic manipulation of key determinants of ion flow in glutamate receptor channels in the mouse

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Seeburg,  Peter H.
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

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Single,  Frank Nicolai
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

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Kuner,  Thomas
Interdisciplinary WIN-Research Group on Olfactory Dynamics, Max Planck Institute for Medical Research, Max Planck Society;
Synaptic Transmission MNTB, Max Planck Institute for Medical Research, Max Planck Society;
Synaptic Transmission, Max Planck Institute for Medical Research, Max Planck Society;
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;
Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society;

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Higuchi,  Miyoko
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

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Sprengel,  Rolf
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Seeburg, P. H., Single, F. N., Kuner, T., Higuchi, M., & Sprengel, R. (2001). Genetic manipulation of key determinants of ion flow in glutamate receptor channels in the mouse. Brain Research, 907(1), 233-243. doi:10.1016/S0006-8993(01)02445-3.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0029-223A-D
Abstract
Glutamate receptor channels are built around an ancient pore loop structure which defines the inner channel environment and which is connected to structures for channel gating. This pore loop, which corresponds to the M2 region of the receptor subunits, enters the lipid bilayer from the intracellular side in an α-helical configuration, then kinks to form a random coil and exits the lipid bilayer at the intracellular side. The narrow constriction of the channel is formed by amino acid residues that occupy a position shortly after the end of the α-helical part of M2. These residues determine ion selectivity and conductance properties of the glutamate-gated channel. The critical residues are asparagines for NMDA receptor subunits and glutamine or arginine for AMPA and kainate receptor subunits. Presence of arginine in the critical channel position of AMPA and kainate receptors is controlled by site-selective RNA editing. To study the importance of these critical channel residues in the mouse, we introduced codon changes in the endogenous genes for NMDA and AMPA receptor subunits. Our results show that changes in the critical channel position are not tolerated, but lead to early death. Therefore, the impact on adult synaptic function and plasticity by glutamate receptor channels with changed ion selectivity and conductance needs to be addressed by conditional expression of the mutant receptors.