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Title: | Molecular mechanisms contributing to TARP regulation of channel conductance and polyamine block of calcium-permeable AMPA receptors. |
Author: | Soto del Cerro, David Coombs, Ian D. Gratacòs i Batlle, Esther Farrant, Mark Cull-Candy, Stuart G. |
Keywords: | Biologia molecular Neurociències Receptors de neurotransmissors Molecular biology Neurosciences Neurotransmitter receptors |
Issue Date: | 27-Aug-2014 |
Publisher: | The Society for Neuroscience |
Abstract: | Many properties of fast synaptic transmission in the brain are influenced by transmembrane AMPAR regulatory proteins (TARPs) that modulate the pharmacology and gating of AMPA-type glutamate receptors (AMPARs). Although much is known about TARP influence on AMPAR pharmacology and kinetics through their modulation of the extracellular ligand-binding domain (LBD), less is known about their regulation of the ion channel region. TARP-induced modifications in AMPAR channel behavior include increased single-channel conductance and weakened block of calcium-permeable AMPARs (CP-AMPARs) by endogenous intracellular polyamines. To investigate how TARPs modify ion flux and channel block, we examined the action of γ-2 (stargazin) on GluA1 and GluA4 CP-AMPARs. First, we compared the permeation of organic cations of different sizes. We found that γ-2 increased the permeability of several cations but not the estimated AMPAR pore size, suggesting that TARP-induced relief of polyamine block does not reflect altered pore diameter. Second, to determine whether residues in the TARP intracellular C-tail regulate polyamine block and channel conductance, we examined various γ-2 C-tail mutants. We identified the membrane proximal region of the C terminus as crucial for full TARP-attenuation of polyamine block, whereas complete deletion of the C-tail markedly enhanced the TARP-induced increase in channel conductance; thus, the TARP C-tail influences ion permeation. Third, we identified a site in the pore-lining region of the AMPAR, close to its Q/R site, that is crucial in determining the TARP-induced changes in single-channel conductance. This conserved residue represents a site of TARP action, independent of the AMPAR LBD. |
Note: | Reproducció del document publicat a: https://doi.org/10.1523/JNEUROSCI.0383-14.2014 |
It is part of: | Journal of Neuroscience, 2014, vol. 34, num. 35, p. 11673-11683 |
URI: | http://hdl.handle.net/2445/118862 |
Related resource: | https://doi.org/10.1523/JNEUROSCI.0383-14.2014 |
ISSN: | 0270-6474 |
Appears in Collections: | Articles publicats en revistes (Biomedicina) Publicacions de projectes de recerca finançats per la UE |
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