Modeling of the pore domain of the GLUR1 channel: homology with K+ channel and binding of channel blockers

Biophysical Journal
Denis B TikhonovL G Magazanik

Abstract

Molecular models of the M2 segments of the GluR1 channel have been elaborated using a molecular mechanics approach. The models are based on the homology between pore-lining segments of AMPA receptor channels and the KcsA K+ channel and on cyclic H bonds at the Q/R site of the AMPA receptor channel. The N-terminal region of an M2 segment of the channel is assumed, like that of the K+ channel, to adopt a helical conformation. Due to a deletion, the C-terminal end of the M2 segment of the AMPA receptor is more stretched than that of the K+ channel. As a result, only a single oxygen ring may be exposed to the AMPA receptor channel pore. Data on the block of AMPA receptor channels by dicationic adamantane derivatives have been used to select the most relevant model. The model with the oxygen of a Gly residue (position +2 from the Q/R site) exposed to the pore best fits the experimental data. This model also fits experimental data for another class of AMPA receptor antagonists, the polyamine amides. According to the model, the side-chains of the C-terminal residues are involved in intra-receptor interactions that stabilize the structure of the channel rather than in interactions with ions in the pore.

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Citations

Jan 14, 2009·Journal of Molecular Neuroscience : MN·Tatyana B TikhonovaLev G Magazanik
Apr 7, 2004·Toxicon : Official Journal of the International Society on Toxinology·Ian R Mellor, Peter N R Usherwood
Aug 17, 2011·Biochemistry·Oleg I BaryginDenis B Tikhonov
Feb 26, 2013·Chemical Reviews·Lukas WankaPeter R Schreiner
Jan 17, 2012·Nature Neuroscience·Beth Siegler RetchlessJon W Johnson
Aug 19, 2010·Pharmacological Reviews·Stephen F TraynelisRay Dingledine
Mar 10, 2010·Biochemistry. Biokhimii︠a︡·A A VassilevskiE V Grishin
Jun 30, 2004·Medicinal Research Reviews·Kristian Strømgaard, Ian Mellor
Aug 30, 2008·Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP·I M FedorovaD B Tikhonov
Feb 6, 2004·Journal of Neurochemistry·Boris S Zhorov, Denis B Tikhonov
Feb 3, 2005·Toxicon : Official Journal of the International Society on Toxinology·Kristian StrømgaardStine B Vogensen
Sep 13, 2003·Journal of Neurochemistry·K V BolshakovL G Magazanik
May 9, 2012·European Journal of Pharmacology·David W McClymontIan R Mellor
Nov 19, 2003·Neuron·Ingo H GregerEdward B Ziff
Oct 15, 2003·Neuron·David S Bredt, Roger A Nicoll
Aug 21, 2007·Neurochemistry International·Gábor SzénásiLaszlo G Harsing
Jul 9, 2004·Biophysical Journal·Denis B TikhonovPeter N R Usherwood
Aug 22, 2003·The Journal of Biological Chemistry·Nathalie Strutz-SeebohmMichael Hollmann
Aug 31, 2006·Magnetic Resonance in Chemistry : MRC·Kristian StrømgaardJerzy W Jaroszewski
Apr 25, 2007·Molecular Membrane Biology·Denis B Tikhonov
Jan 7, 2005·Journal of Medicinal Chemistry·Malene R JørgensenJerzy W Jaroszewski
Sep 1, 2006·Journal of Medicinal Chemistry·Trine F AndersenKristian Strømgaard

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