Modeling noncompetitive antagonism of a nicotinic acetylcholine receptor

Biophysical Journal
Denis B TikhonovP N R Usherwood

Abstract

Models of closed and open channel pores of a muscle-type nicotinic acetylcholine receptor (nAChR) channel comprising M1 and M2 segments are presented. A model of the closed channel is proposed in which hydrophobic residues of the Equatorial Leucine ring screen the oxygen domain formed by the Serine ring, thereby preventing ion flux without completely occluding the pore. This model demonstrates a high similarity with the structure derived from a recent electron microscopy study. We propose that hydrophobic residues of the Equatorial Leucine ring are retracted when the pore is open. Our models provide a possible resolution of the nAChR gate controversy. We have also obtained explanations for the complex mechanisms underlying inhibition of nAChR by philanthotoxins (PhTXs). PhTX-343, containing a spermine moiety with a charge of +3, binds deep in the pore near the Serine ring where classical open channel blockers of nAChR bind. In contrast, PhTX-(12), which has a single charged amino group is unable to reach deeply located rings because of steric restrictions. Both philanthotoxins may bind to a hydrophobic site located close to the external entrance of the pore in a region that includes residues associated with the regulation of de...Continue Reading

References

Jun 1, 1988·Trends in Neurosciences·H Jackson, P N Usherwood
Jul 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·A T EldefrawiP N Usherwood
Oct 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·Z Li, H A Scheraga
Jun 3, 2000·Annual Review of Pharmacology and Toxicology·P J CorringerJ P Changeux
Mar 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Yong YuArthur Karlin
Jun 27, 2003·Nature·Atsuo MiyazawaNigel Unwin
Nov 25, 2003·FEBS Letters·Oliver BecksteinMark S P Sansom
Apr 7, 2004·Toxicon : Official Journal of the International Society on Toxinology·Ian R Mellor, Peter N R Usherwood
Jun 30, 2004·Medicinal Research Reviews·Kristian Strømgaard, Ian Mellor

❮ Previous
Next ❯

Citations

Sep 21, 2010·Quarterly Reviews of Biophysics·Andrew J ThompsonSarah C R Lummis
Mar 10, 2010·Biochemistry. Biokhimii︠a︡·A A VassilevskiE V Grishin
Jan 9, 2007·Journal of Molecular Graphics & Modelling·Huabei ZhangQinqin Ma
May 16, 2007·British Journal of Pharmacology·A J ThompsonS C R Lummis
May 9, 2012·European Journal of Pharmacology·David W McClymontIan R Mellor
Dec 15, 2010·Toxicon : Official Journal of the International Society on Toxinology·Paulo C GomesMario S Palma
Jul 26, 2008·Molecular Pharmacology·Iva BruhovaBoris S Zhorov

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antipsychotic Drugs

Antipsychotic drugs are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Discover the latest research on antipsychotic drugs here