A Role for Leu118 of loop E in agonist binding to the α7 nicotinic acetylcholine receptor

Shiva Amiri, Masaru Shimomura, Ranjit Vijayan, Hisashi Nishiwaki, Miki Akamatsu, Kazuhiko Matsuda, Andrew K. Jones, Mark S.P. Sansom, Philip C. Biggin, David B. Sattelle

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating fast cholinergic synaptic transmission in the brain and at neuromuscular junctions. We used the structure of the acetylcholine binding protein from Lymnaea stagnalis to model the chicken α7 agonist-binding domain. The initial models and a preliminary docking study suggested that position Leu118 may play an important role in determining agonist actions on α7. A prediction from these in silico studies, that L118E and L118D would retain binding to acetylcholine but L118K and L118R would not, was confirmed in electrophysiological studies on functional recombinant mutant receptors expressed in Xenopus laevis oocytes. The functional studies also demonstrated that residues at position 118 have a dramatic effect on the actions of imidacloprid (a partial agonist of wild-type α7 receptors) and its des-nitro derivative. Molecular dynamics simulations confirmed that Leu118 can strongly influence agonist binding and that the model was robust in terms of its prediction for acetylcholine binding. Together, the results indicate a role for Leu118 in influencing agonist actions on α7 nAChRs.

Original languageEnglish
Pages (from-to)1659-1667
Number of pages9
JournalMolecular Pharmacology
Volume73
Issue number6
DOIs
Publication statusPublished - Jun 2008
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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