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Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor

F Revah1, D Bertrand, J L Galzi

  • 1Neurobiologie Moléculaire, Unité de Recherche Associée au Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France.

Nature
|October 31, 1991
PubMed

Insights

Mutations in the alpha 7 acetylcholine receptor reveal a link between channel structure and desensitization. Altering a key leucine residue impacts agonist binding, channel gating, and desensitization rates.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biophysics

Background:

  • Ligand-gated ion channels, like the acetylcholine receptor, activate rapidly but desensitize with prolonged agonist exposure.
  • Desensitization involves distinct closed states with higher agonist affinity than active states.
  • The alpha 7 nicotinic acetylcholine receptor (α7 nAChR) is a homo-oligomeric channel implicated in various brain functions.

Purpose of the Study:

  • Investigate the role of structural elements in the desensitization of the chick brain α7 nAChR.
  • Utilize site-directed mutagenesis to probe the function of conserved residues within the channel.

Main Methods:

  • Site-directed mutagenesis of the chick brain α7 nAChR.
  • Expression of mutated receptors in Xenopus oocytes.
  • Electrophysiological recordings to assess channel function, desensitization, and blocker sensitivity.

Main Results:

  • Mutation of Leucine 247 (L247) in the MII segment, facing the channel lumen, suppressed QX-222 inhibition.
  • L247 mutations decreased desensitization rates and increased apparent acetylcholine affinity.
  • Mutant channels exhibited abolished current rectification and an additional low-concentration conducting state.

Conclusions:

  • Leucine 247 is crucial for normal desensitization kinetics and gating of the α7 nAChR.
  • Mutation of L247 may unmask or stabilize a high-affinity desensitized state, rendering it conductive.
  • Structural insights into α7 nAChR desensitization mechanisms were gained.

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