Neurotoxicity of channel mutations in heterologously expressed α7-nicotinic acetylcholine receptors

Ronald J. Lukas, Linda Lucero, Bruno Buisson, Jean Luc Galzi, Elzbieta Puchacz, John D. Fryer, Jean Pierre Changeux, Daniel Bertrand

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Nicotinic acetylcholine receptors (nAChR) composed of chick α7 subunits mutated to threonine at amino acid valine-251 in the putative channel-lining M2 domain were expressed heterologously in several neuron-like and non-neuronal mammalian cell lines. Expression of mutant α7-nAChR is toxic to neuron-like cells of the human neuroblastoma cell lines SH-SY5Y and IMR-32, but not to several other cell types. Growth in the presence of the α7-nAChR antagonist methyllycaconitine (MLA) protects against neurotoxicity, as does gradual downregulation of functional, mutant α7-nAChR in surviving transfected SH-SY5Y cells. Relative to wild-type α7-nAChR, functional α7-nAChR mutants show a higher affinity for agonists, slower rates of desensitization, and sensitivity to dihydro-β-erythroidine (DHβE) as an agonist, but they retain sensitivity to MLA as a competitive antagonist. These findings demonstrate that expression of hyperfunctional, mutant forms of Ca2+-permeable α7-nAChR is toxic to neuron-like cells.

Original languageEnglish (US)
Pages (from-to)1849-1860
Number of pages12
JournalEuropean Journal of Neuroscience
Volume13
Issue number10
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

Nicotinic Receptors
Mutation
Poisons
Neurons
Cell Line
Valine
Cholinergic Antagonists
Threonine
Neuroblastoma
Down-Regulation
Amino Acids
Growth

Keywords

  • α-Bungarotoxin
  • Chick
  • Human
  • Neuronal cell death
  • Nicotine

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Neurotoxicity of channel mutations in heterologously expressed α7-nicotinic acetylcholine receptors. / Lukas, Ronald J.; Lucero, Linda; Buisson, Bruno; Galzi, Jean Luc; Puchacz, Elzbieta; Fryer, John D.; Changeux, Jean Pierre; Bertrand, Daniel.

In: European Journal of Neuroscience, Vol. 13, No. 10, 2001, p. 1849-1860.

Research output: Contribution to journalArticle

Lukas, RJ, Lucero, L, Buisson, B, Galzi, JL, Puchacz, E, Fryer, JD, Changeux, JP & Bertrand, D 2001, 'Neurotoxicity of channel mutations in heterologously expressed α7-nicotinic acetylcholine receptors', European Journal of Neuroscience, vol. 13, no. 10, pp. 1849-1860. https://doi.org/10.1046/j.0953-816X.2001.01560.x
Lukas, Ronald J. ; Lucero, Linda ; Buisson, Bruno ; Galzi, Jean Luc ; Puchacz, Elzbieta ; Fryer, John D. ; Changeux, Jean Pierre ; Bertrand, Daniel. / Neurotoxicity of channel mutations in heterologously expressed α7-nicotinic acetylcholine receptors. In: European Journal of Neuroscience. 2001 ; Vol. 13, No. 10. pp. 1849-1860.
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