Premium
Neurotoxicity of channel mutations in heterologously expressed α7‐nicotinic acetylcholine receptors
Author(s) -
Lukas Ronald J.,
Lucero Linda,
Buisson Bruno,
Galzi JeanLuc,
Puchacz Elzbieta,
Fryer John D.,
Changeux JeanPierre,
Bertrand Daniel
Publication year - 2001
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.0953-816x.2001.01560.x
Subject(s) - methyllycaconitine , neurotoxicity , neuron , mutant , nicotinic acetylcholine receptor , chemistry , agonist , receptor , microbiology and biotechnology , acetylcholine receptor , nicotinic agonist , nicotinic antagonist , transfection , biochemistry , biology , neuroscience , toxicity , organic chemistry , gene
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 Ca 2+ ‐permeable α7‐nAChR is toxic to neuron‐like cells.