Neurotoxicity Of Channel Mutations In Heterologously Expressed Î±7-Nicotinic Acetylcholine Receptors
Nicotinic acetylcholine receptors (nAChR) composed of chick Î±7 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 Î±7-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 Î±7-nAChR antagonist methyllycaconitine (MLA) protects against neurotoxicity, as does gradual downregulation of functional, mutant Î±7-nAChR in surviving transfected SH-SY5Y cells. Relative to wild-type Î±7-nAChR, functional Î±7-nAChR mutants show a higher affinity for agonists, slower rates of desensitization, and sensitivity to dihydro-Î²-erythroidine (DHÎ²E) 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 Î±7-nAChR is toxic to neuron-like cells.
European Journal of Neuroscience
Digital Object Identifier (DOI)
Lukas, Ronald J.; Lucero, Linda; Buisson, Bruno; Galzi, Jean Luc; Puchacz, Elzbieta; Fryer, John D.; Changeux, Jean Pierre; and Bertrand, Daniel, "Neurotoxicity Of Channel Mutations In Heterologously Expressed Î±7-Nicotinic Acetylcholine Receptors" (2001). Translational Neuroscience. 252.