Neurotoxicity through abnormal activation of membrane channels is a potential cause of neurodegenerative disease. Here we show that a gain-of-function mutation, deg-3(u662), leads to the degeneration of a small set of neurons in the nematode C. elegans. The deg-3 gene encodes a nicotinic acetylcholine receptor α subunit, which in the region of transmembrane domain II is most similar to the neuronal α7 subunits from rat and chicken. The u662 mutation changes a residue in the second transmembrane domain, the domain thought to form the channel pore. A similar change in the equivalent amino acid in the chick protein produces channels that desensitize slowly. Channel hyperactivity may underlie the degenerations seen in the C. elegans deg-3(u662) mutants, since antagonists of nicotinic acetylcholine receptors suppress the deg3(u662) mutant phenotypes.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health grant GM34775 and a McKnight Development Award to M. C. and by an European Molecular Biology Organization long-term fellowship to M. T. We wish to thank Lorna Role, Jose Ramirez-Latorre, John Fleming, Hongping Du, and Chuck Ma for their help in this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC Section 1734 solely to indicate this fact.