NRA-2, a nicalin homolog, regulates neuronal death by controlling surface localization of toxic C. elegans DEG/ENaCs [Membrane Biology]

February 24th, 2014 by Kamat, S., Yeola, S., Bianchi, L., Driscoll, M.

Hyperactivated DEG/ENaCs induce neuronal death through excessive cation influx and disruption of intracellular calcium homeostasis. C. elegans DEG/ENaC MEC-4 is hyperactivated by the (d) mutation and induces death of touch neurons. The analogous substitution in MEC-10 (MEC-10(d)) co-expressed in the same neurons, is only mildly neurotoxic. We exploited the lower toxicity of MEC-10(d) to identify RNAi knockdowns that enhance neuronal death. We report here that knockout of the C. elegans nicalin homolog NRA-2 enhances MEC-10(d)-induced neuronal death. Cell biological assays in C. elegans neurons show that NRA-2 controls the distribution of MEC-10(d) between the ER and the cell surface. Electrophysiological experiments in Xenopus oocytes support this notion and suggest that control of channel distribution by NRA-2 is dependent on the subunit composition. We propose that nicalin/NRA-2 functions in a quality control mechanism to retain mutant channels in the ER, influencing the extent of neuronal death. Mammalian nicalin may have a similar role in DEG/ENaC biology, therefore influencing pathological conditions like ischemia.