title: NRA-2, a nicalin homolog, regulates neuronal death by controlling surface localization of toxic Caenorhabditis elegans DEG/ENaC channels.
abstract: Hyperactivated DEG/ENaCs induce neuronal death through excessive cation influx and disruption of intracellular calcium homeostasis. Caenorhabditis 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 knock-out 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 endoplasmic reticulum 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 endoplasmic reticulum, influencing the extent of neuronal death. Mammalian nicalin may have a similar role in DEG/ENaC biology, therefore influencing pathological conditions like ischemia.
authors.affiliation: Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Shaunak
authors.initials: S
authors.lastname: Kamat
authors.affiliation: Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Shrutika
authors.initials: S
authors.lastname: Yeola
authors.affiliation: Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Wenying
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, Florida 33136. Electronic address: jackman.14@osu.edu.
authors.forename: Laura
authors.initials: L
authors.lastname: Bianchi
authors.affiliation: Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854. Electronic address: driscoll@dls.rutgers.edu.
authors.forename: Monica
authors.initials: M
authors.lastname: Driscoll
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D034622:RNA Interference; D014981:Xenopus
chemical_list: D029742:Caenorhabditis elegans Proteins; D053503:Epithelial Sodium Channels; D002118:Calcium
keywords: C. elegans; C. elegans, Nicalin, Quality Control, Trafficking; ER Quality Control; Intracellular Trafficking; Ion Channels; Neurodegeneration