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Functional Evaluation of Biological Neurotoxins in Networked Cultures of Stem Cell-derived Central Nervous System Neurons
Published on: February 5, 2015
Intersubunit interactions between mutant DEG/ENaCs induce synthetic neurotoxicity
1Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA.
Cell Death and Differentiation
|August 2, 2008
Summary
Neuronal death from ion channel hyperactivation can be worsened by specific mutations. A novel mutation, MEC-4(A149V), synergizes with MEC-10(d) to enhance neurotoxicity, highlighting calcium
Area of Science:
- Neuroscience
- Ion Channel Biology
- Molecular Genetics
Background:
- Ion channel hyperactivation, particularly of Degenerin/epithelial amiloride-sensitive Na(+) channels (DEG/ENaC), contributes to neuronal loss in conditions like stroke and neurodegenerative diseases.
- Acidosis-induced hyperactivation of ASIC1a in the mammalian brain and genetic hyperactivation of the C. elegans MEC-4(d) channel exemplify DEG/ENaC-mediated neurotoxicity.
- Mutant MEC-10(d) subunits show weak neurotoxicity, providing a basis for screening for mutations that enhance neuronal death.
Purpose of the Study:
- To identify novel extragenic mutations that enhance neuronal necrosis in Caenorhabditis elegans.
- To characterize the mechanism by which identified mutations contribute to neurotoxicity within the DEG/ENaC channel superfamily.
- To investigate the role of specific ion currents, particularly Ca(2+), in mediating DEG/ENaC-induced neuronal death.
Main Methods:
- Genetic screening of Caenorhabditis elegans mec-10(d) mutant lines to identify enhancers of neuronal necrosis.
- Characterization of the identified enhancer mutation, MEC-4(A149V), for its effects on touch sensation and neurotoxicity.
- Functional analysis of the MEC-4(A149V) and MEC-10(d) combined channel in Xenopus oocytes to measure ion currents (Na(+) and Ca(2+)) and amiloride binding.
Main Results:
- A novel variant, MEC-4(A149V), was identified as a potent enhancer of mec-10(d)-induced neuronal necrosis.
- MEC-4(A149V) alone does not cause necrosis but synergizes with MEC-10(d) to form a strongly neurotoxic channel.
- The combined MEC-4(A149V)+MEC-10(d) channel exhibits increased Na(+) and Ca(2+) currents, with a disproportionate rise in Ca(2+) permeability, and altered amiloride binding.
Conclusions:
- This study reports the first instance of synergistically toxic intersubunit interactions within the DEG/ENaC channel class.
- The findings suggest that elevated Ca(2+) influx through DEG/ENaC channels may be a critical determinant of neuronal survival versus necrosis.
- MEC-4(A149V) represents a valuable tool for studying the mechanisms underlying DEG/ENaC channel-mediated neurotoxicity and potential therapeutic targets.
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