Abstract
ABERRANT ion channel activity plays a causative role in several human disorders1–3. Inappropriately regulated channel activity also appears to be the basis for neurodegeneration induced by dominant mutations of Caenorhabditis elegans mec-4 (mec-4(d)), a member of the degenerin gene family postulated to encode a subunit of a mechanosensory channel4. The degenerin gene family has been defined by two C. elegans genes, mec-4 and deg-1 (ref. 5), which can mutate to gain-of-function alleles that induce degeneration of specific groups of neurons. A related mammalian gene, rat α-rENaC, induces an amiloride-sensitive Na+ current when introduced to Xenopus oocytes 6, strongly suggesting that degenerin genes encode ion channel proteins. Deduced amino-acid sequences of the degenerins include two predicted membrane-spanning domains6,7. Here we show that conserved amino acids within the second membrane-spanning domain (MSDII) are critical for MEC-4 activity and that specific substitutions within MSDII, whether encoded in cis or in trans to a mec-4(d) mutation, block or delay the onset of degeneration. Remarkably, MSDII from two other family members, C. elegans deg-1 (ref. 5) and rat α-rENaC (ref. 6), can functionally substitute for MEC-4 MSDII in chimaeric proteins. Our results support a structural model for a mechanosensory channel in which multiple MEC-4 subunits are oriented such that MSDII lines the channel pore, and a neurodegeneration model in which aberrant ion flow through this channel is a key event.
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References
Ptacek, L. J. et al. Ann. Neurol. 33, 300–307 (1993).
Koch, M. C. et al. Science 257, 797–800 (1992).
Sheppard, D. N. et al. Nature 362, 160–164 (1993).
Driscoll, M. & Chalfie, M. Nature 349, 588–593 (1991).
Chalfie, M. & Wolinsky, E. Nature 345, 410–416 (1990).
Canessa, C. M., Horsiberger, J. D. & Rossier, B. C. Nature 361, 467–470 (1993).
Chalfie, M., Driscoll, M. & Huang, M. Nature 361, 504 (1993).
Betz, H. Biochemistry 29, 3591–3599 (1990).
Unwin, N. Cell 72, 31–41 (1993).
Chalfie, M. & Sulston, J. Devl. Biol. 82, 358–370 (1981).
Chalfie, M. & Au, M. Science 243, 1027–1033 (1989).
Driscoll, M. J. Neurobiol. 23, 1327–1351 (1992).
Hamelin, M., Scott, I. M., Way, J. C. & Culotti, J. G. EMBO J. 11, 2885–2893 (1992).
Canessa, C. M. et al. Nature 367, 463–467 (1994).
Huang, M. & Chalfie, M., Nature 367, 467–470 (1994).
Morris, C. E. J. Membr. Biol. 113, 93–107 (1990).
French, A. S. A. Rev. Physiol. 54, 135–152 (1992).
Kramer, J. M., French, R. P., Park, E. C. & Johnson, J. J. Molec. cell. Biol. 10, 2081–2089 (1990).
Kunkel, T. A., Roberts, J. D. & Zakar, R. A. Meth. Enzym. 154, 367–382 (1987).
Mello, C. C., Kramer, J. M., Stinchcomb, D. & Ambros, V. EMBO J. 10, 3959–3970 (1992).
Genetics Computer Group, Inc. Program manual version 7 (University Research Park, Madison, Wl, 1991).
Brenner, S. Genetics 77, 71–94 (1974).
Fire, A., Harrison, S. W. & Dixon, D. Gene 93, 189–198 (1990).
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Hong, K., Driscoll, M. A transmembrane domain of the putative channel subunit MEC-4 influences mechanotransduction and neurodegeneration in C. elegans. Nature 367, 470–473 (1994). https://doi.org/10.1038/367470a0
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DOI: https://doi.org/10.1038/367470a0
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