Ks. Hong et M. Driscoll, A TRANSMEMBRANE DOMAIN OF THE PUTATIVE CHANNEL SUBUNIT MEC-4 INFLUENCES MECHANOTRANSDUCTION AND NEURODEGENERATION IN C-ELEGANS, Nature, 367(6462), 1994, pp. 470-473
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 ge
ne family postulated to encode a subunit of a mechanosensory channel4.
The degenerin gene family has been defined by two C. elegans genes, m
ec-4 and deg-1 (ref. 5), which can mutate to gain-of-function alleles
that induce degeneration of specific groups of neurons. A related mamm
alian gene, rat alpha-rENaC, induces an amiloride-sensitive Na+ curren
t when introduced to Xenopus oocytes6, strongly suggesting that degene
rin genes encode ion channel proteins. Deduced amino-acid sequences of
the degenerins include two predicted membrane-spanning domains6,7. He
re we show that conserved amino acids within the second membrane-spann
ing domain (MSDII) are critical for MEC-4 activity and that specific s
ubstitutions 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
alpha-rENaC (ref. 6), can functionally substitute for MEC-4 MSDII in
chimaeric proteins. Our results support a structural model for a mecha
nosensory channel in which multiple MEC-4 subunits are oriented such t
hat MSDII lines the channel pore, and a neurodegeneration model in whi
ch aberrant ion flow through this channel is a key event.