Insight into DEG/ENaC Channel Gating from Genetics and Structure

Abstract

The founding members of the superfamily of DEG/ENaC ion channel proteins are C. elegans proteins that form mechanosensitive channels in touch and pain receptors. For more than a decade, the research community has used mutagenesis to identify motifs that regulate gating. This review integrates insight derived from unbiased in vivo mutagenesis screens with recent crystal structures to develop new models for activation of mechanically-gated DEGs.

Activation of the Caenorhabditis elegans Degenerin Channel by Shear Stress Requires the MEC-10 Subunit

“…7). The finger domains within the ECD of MEC-4 and MEC-10 are noticeably longer than that of their mammalian orthologues, including blocks of cysteine-rich sequences at the start and end of the finger domains, and a 22-amino acid degenerinunique sequence has been proposed to influence channel gating (33,35). It has also been proposed that the finger domains are responsible, in part, for the diversity of extracellular factors that regulate members in this family (12).…”

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

“…For detailed discussions of ASIC structurefunction aspects, see also Grunder and Chen (2010) and Sherwood et al (2012). An insightful overview of degenerin structure-function aspects is given by Eastwood and Goodman (2012).…”

“…The degenerin residue and the amiloride binding site. Gly432 constitutes the DEG site, a conserved small residue in all ENaC/DEG channels, whose replacement by larger residues induces constitutive activity in most family members, leading to degeneration of sensory neurons in C. elegans (Eastwood and Goodman, 2012). Substitution of the DEG residue induced in ASIC2a, besides a constitutive current, a slowing of desensitization and an altered pH dependence of the H + -induced current (Adams et al, 1998;Champigny et al, 1998).…”

Hairy Sensation

“…This process, collectively termed mechanotransduction, was found to be mediated by three biophysically and pharmacologically distinct types of mechanically activated transduction currents, termed rapidly adapting (RA) (FIGURE 2A), intermediately adapting (IA), and slowly adapting (SA) current (16,27,38,39). The molecular identity of the ion channels that mediate these currents in mammals is still unknown, but several mechanotransduction genes have been identified in model organisms such as Caenorhabditis elegans and Drosophila melanogaster (14,19,40,61). In primary cultures of DRG neurons, nociceptors and mechanoreceptors can be distinguished by means of their action potential configuration, but such physiological signatures do not allow one to discriminate between different mechanoreceptor subtypes (21).…”