Functional features of the "finger" domain of DEG/ENaC channels MEC-4 and UNC-8

UNC-8 and MEC-4 are two members of the DEG/ENaC family of voltage-independent Na+ channels that share a high degree of sequence homology and functional similarity. For example, both can be hyperactivated by genetic mutations (UNC-8(d) and MEC-4(d)) that induce neuronal death by necrosis. Both depend in vivo on chaperone protein MEC-6 for function, as demonstrated by the finding that neuronal death induced by hyperactive UNC-8 and MEC-4 channels is prevented by null mutations in mec-6. UNC-8 and MEC-4 differ functionally in three major ways: 1) MEC-4 is calcium permeable whereas UNC-8 is not; 2) UNC-8, but not MEC-4, is blocked by extracellular calcium and magnesium in the micromolar range; 3) MEC-6 increases the number of MEC-4 channels at the cell surface in oocytes but does not have this effect on UNC-8. We previously reported that Ca2+ permeability of MEC-4 is conferred by the second transmembrane domain. We show here that the extracellular "finger" domain of UNC-8 is sufficient to mediate inhibition b...