Evolution, hibernation, and inactivation of voltage-gated Na channels

At 6°C, when atria of most mammals cannot be activated, isolated atria of 13-lined ground squirrels, a model hibernator, have intracellular action potentials (AP) that are enlarged in duration and overshoot. Avoidance or delay of inactivation was postulated as playing a role in the retention and enhancement of the AP. In a published genomic study, the TTX-sensitive voltage-gated Na channel Nav1.2 was identified as being "more rapidly evolving." In published sequences of this channel in five species of hibernators, a methionine replaces leucine in the sequence, NQATL, of transmembrane segment six of domain one (DIS6), but not in any of the 10 species of nonhibernating placental mammals. Among other TTX-sensitive channels, Nav1.1 possesses the same mutation in 8 of 9 hibernators as does Nav1.4 in bats and Nav1.3 in groundhogs, but those isoforms do not possess the mutation in any nonhibernator. All four channels occur in the heart muscle. While far less abundant than Nav1.5, they may supplement it during physiological stress. In a model of Nav1.4A, methionine replacing leucine in NEATL (homolog of NQATL) was found to form two hydrogen bonds with the asparagine of NEATL. Leucine formed none. That asparagine is highly conserved in all members of the Nav1 family and mpdulates both fast and slow inactivation. Hypothesis: At temperatures approaching 0°C, greater stickiness of methionine enhances the nearby arginine's modulation of fast and slow inactivation, thus helping to sustain excitability in hearts of hibernators that possess the M-for-L mutation.