Repeated functional convergent effects of NaV1.7 on acid insensitivity in hibernating mammals

Hibernating mammals need to be insensitive to acid in order to cope with conditions of high CO₂; however, the molecular basis of acid tolerance remains largely unknown. The African naked mole-rat (Heterocephalus glaber) and hibernating mammals share similar environments and physiological features. In the naked mole-rat, acid insensitivity has been shown to be conferred by the functional motif of the sodium ion channel Na_V1.7. There is now an opportunity to evaluate acid insensitivity in other taxa. In this study, we tested for functional convergence of Na_V1.7 in 71 species of mammals, including 22 species that hibernate. Our analyses revealed a functional convergence of amino acid sequences, which occurred at least six times independently in mammals that hibernate. Evolutionary analyses determined that the convergence results from both parallel and divergent evolution of residues in the functional motif. Our findings not only identify the functional molecules responsible for acid insensitivity in hibernating mammals, but also open new avenues to elucidate the molecular underpinnings of acid insensitivity in mammals.