Ion Channel Blocks Acid Pain

African naked mole rats, the only mammals known to be impervious to acid-related pain, should thank sodium channels in their neurons for the unique sensory trait, a new study suggests (Science, DOI: 10.1126/science.1213760). Understanding how the hairless, toothy rodents have evolved to handle the high levels of acid in their tissue might help scientists tackle human inflammatory conditions in which acidosis occurs.

To elucidate the molecular mechanism behind the mole rats’ acid insensitivity, Gary R. Lewin of Max Delbrück Center for Molecular Medicine, in Germany, and coworkers first compared the behavior of acid-sensing ion channels (ASICs) in the neurons of the hairless rodents with their behavior in mice. “At the beginning of the project, we thought that mole rats, which live underground in high-CO₂ acidic environments, might not express ASICs or that the channels were somehow different,” explains postdoc Ewan St. John Smith. But the team found no significant differences between the ASICs in mole rats and mice.

Lewin’s group then closely investigated the voltage-gated sodium ion channel Na_v1.7, the membrane protein that ultimately allows neurons to fire, in both animals. The researchers determined that in naked mole rats, acidic protons block Na_v1.7. The hairless critters, the team found, have a negatively charged amino acid motif in one region of their Na_v1.7 channels where mice—and humans—have a positively charged motif. The researchers think acidic protons might disable the sodium channel in mole rats by interaction with these negatively charged residues.

This “interesting finding,” says Cheryl L. Stucky, a neuroscientist at the Medical College of Wisconsin, might one day lead to a therapy for acid-related pain conditions, such as that caused by severe sickle cell disease. “If you could upregulate the channel to be inhibited by acid”—perhaps via small molecules or gene therapy—“you could put the brake on neuron firing during pain.”

The next step for his team, Lewin says, is to determine whether mice engineered with a copy of the naked mole rats’ Na_v1.7 gene become insensitive to acid pain.