When life gives naked mole rats lemons, the wrinkled, buck-toothed rodents probably don’t care. They are impervious to the sting of acid.
But scientists in Berlin are onto the secret of the social rodents’ acid insensitivity. Naked mole rats’ acid sensors work just fine, but a protein responsible for relaying messages about acid’s presence to the nervous system is easily blocked by the same positively charged hydrogen ions that lend substances acidity, researchers report in the Dec. 16 Science. The discovery may give researchers clues about where to target drugs that could relieve pain associated with inflammation.
“I’ve been trying to figure out this question in mole rats for a number of years, and the answer has been elusive,” says Thomas Park, a neuroscientist at the University of Illinois at Chicago who was not involved in the study.
It was Park who first got Gary Lewin of the Max Delbrück Center for Molecular Medicine in Berlin interested in studying naked mole rats. Lewin and Ewan St. John Smith, a postdoctoral researcher in Lewin’s lab, led the new research.
Mole rats live in large social groups in burrows underground. The crowded, confined conditions cause carbon dioxide levels to rise to as high as 8 to 10 percent of the air — a concentration that would cause a person to pass out within five to 10 minutes. High carbon dioxide and low oxygen levels make body tissues acidic, something that is very painful for nearly all mammals. (Inflammation also raises acidity in tissues, producing pain.) If mole rats had not evolved a way to ignore acid the little rodents would be in constant agony, Lewin says.
Most researchers thought the animals’ insensitivity to acid probably stemmed from a lack of functional acid sensors in pain nerves, says Harold Zakon, a neurobiologist at the University of Texas at Austin. “But there’s a little unexpected kick here,” he says.
Naked mole rats do have fully functional acid sensors. “To our great surprise they are all there and are even more active and easily opened” than similar acid sensors in mice, Lewin says. “That left us in a bit of a puzzle.”
Usually when sensors detect acid or other substances, nerve cells change their electrical properties, then fire off an electrical message to the rest of the nervous system. The pain nerves in the naked mole rats change their electrical properties but never send the message, the researchers found.
“It’s as if, in the naked mole rat, acid is acting like a local anesthetic,” says Lewin.
The team traced the missing message to a protein called a sodium channel in the pain nerves. Naked mole rats have a slightly different version of the sodium channel — named Nav1.7 in most mammals and SCN9A in humans — than most other mammals, except for cave-dwelling microbats, which also live in chemically challenging environments.
The mole rats and bats have three amino acids near the hole of the doughnut-shaped sodium channel that are negatively charged. Those amino acids apparently attract hole-blocking positively charged protons more strongly than the amino acids found in the human and mouse versions of the protein. When the researchers engineered human cells with the naked mole rat version of the sodium channel, the human cells reacted like the mole rat cells do.
If researchers can figure out how to block the same part of the sodium channel in humans, the result could be a painkiller that takes away pain but doesn’t make people groggy the way many analgesics do now, says Geoffrey Woods, a clinical geneticist at the University of Cambridge in England.