Force-detecting protein senses when lungs fill with air

Mouse study reveals mechanical sensor that helps regulate breathing

mouse lung nerve endings

BREATHLESS  Nerve endings in the lungs send signals — triggered by force-detecting proteins — to the brain and spinal cord that help regulate breathing. When mice lack these proteins in particular clusters of nerves, the mice either die within 24 hours of birth (blue, purple) or have breathing problems as adults (red).

C. Goridis/Nature 2016

Scientists investigating what keeps lungs from overinflating can quit holding their breath.

Experiments in mice have identified a protein that senses when the lungs are full of air. This protein helps regulate breathing in adult mice and gets breathing going in newborn mice, researchers report online December 21 in Nature.

If the protein plays a similar role in people — and a few studies suggest that it does — exploring its activity could help explain disorders such as sleep apnea or chronic obstructive pulmonary disease.

“These are extremely well done, very elegant studies,” says neonatologist Shabih Hasan of the University of Calgary in Canada, a specialist in breathing disorders in newborns. Researchers knew that feedback between the lungs and brain maintains normal breathing. But “this research give us an understanding at the cellular level,” says Hasan. “It’s a major advance.”

Called Piezo2, the protein forms channels in the membranes of nerve cells in the lungs. When the lungs stretch, the Piezo2 channels detect the distortion caused by the mechanical force of breathing and spring open, triggering the nerves to send a signal.

Led by neuroscientist Ardem Patapoutian, researchers discovered that the channels send signals along three different pathways. Mice bred to lack Piezo2 in a cluster of nerve cells that send messages to the spinal cord had trouble breathing and died within 24 hours. Similarly, newborn mice missing Piezo2 channels in nerves that communicate with the brain stem via a structure called the jugular ganglion also died.

Mice lacking Piezo2 in the nodose ganglion, a structure that also links to the brain stem, lived to adulthood. But their breathing was abnormal and an important safety mechanism in the lungs of these mice didn’t work. Called the Hering-Breuer reflex, it kicks in when the lungs are in danger of overinflating. When functioning properly, Piezo2’s signal prevents potentially harmful overinflation by temporarily halting breathing. Known as apnea, this cessation of breathing can be dangerous in other instances but prevents damage in this case.

“Breathing is a mechanical process,” says Patapoutian, a Howard Hughes Medical Institute investigator at the Scripps Research Institute in La Jolla, Calif. “Intuitively, you could imagine that lung stretch sensors could play an important role in regulating breathing pattern. Amazingly, however, no definitive proof for such a feedback mechanism existed.”

Previous work in mice by Patapoutian and colleagues found that Piezo2 channels play a major role in sensing touch. The channels also function in proprioception, the sense of where body parts are in relation to each other, Patapoutian and colleagues reported last year.

Two recent studies by different research teams have found that people with mutations in a Piezo2 gene have problems with touch, proprioception and, in one study, breathing. Although small, the studies suggested that investigating Piezo2 in people could shed light on breathing disorders or other problems. The protein channels might play a role in sensing the “fullness” of the stomach and bladder and perhaps other mechanical processes such as heart rate control, Patapoutian says.

Investigating Piezo2 could also help explain how newborn lungs transition from being fluid-filled to breathing air, says neuroscientist Christo Goridis of the École des Neurosciences Paris.

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