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Protein monitors lung volume, regulates our breathing

A protein originally discovered at The Scripps Research Institute (TSRI) appears to be involved in how the body controls breathing, according to a new study led by scientists at TSRI and Harvard Medical School.

The study, published in Nature, shows how the Piezo2 protein, previously shown to be the principal sensor of touch and proprioception (or sense of the relative position of neighbouring parts of the body), also plays a critical role in sensing lung expansion. 

"The discoveries here could provide important clues on how to treat patients with respiratory disorders" said senior author Ardem Patapoutian, a professor at TSRI and a Howard Hughes Medical Institute (HHMI) investigator.

Using genetically modified mice models, researchers found newborn mice without a Piezo2 channel show severe respiratory distress leading to death.

They believe their study helps shed light on sudden infant death syndrome (SIDS) in human babies, which is thought to be associated with dysfunctional airway sensory neurons.

Adult mice without the Piezo2 channel in their sensory neurons, exhibit significantly increased tidal volume (the amount of inhaled air in lungs) as well as an impaired Hering-Breuer reflex, an inhibitory reflex preventing lung over-expansion.

The Piezo2 ion channel was originally discovered in Patapoutian's lab in 2010 — as a novel mechanosensor (which senses the mechanical stimuli such as pressure or stretch).

Follow-up studies reveals the Piezo2 channel is present in sensory neurons — is required for sensing touch and muscle stretch in mice.

These studies led researchers to wonder if Piezo2 plays a role as a general stretch sensor in other organs — like the lungs.

"Previous studies suggested the existence of lung inflation sensors; however, their molecular identity or physiological importance has not been clarified," adds Patapoutian.

Researchers tackled this question by generating Piezo2 "knockout" mice, in which the Piezo2 channel is deleted throughout the animal — or only from sensory neurons (specifically, vagal sensory neurons known to control breathing). They found that Piezo2 is essential for establishing proper breathing and lung expansion in newborn mice. Piezo2-deficient newborn mice showed unexpanded lungs and significantly more shallow breathing.

"The lungs communicate with the brain via sensory neurons. The Piezo2 channel in sensory neurons generates a message about lung volume changes, and Piezo2-containing sensory neurons deliver that message to the brain.

"Piezo2-deficient mice cannot generate an accurate message about lung volume changes. As a result, these mice do not receive proper output from the brain."

Keiko Nonomura, TSRI Research Associate, co-first author of the study with TSRI Research Associate Seung-Hyun Woo.

Strikingly, according to recently published papers, Piezo2-deficient human infants also show shallow breathing and require medical attention.

"Piezo2-deficient newborn mice develop normally until birth. The problem only arise once the mice are born and try to breathe on their own" added Nonomura.

The researchers were surprised to see an unexpected consequence of deleting Piezo2 in sensory neurons of adult mice. When the Piezo2 channel was deleted either in all sensory neurons or only from vagal sensory neurons, adult mice could still breathe, but they inhaled significantly more air than Piezo2-intact mice.

Under normal conditions, animals stop breathing when they are forced to breathe in more air, but Piezo2-deficient adult mice lack the Hering-Breuer reflex and continued breathing when they were forced to breathe in more air.

Why this difference between adults and newborns? Researchers believe that Piezo2 performs different functions in newborns and adults because establishing autonomous breathing in newborns is more complex.

"At birth, the newborn respiratory system undergoes drastic structural changes as liquid-filled, compressed, fetal airways are being cleared to be inflated with air.

"Therefore, newborn airways experience larger mechanical changes, compared to adult airways, which have already established normal breathing."

Ardem Patapoutian PhD, Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA

This data, for the first time, defines the importance of mechano-sensory transference of DNA from one bacterium to another — via a virus — in adult respiration. This research is also relevant to our understanding of respiratory diseases as chronic obstructive pulmonary disease (COPD) and sleep apnea appear to be tied to disruption in airway sensory feedback.

The team believes future studies could use similar genetic manipulation to better understand the role of Piezo2 in other physiological processes — such as heart rate control and bladder function.

Respiratory dysfunction is a notorious cause of perinatal mortality in infants and sleep apnoea in adults, but the mechanisms of respiratory control are not clearly understood. Mechanical signals transduced by airway-innervating sensory neurons control respiration; however, the physiological significance and molecular mechanisms of these signals remain obscured. Here we show that global and sensory neuron-specific ablation of the mechanically activated ion channel Piezo2 causes respiratory distress and death in newborn mice. Optogenetic activation of Piezo2+ vagal sensory neurons causes apnoea in adult mice. Moreover, induced ablation of Piezo2 in sensory neurons of adult mice causes decreased neuronal responses to lung inflation, an impaired Hering–Breuer mechanoreflex, and increased tidal volume under normal conditions. These phenotypes are reproduced in mice lacking Piezo2 in the nodose ganglion. Our data suggest that Piezo2 is an airway stretch sensor and that Piezo2-mediated mechanotransduction within various airway-innervating sensory neurons is critical for establishing efficient respiration at birth and maintaining normal breathing in adults.

In addition to Nonomura, Woo and Patapoutian, authors of the study, "Piezo2 senses airway stretch and mediates lung inflation-induced apnoea," were Rui B. Chang and Stephen D. Liberles of Harvard Medical School; Astrid Gillich of HHMI and the Stanford University School of Medicine; Zhaozhu Qiu, previously of TSRI and the Genomics Institute of the Novartis Foundation, now at Johns Hopkins University; Allain G. Francisco of HHMI and TSRI; and Sanjeev S. Ranade, previously of HHMI and TSRI, and now at the Gladstone Institutes.

This research was supported by the National Institutes of Health (grants R01DE022358 and R01HL132255), a Giovanni Armenise-Harvard Foundation Grant and the Howard Hughes Medical Institute.

About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Sciences, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www.scripps.edu.

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Immunofluorescence of PIEZO2 Antibody - Staining of human cell line
U-2 OS shows positivity in nucleus, cytoplasm & focal adhesions.
Image Credit:Novus Biologicals



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