The Piezo2 protein senses changes in lung volume, acting in different neurons to convey this information to the brain. This finding adds to the list of roles for Piezo2 in mechanosensation. See Article p.176
As we breathe, our lungs and airways are continuously exposed to extensive mechanical forces. For instance, during exercise, the average man can inhale 3.5 litres of air with each breath, drastically stretching the airways to accommodate the change in lung volume. These forces are sensed by stretch-receptor neurons, whose activation triggers physiological responses. The role of the lung stretch receptors in normal breathing, and the molecular mechanisms involved in mechanosensation in this context have not been clear. Nonomura et al.1 take a crucial step forward on page 176 by demonstrating that the protein Piezo2 has a central role in respiration and the lung's stretch response in mice.
The first documented role of stretch receptors was in a safety mechanism called the Hering–Breuer inflation reflex2, which is thought to protect the lungs from overexpansion. But many investigators now believe that stretch receptors also play a part in the termination of inspiration and the control of expiratory time under normal conditions. Which neurons might mediate these responses? Vagal sensory neurons, which innervate the airways, convey sensory information from the lungs to the brain's respiratory-control centres3. A report last year4 in mice demonstrated that stimulation of a subpopulation of vagal sensory neurons — those that express the gene P2ry1 and whose cell bodies are clustered in a structure called the nodose ganglion — caused an abrupt pause in respiration, making them good candidates for mediators of the Hering–Breuer reflex.
Piezo2 is a major transducer of mechanical forces for touch sensation and muscle proprioception5 — the ability to sense the relative positions of different muscles. Nonomura et al. set out to investigate whether the protein is also involved in mechanosensation in the Hering–Breuer inflation reflex, and in respiration more generally.
First, the authors analysed Piezo2 gene expression in sensory neurons that innervate the lungs and airways. Expression of Piezo2 was detected in a subpopulation of vagal sensory neurons in the nodose ganglion and in a neighbouring structure, the jugular ganglion. In addition, the researchers found the gene to be expressed in a population of spinal sensory neurons in the dorsal root ganglia, which project to the spinal cord. In the lung tissue, Piezo2 expression was found only in structures called neuroepithelial cell bodies, whose function is not clear.
Next, Nonomura et al. used genetic techniques to delete Piezo2 in specific neurons in mice (Fig. 1). When Piezo2 was ablated in the jugular and dorsal-root neurons, but spared in the nodose neurons, animals showed signs of respiratory distress and died shortly after birth. By contrast, when the gene was deleted exclusively in nodose neurons, the animals reached adulthood.
The authors found that a lack of Piezo2 in nodose neurons in adulthood led to impairment of the Hering–Breuer reflex and to abolition of vagal-nerve responses to artificial lung inflation. In addition, the mice inhaled more air per breath than their wild-type siblings, suggesting that the detection of lung-volume changes in these animals was imprecise. This experiment demonstrates that Piezo2 is crucial for mechanosensation not only in the artificial situation of lung inflation, but also during normal breathing. Thus, Nonomura and colleagues have firmly established that Piezo2 in nodose sensory neurons is the main mediator of the lung stretch response in adulthood, and is essential for a normal breathing pattern.
Finally, the authors engineered Piezo2-expressing fibres in the vagus nerve, which contains the projections of the vagal sensory neurons, to also express a light-sensitive ion-channel protein. Stimulation of these fibres with light caused an immediate cessation of respiration, as had previously been observed for the P2ry1-expressing nodose neurons4. Collectively, the authors' results demonstrate that Piezo2 is the essential mechanotransducer in vagal neurons.
Many avenues remain for further investigation. First, what is the cause of respiratory distress, impaired lung expansion and death at birth when Piezo2 is deleted in the dorsal-root and jugular neurons? The lungs of mammals undergo major changes at birth, as the liquid that filled them in the womb is replaced by air. The defects must arise from loss of some form of mechanoreception, but what precisely Piezo2 senses during these drastic alterations, and which of the two types of neuron normally conveys this information, remains to be defined.
Second, what is the role of the Piezo2-expressing neuroepithelial cell bodies in the lung? Nonomura and colleagues showed that these cells are contacted by afferents from neurons that also express or have expressed Piezo2. As such, they speculate that the neuroepithelial cell bodies sense lung inflation, but direct evidence for this supposition remains to be found.
Third, the current study did not investigate whether the P2ry1-expressing neurons —which express Piezo2 (ref. 4) — are the ones that mediate the lung stretch response in adult mice. The genetically engineered mice needed to perform this experiment are available. If it is Piezo2 in the P2ry1-expressing neurons that mediates the stretch response, the story will have come full circle. If not, the reality is more complex, and merits further exploration.
Finally, we still lack knowledge about the way in which Piezo2 senses the forces exerted by lung inflation. In other systems, tension in the lipid bilayer of the cell membrane is thought to activate mechanosensitive ion channels, but whether this is true for the Piezo channels is not known5. A mechanistic understanding of this process would help to reveal how airway tension is transduced into nerve activity.
Defective airway mechanotransduction might be a contributing factor in respiratory diseases. For example, a blunted Hering–Breuer reflex has been reported in patients with chronic obstructive pulmonary disease6 and in an animal model of a disease called lung fibrosis, in which lung tissue becomes thickened, stiff and scarred7. There is also evidence to suggest that vagal innervation of the lungs is crucial for the establishment of adequate breathing at birth, when expansion of the newborn lung leads to huge pressure changes8. By providing insight into the mechanisms involved in the lung's stretch response, Nonomura and colleagues' study could lead to a better understanding of the role of this crucial response in disease.