Piezo2 senses airway stretch and mediates lung inflation-induced apnoea

Abstract

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.

Distal Arthrogryposis with Impaired Proprioception and Touch: Description of an Early Phenotype in a Boy with Compound Heterozygosity of PIEZO2 Mutations and Review of the Literature

“…The loss-of-function and gain-of-function mutations are consistent with the musculoskeletal symptomatology in PIEZO2 -associated diseases, where both reduced and enhanced protein activity of PIEZO2 have diverse negative effects. PIEZO2 is also a versatile airway stretch sensor of lung inflation, and it is critical for proper lung expansion, establishing efficient respiration at birth and maintaining normal breathing in adult mice [Nonomura et al, 2017]. These data are compatible with human PIEZO2 -associated phenotypes in respect to respiratory distress in the neonatal period in DAIPT patients as well as with regard to the progressive restrictive lung disease in adults with DA5.…”

Structure of the mechanically activated ion channel Piezo1

“…Mechanically activated (MA) channels confer force sensitivity to cells and organisms by allowing the passage of ions across the membrane in response to a mechanical stimulus 1 . Piezo1 and Piezo2 were identified in 2010 as a conserved class of eukaryotic MA ion channels 2,3 involved in various mechanotransduction pathways, including touch sensation 4 , proprioception 5 , nociception 6 , vascular development 7 , and breathing 8 . In humans, gain-of-function (GOF) mutations in Piezo1 are linked to dehydrated hereditary stomatocytosis (DHS) 9–12 , a disease in which red blood cells are dehydrated and have increased permeability to cations, and GOF Piezo2 mutations are associated with distal arthrogryposis 13 .…”

TACAN is an essential component of the mechanosensitive ion channel responsible for pain sensing

“…Much like the Piezo family of MSC, which was found to be involved in touch (Ranade et al, 2014b), proprioception (Woo et al, 2015), lung inflation (Nonomura et al, 2017), vascular development (Ranade et al, 2014a), and red blood cell volume regulation (Cahalan et al, 2015;Ma et al, 2018), TACAN is expressed in many tissues and likely to play important roles in several mechanotransduction processes. TACAN also has a homolog in mammalian cells, TMEM120B, but its heterologous expression did not increase mechanically-evoked currents ( Figure S6).…”