Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation–induced surfactant secretion
Gui-Lan Chen, … , Jin Zhang, Bo Zeng
Gui-Lan Chen, … , Jin Zhang, Bo Zeng
Published December 21, 2023
Citation Information: J Clin Invest. 2024;134(5):e174508. https://doi.org/10.1172/JCI174508.
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Research Article Pulmonology

Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation–induced surfactant secretion

Abstract

Pulmonary surfactant is a lipoprotein complex lining the alveolar surface to decrease the surface tension and facilitate inspiration. Surfactant deficiency is often seen in premature infants and in children and adults with respiratory distress syndrome. Mechanical stretch of alveolar type 2 epithelial (AT2) cells during lung expansion is the primary physiological factor that stimulates surfactant secretion; however, it is unclear whether there is a mechanosensor dedicated to this process. Here, we show that loss of the mechanosensitive channels TMEM63A and TMEM63B (TMEM63A/B) resulted in atelectasis and respiratory failure in mice due to a deficit of surfactant secretion. TMEM63A/B were predominantly localized at the limiting membrane of the lamellar body (LB), a lysosome-related organelle that stores pulmonary surfactant and ATP in AT2 cells. Activation of TMEM63A/B channels during cell stretch facilitated the release of surfactant and ATP from LBs fused with the plasma membrane. The released ATP evoked Ca2+ signaling in AT2 cells and potentiated exocytic fusion of more LBs. Our study uncovered a vital physiological function of TMEM63 mechanosensitive channels in preparing the lungs for the first breath at birth and maintaining respiration throughout life.

Authors

Gui-Lan Chen, Jing-Yi Li, Xin Chen, Jia-Wei Liu, Qian Zhang, Jie-Yu Liu, Jing Wen, Na Wang, Ming Lei, Jun-Peng Wei, Li Yi, Jia-Jia Li, Yu-Peng Ling, He-Qiang Yi, Zhenying Hu, Jingjing Duan, Jin Zhang, Bo Zeng

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Figure 2

Properties of lung inflation– and stretch-induced Ca2+ transients in AT2 cells.

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Properties of lung inflation– and stretch-induced Ca2+ transients in AT2...
(A) Density of spiking AT2 cells in lungs ventilated with different tidal volumes for 5 minutes. The number of GCaMP6f-spiking cells was divided by the number of tdTomato+ cells (i.e., total number of AT2 cells) in the same area to calculate the percentage. n = 3 lung lobes. **P < 0.01 and ****P < 0.0001, by 1-way ANOVA with Tukey’s test. (B) Rapid decay of spiking AT2 cell density after ventilation with a tidal volume of 200 μL for 2 minutes and 5 minutes, respectively. Data were fitted with a single exponential decay function. n = 5 lung lobes. (C) Percentage of spiking AT2 cells in lungs instilled with 150 μL vehicle (0.1% DMSO), the Cx43 blocker Gap26 (500 μM), the pannexin blocker probenecid (2 mM), the Cl– channel blocker DIDS (200 μM), or NPPB (100 μM) after ventilation with a tidal volume of 150 μL for 5 minutes. n = 6 (vehicle) and 4 (others) lung lobes. NS, by 1-way ANOVA. (D) Percentage of spiking AT2 cells in lungs instilled with 150 μL clodronate (100 μM) or control solution. The data were fitted with a biphasic dose-response curve (corresponding to the abundance of ATP-containing LBs). n = 6 lung lobes. *P < 0.05 and ***P < 0.001, by 2-way ANOVA with Šidák’s test. (E) Lack of a direct stretch-activated Ca2+ response in primary AT2 cells cultured on an elastic membrane. Apyrase (10 U/mL) was used to eliminate ATP released into the extracellular space. n = 12 cells. (F) Stretch-induced, ATP-mediated Ca2+ oscillations in primary AT2 cells. Each trace represents fluorescence of an AT2 cell. n = 26 cells.