Year: 2026
Type: article
Abstract: Hypercapnia, elevated carbon dioxide (CO2), is common in advanced chronic obstructive pulmonary disease (COPD) and predicts poor clinical outcomes. Traditionally considered a consequence of disease severity, hypercapnia may drive disease progression by promoting airway dysfunction. Here, we show that hypercapnia acts as an active stressor, driving airway smooth muscle (ASM) constriction through a stromal interaction molecule 1-dependent (STIM1-dependent) pathway. Hypercapnia rapidly activates ERK, triggering sarcoplasmic reticulum calcium (Ca2+) release via phosphorylation of the inositol 1,4,5-trisphosphate receptor. ERK also induces nuclear translocation of the transcription factor c-Fos, enhancing STIM1 transcription. These responses were observed under both supraphysiological (~120 mmHg) and clinically relevant (50-60 mmHg) hypercapnia. Increased STIM1 abundance sustains store-operated Ca2+ entry (SOCE), amplifying ASM signaling. In mice, hypercapnia increased ASM and airway contractility in a STIM1-dependent manner. Human genetic analyses revealed noncoding STIM1 variants associated with reduced lung expression that were enriched in patients with COPD. These variants correlated with lower airway resistance under normocapnia; however, this benefit was lost during hypercapnia, indicating a potential gene-environment interaction. Together, our findings position STIM1 as a key mechanistic node linking hypercapnia to Ca2+ dysregulation and airway obstruction, defining a CO2/ERK/STIM1/SOCE axis with translational relevance to chronic lung disease.
Source: JCI Insight
Authors: Masahiko Shigemura, Vitalii Kryvenko, Jennifer A. Pacheco, Megan J. Puckelwartz, Milos Aleksic, Natalia D. Magnani, Emma Thompson, Francisco Javier Martin-Romero, Eoin P. Cummins, Werner Seeger, Andreas Bräuninger, Lynn C. Welch, G.R. Scott Budinger, Emilia Lecuona, Laura A. Dada, Ankit Bharat, István Vadász, Murali Prakriya, Jacob I. Sznajder
Institutions: Northwestern University, Kobe University, Justus-Liebig-Universität Gießen, German Center for Lung Research, Universities of Giessen and Marburg Lung Center, Cardio-Pulmonary Institute, Universidad de Buenos Aires, University of Chicago, Universidad de Extremadura, University College Dublin
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Northwestern University, Science Foundation Ireland, University College Dublin, Bundesministerium für Bildung und Forschung, Deutsches Zentrum für Lungenforschung, National Institutes of Health, Feinberg School of Medicine, National Heart, Lung, and Blood Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1323973185, G2141234337, Complementary pathways of necroptosis in recipient and donor lung tissue that drive primary lung allograft dysfunction, G322890519, Integrated mechanisms of primary and chronic graft dysfunction following lung transplantation, Hypercapnia and Suppression of Anti-viral Host Defense, Carbon dioxide as a regulator of inflammatory signaling., G9000025161, G9000065092, G9000095327, G9000153249, G9000326773, Northwestern University Skin Biology and Diseases Resource-based Center
OpenAlex ID: W7169061250
FWCI:
Cites:
Cited by:
Related to: