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ResearchIn-Press PreviewCell biologyMuscle biologyPulmonology Open Access | 10.1172/jci.insight.202475

Hypercapnia enhances airway smooth muscle contractility via STIM1-dependent Ca2+ signaling

Masahiko Shigemura,1 Vitalii Kryvenko,2 Jennifer A. Pacheco,3 Megan J. Puckelwartz,3 Milos Aleksic,4 Natalia D. Magnani,5 Emma E. Thompson,6 Francisco Javier Martin-Romero,7 Eoin P. Cummins,8 Werner Seeger,9 Andreas Bräuninger,10 Lynn C. Welch,11 G.R. Scott Budinger,11 Emilia Lecuona,1 Laura A. Dada,11 Ankit Bharat,1 István Vadász,13 Murali Prakriya,14 and Jacob I. Sznajder11

1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

Find articles by Shigemura, M. in: PubMed | Google Scholar |

1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

Find articles by Kryvenko, V. in: PubMed | Google Scholar

1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

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1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

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1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

Find articles by Aleksic, M. in: PubMed | Google Scholar

1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

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1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

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1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

Find articles by Martin-Romero, F. in: PubMed | Google Scholar

1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

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1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

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1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

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1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

Find articles by Welch, L. in: PubMed | Google Scholar |

1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

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1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

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1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

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1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

Find articles by Bharat, A. in: PubMed | Google Scholar

1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

Find articles by Vadász, I. in: PubMed | Google Scholar |

1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

Find articles by Prakriya, M. in: PubMed | Google Scholar

1Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2The Cardio-Pulmonary Institute Justus Liebig University Giessen German Cent, Universities of Giessen & Marburg Lung Center, Giessen, Germany

3Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

6Department of Human Genetics, University of Chicago, Chicago, United States of America

7Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain

8School of Medicine, University College Dublin, Dublin, Ireland

9Department of Internal Medicine II, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

10Institute of Pathology, Justus Liebig University, Giessen, Germany

11Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

12Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, chicago, United States of America

13Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany

14Department of Pharmacology, Feinberg School of Medicine, Northwestern University, chicago, United States of America

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Published July 16, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.202475.
Copyright © 2026, Shigemura et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 16, 2026 - Version history
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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 (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 COPD patients. 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.

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