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

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.

• Shigemura, M.
• Kryvenko, V.
• Pacheco, J. A.
• Puckelwartz, M. J.
• Aleksic, M.
• Magnani, N. D.
• Thompson, E.
• Martin-Romero, F. J.
• Cummins, E. P.
• Seeger, W.
• Brauninger, A.
• Welch, L. C.
• Budinger, G. R. S.
• Lecuona, E.
• Dada, L. A.
• Bharat, A.
• Vadasz, I.
• Prakriya, M.
• Sznajder, J. I.