Calcium Signaling in Airway Smooth Muscle Remodeling

  • Tengyao Song
  • Yun-Min ZhengEmail author
  • Yong-Xiao WangEmail author


Asthma is characterized by airway remodeling. One of the most important manifestations of airway remodeling is an increased mass of airway smooth muscle cells (ASMCs), which is mainly due to hyperplasia (increased cell number). Hyperplasia can result from an increase in cell proliferation, an increase in migration, or a decrease in cell apoptosis. Understanding of the mechanisms underlying ASMC remodeling may give rise to novel avenues for the therapy of asthma and other respiratory diseases. Recent studies from our group and others suggest that Ca2+ signaling is important in airway remodeling. Gene and protein expression of Ca2+ pump sarco/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) has been shown to be reduced in ASMCs from patients with moderately severe asthma. Conversely, transient receptor potential canonical 3 (TRPC3) channel expression and activity are significantly increased in asthmatic ASMCs, resulting in increased extracellular Ca2+ influx, activation of the protein tyrosine kinase 2 (PTK2)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/calcineurin signaling axis, increased cyclin D1 transcription and proliferation, and, ultimately, airway remodeling. Orai1-encoded Ca2+-release-activated Ca2+ (CRAC) channels and stromal interacting molecule 1 (STIM1) also appear to participate in mediating platelet-derived grow factor (PDGF)-dependent store-operated Ca2+ entry (SOCE) and the proliferation and migration of ASMCs in asthma. This increased Ca2+ signaling may augment the activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) to phosphorylate cyclic adenosine monophosphate (cAMP) response element binding (CREB) and activate various genes that regulate the cell cycle, thereby leading to asthmatic airway remodeling. Airway remodeling may also be associated with an increased size of ASMCs (hypertrophy). This cellular response is mediated by phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/eukaryotic translation initiation factor 4E (eIF-4F), ribosomal S6 kinase (RSK)/S6-related kinase, and glycogen synthase kinase 3β (GSK3β) signaling pathways, all of which are Ca2+ dependent. Evidently, continual studies in the field will significantly improve our current knowledge regarding the molecular mechanisms of asthma and other airway disorders.


TRPC3 channels Calcium signaling NF-κB Airway remodeling Asthma 



4E-binding protein




Airway smooth muscle


ASM cell




Ca2+/CaM-dependent kinase


Cyclic adenosine monophosphate


Ca2+-induced Ca2+ release


Ca2+-release-activated Ca2+


cAMP response element binding




Early growth response protein 1


Eukaryotic translation initiation factor 2B


Eukaryotic translation initiation factor 4E


Extracellular signal-regulated kinase


G-protein-coupled receptor


Glycogen synthase kinase


Inositol trisphosphate


IP3 receptor


Intracellular Ca2+ concentration


C-Jun amino-terminal kinase 2




Muscarinic M3 acetylcholine receptor


Mitogen-activated protein kinases phosphatase 1


Mammalian target of rapamycin


Nuclear factor of activated T-cells


Nuclear factor kappa-light-chain-enhancer of activated B cells


Nonselective cation channel


Plasminogen activator inhibitor-1


Platelet-derived growth factor


Phosphoinositide 3-kinase


Phosphatidylinositol 4, 5-bisphosphate


Ribosomal S6 kinase


Ryanodine receptor


Sarco/endoplasmic reticulum Ca2+ ATPase


Store-operated Ca2+ channel


Store-operated Ca2+ entry


Sarcoplasmic reticulum


Stromal interacting molecule


Transient receptor potential canonical


Voltage-dependent Ca2+ channel


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© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Center for Cardiovascular Sciences (MC-8)Albany Medical CollegeAlbanyUSA

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