Airway smooth muscle STIM1 and Orai1 are upregulated in asthmatic mice and mediate PDGF-activated SOCE, CRAC currents, proliferation, and migration
| Autor: | Peter A. Vincent, Khalid Matrougui, Wei Zhang, José C. González-Cobos, Mohamed Trebak, Harold A. Singer, Rajender K. Motiani, Amy M. Spinelli, Xuexin Zhang, Sarah E Rowan, Joshua P Garrett |
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| Rok vydání: | 2012 |
| Předmět: |
inorganic chemicals
Male medicine.medical_specialty Platelet-derived growth factor ORAI1 Protein Physiology medicine.medical_treatment Clinical Biochemistry Myocytes Smooth Muscle Article Membrane Potentials Rats Sprague-Dawley chemistry.chemical_compound Mice Downregulation and upregulation Cell Movement Physiology (medical) Internal medicine medicine Myocyte Animals Calcium Signaling Stromal Interaction Molecule 1 RNA Small Interfering Cell Proliferation Platelet-Derived Growth Factor Membrane Glycoproteins Voltage-dependent calcium channel biology ORAI1 Growth factor STIM1 Asthma Cell biology Rats Up-Regulation Mice Inbred C57BL Trachea Disease Models Animal Endocrinology chemistry biology.protein Calcium Calcium Channels Platelet-derived growth factor receptor |
| Zdroj: | Pflugers Archiv : European journal of physiology. 464(5) |
| ISSN: | 1432-2013 |
| Popis: | Airway smooth muscle cell (ASMC) remodeling contributes to the structural changes in the airways that are central to the clinical manifestations of asthma. Ca(2+) signals play an important role in ASMC remodeling through control of ASMC migration and hypertrophy/proliferation. Upregulation of STIM1 and Orai1 proteins, the molecular components of the store-operated Ca(2+) entry (SOCE) pathway, has recently emerged as an important mediator of vascular remodeling. However, the potential upregulation of STIM1 and Orai1 in asthmatic airways remains unknown. An important smooth muscle migratory agonist with major contributions to ASMC remodeling is the platelet-derived growth factor (PDGF). Nevertheless, the Ca(2+) entry route activated by PDGF in ASMC remains elusive. Here, we show that STIM1 and Orai1 protein levels are greatly upregulated in ASMC isolated from ovalbumin-challenged asthmatic mice, compared to control mice. Furthermore, we show that PDGF activates a Ca(2+) entry pathway in rat primary ASMC that is pharmacologically reminiscent of SOCE. Molecular knockdown of STIM1 and Orai1 proteins inhibited PDGF-activated Ca(2+) entry in these cells. Whole-cell patch clamp recordings revealed the activation of Ca(2+) release-activated Ca(2+) (CRAC) current by PDGF in ASMC. These CRAC currents were abrogated upon either STIM1 or Orai1 knockdown. We show that either STIM1 or Orai1 knockdown significantly inhibited ASMC proliferation and chemotactic migration in response to PDGF. These results implicate STIM1 and Orai1 in PDGF-induced ASMC proliferation and migration and suggest the potential use of STIM1 and Orai1 as targets for ASMC remodeling during asthma. |
| Databáze: | OpenAIRE |
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