Up-regulation of KCa3.1 promotes human airway smooth muscle cell phenotypic modulation.
Airway smooth muscle (ASM) cell phenotype modulation, characterized by reversible switching between contractile and proliferative phenotypes, is considered to contribute to proliferative diseases such as allergic asthma and chronic obstructive pulmonary disease (COPD). KCa3.1 has been suggested to be involved in regulating ASM cell activation, proliferation, and migration. However, little is known regarding the exact role of KCa3.1 in ASM cell phenotypic modulation. To elucidate the role of KCa3.1 in regulating ASM cell phenotypic modulation, we investigated the effects of KCa3.1 channels on ASM contractile marker protein expression, proliferation and migration of primary human bronchial smooth muscle (BSM) cells. We found that PDGF increased KCa3.1 channel expression in BSM cells with a concomitant marked decrease in the expression of contractile phenotypic marker proteins including smooth muscle myosin heavy chain (SMMHC), smooth muscle α-actin (α-SMA), myocardin and KCa1.1. These changes were significantly attenuated by the KCa3.1 blocker, TRAM-34, or gene silencing of KCa3.1. Pharmacological blockade or gene silencing of KCa3.1 also suppressed PDGF-induced human BSM cell migration and proliferation accompanied by a decrease in intracellular free Ca(2+) levels as a consequence of membrane depolarization, resulting in a reduction in cyclin D1 level and cell cycle arrest at G0-G1 phase. Additionally, PDGF-induced up-regulation of KCa3.1 and down-regulation of BSM contractile marker proteins were regulated by the ERK inhibitor U0126 and the AKT inhibitor LY294002. These findings highlight a novel role for the KCa3.1 channel in human BSM cell phenotypic modulation and provide a potential target for therapeutic intervention for proliferative airway diseases.
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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ZH
Yu
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Wang
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Song
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Lu
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Hou
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Cui
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Chen
D000199:Actins / Q000096:biosynthesis; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D020868:Gene Silencing; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000096:biosynthesis / Q000235:genetics; D009025:Morpholines / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000096:biosynthesis; D009570:Nitriles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000096:biosynthesis; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D015534:Trans-Activators / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects; D000099251:Myocardin
D000199:Actins; D002070:Butadienes; D002118:Calcium; D002867:Chromones; D019938:Cyclin D1; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D009025:Morpholines; D018995:Myosin Heavy Chains; D009570:Nitriles; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D015534:Trans-Activators; D000099251:Myocardin; C494841:KCNMA1 protein, human; C496923:KCNN4 protein, human; C411671:TRAM 34; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
DiBAC (PubChem CID 15688); Human bronchial smooth muscle cells; KCa3.1; LY294002 (PubChem CID 3973); Migration; Phenotypic modulation; Proliferation; TRAM-34 (PubChem CID 656734); U0126 (PubChem CID 3006531)