title: A-kinase-anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle.
abstract: β2-Agonist inhibitors can relieve chronic obstructive pulmonary disease (COPD) symptoms by stimulating cyclic AMP (cAMP) signaling. A-kinase-anchoring proteins (AKAPs) compartmentalize cAMP signaling by establishing protein complexes. We previously reported that the β2-agonist fenoterol, direct activation of protein kinase A (PKA), and exchange factor directly activated by cAMP decrease cigarette smoke extract (CSE)-induced release of neutrophil attractant interleukin-8 (IL-8) from human airway smooth muscle (ASM) cells. In the present study, we tested the role of AKAPs in CSE-induced IL-8 release from ASM cells and assessed the effect of CSE on the expression levels of different AKAPs. We also studied mRNA and protein expression of AKAPs in lung tissue from patients with COPD. Our data show that CSE exposure of ASM cells decreases AKAP5 and AKAP12, both capable of interacting with β2-adrenoceptors. In lung tissue of patients with COPD, mRNA levels of AKAP5 and AKAP12 were decreased compared with lung tissue from controls. Using immunohistochemistry, we detected less AKAP5 protein in ASM of patients with COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II compared with control subjects. St-Ht31, which disrupts AKAP-PKA interactions, augmented CSE-induced IL-8 release from ASM cells and diminished its suppression by fenoterol, an effect mediated by disturbed ERK signaling. The modulatory role of AKAP-PKA interactions in the anti-inflammatory effects of fenoterol in ASM cells and the decrease in expression of AKAP5 and AKAP12 in response to cigarette smoke and in lungs of patients with COPD suggest that cigarette smoke-induced changes in AKAP5 and AKAP12 in patients with COPD may affect efficacy of pharmacotherapy.
authors: University of Groningen, Department of Molecular Pharmacology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands; Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany; w.j.poppinga@rug.nl.
authors: Wilfred J
authors: http://orcid.org/0000-0002-2711-2411
authors: WJ
authors: Poppinga
authors: University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands;
authors: Irene H
authors: IH
authors: Heijink
authors: University of Groningen, Department of Molecular Pharmacology, Groningen, The Netherlands; Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany;
authors: Laura J
authors: LJ
authors: Holtzer
authors: Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany;
authors: Philipp
authors: P
authors: Skroblin
authors: Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany;
authors: Enno
authors: E
authors: Klussmann
authors: University of Manitoba, Departments of Physiology and Pathophysiology, and Internal Medicine, Winnipeg, Manitoba, Canada;
authors: Andrew J
authors: AJ
authors: Halayko
authors: University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands;
authors: Wim
authors: W
authors: Timens
authors: University of Groningen, Department of Molecular Pharmacology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands; Palm Beach Atlantic University, Lloyd L. Gregory School of Pharmacy, Department of Pharmaceutical Sciences, West Palm Beach, Florida.
authors: Harm
authors: H
authors: Maarsingh
authors: University of Groningen, Department of Molecular Pharmacology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands;
authors: Martina
authors: M
authors: Schmidt
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*
chemical_list: D054758:A Kinase Anchor Proteins; C491162:AKAP12 protein, human; C487775:AKAP5 protein, human; D018797:Cell Cycle Proteins; D016209:Interleukin-8; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: A-kinase-anchoring protein; chronic obstructive pulmonary disease; compartmentalization; cyclic AMP; inflammation
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