A-kinase-anchoring proteins (AKAPs) compartmentalize cAMP signaling by establishing protein complexes. We previously reported that the ␤2-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 ␤2-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.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease mainly caused by cigarette smoke. Current pharmacotherapy involves β2‐agonists and phosphodiesterase inhibitors. Both drugs elevate cAMP, but relieve a distinct subset of COPD symptoms. This may be mediated by A‐kinase anchoring proteins (AKAPs) that compartmentalize cAMP signaling. Here we studied the role of AKAPs in human airway smooth muscle (ASM) secretory function. Using western blot, radio‐assays for PKA binding (RII overlay) and RT‐qPCR we show that human ASM cells express AKAP5, AKAP8, AKAP9, AKAP12 and ezrin, and that cigarette smoke extract (CSE) decreases AKAP5, AKAP9 and AKAP12 expression. In line, we observed reduced mRNA expression of these AKAPs in lung tissue homogenates of COPD patients compared to healthy controls. Disruption of AKAP functions using st‐Ht31 augmented CSE‐induced IL‐8 release and prevented the inhibitory effect of the β2‐agonist fenoterol on CSE‐induced IL‐8 release. St‐Ht31 also diminished the inhibitory effect of fenoterol on CSE‐induced ERK phosphorylation, but not NFκB activation. Thus, the anti‐inflammatory effect of fenoterol on ASM secretory function is mediated by AKAPs. The reduction of specific AKAPs in COPD may disrupt compartmentalized cAMP and thereby affect pharmacotherapy. Supported by Dutch Asthma Foundation grant 3.2.11.015 and a Rosalind Franklin Fellowship.