Function of cAMP scaffolds in obstructive lung disease: Focus on epithelial‐to‐mesenchymal transition and oxidative stress

Abstract

Over the past decades, research has defined cAMP as one of the central cellular nodes in sensing and integrating multiple pathways and as a pivotal role player in lung pathophysiology. Obstructive lung disorders, such as chronic obstructive pulmonary disease (COPD), are characterized by a persistent and progressive airflow limitation and by oxidative stress from endogenous and exogenous insults. The extent of airflow obstruction depends on the relative deposition of different constituents of the extracellular matrix, a process related to epithelial‐to‐mesenchymal transition, and which subsequently results in airway fibrosis. Oxidative stress from endogenous and also from exogenous sources causes a profound worsening of COPD. Here we describe how cAMP scaffolds and their different signalosomes in different subcellular compartments may contribute to COPD. Future research will require translational studies to alleviate disease symptoms by pharmacologically targeting the cAMP scaffolds. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

A-Kinase Anchoring Proteins Diminish TGF-β1/Cigarette Smoke-Induced Epithelial-To-Mesenchymal Transition

“…Chronic obstructive pulmonary disease (COPD), which is primarily induced by cigarette smoke (CS), is characterized by irreversible airflow limitation that is linked to subepithelial airway fibrosis [1]. A vital player during organ fibrosis is epithelial-to-mesenchymal transition (EMT), a process in which epithelial cells gradually lose their epithelial phenotype and undergo transition to typical mesenchymal characteristics, which feature increased mitogenic capacity and enhanced extracellular matrix production [2][3][4][5]. Recent evidence suggests that EMT is involved in the fibrotic processes in the large and small airways during the pathogenesis of COPD as well as lung cancer [6][7][8].…”

A-Kinase Anchoring Proteins Diminish TGF-β1 / Cigarette Smoke-Induced Epithelial-to-Mesenchymal Transition

“…Chronic obstructive pulmonary disease (COPD), which is primarily induced by cigarette smoke (CS), is characterized by irreversible airflow limitation that is linked to subepithelial airway fibrosis [1]. A vital player during organ fibrosis is epithelial-to-mesenchymal transition (EMT), a process in which epithelial cells gradually lose their epithelial phenotype and undergo transition to typical mesenchymal characteristics, featuring increased mitogenic capacity and enhanced extracellular matrix production [2][3][4][5]. Recent evidence suggests that EMT is involved in the fibrotic processes in the large and small airways during the pathogenesis of COPD as well as lung cancer [6][7][8].…”

“…Transforming growth factor-β1 (TGF-β1) is another well-known inducer of EMT [5,9]. The cyclic adenosine monophosphate (cAMP) signaling pathway is one of multiple pathways that are implicated in the regulation of EMT [10][11][12][13].…”

“…They play a critical role in maintaining subcellular compartmentalization of cAMP by generating spatially discrete signaling complexes, which create local gradients of cAMP [14,15]. As scaffolding proteins, AKAPs bind protein kinase A (PKA) and a diverse subset of signaling enzymes, and thereby control cAMP microdomains in a spatio-temporal manner [5,16]. Studies have demonstrated that several AKAPs membranes are involved in TGF-β1-induced EMT in vitro.…”

Adrenoceptors—New roles for old players

“…Another phenomenon that is changing the way we think about the signalling of β‐adrenoceptors and other G s ‐coupled receptors is that the cAMP formed by adenylyl cyclase not only activates protein kinase A but can also bind to Epac (exchange factor activated by cAMP) that elicits a range of different, sometimes even opposing cellular events. Scaffolds involving Epac may play a role in the epithelial–mesenchymal transition and, thereby, contribute to the pathophysiology of diseases such as chronic obstructive pulmonary disease (Zuo, Cattani‐Cavalieri, Valença, Musheshe, & Schmidt, ). Furthermore, there is now compelling evidence that many, if not all, GPCRs can activate more than one pathway and that ligands can bind to a conformation that preferentially activates one of these pathways, relative to a reference ligand.…”