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«Pharmaceuticals 2012, 5, 1291-1331; doi:10.3390/ph5121291 OPEN ACCESS pharmaceuticals ISSN 1424-8247 Review ...»

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Pharmaceuticals 2012, 5, 1291-1331; doi:10.3390/ph5121291



ISSN 1424-8247



Multiple Facets of cAMP Signalling and Physiological Impact:

cAMP Compartmentalization in the Lung

Anouk Oldenburger 1,2,*, Harm Maarsingh 1,2 and Martina Schmidt 1,2


Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV, Groningen, The Netherlands 2 Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands * Author to whom correspondence should be addressed; E-Mail: a.oldenburger@rug.nl;

Tel. +31-50-363-3304; Fax: +31-50-363-6908.

Received: 18 September 2012; in revised form: 15 November 2012 / Accepted: 20 November 2012 / Published: 30 November 2012 Abstract: Therapies involving elevation of the endogenous suppressor cyclic AMP (cAMP) are currently used in the treatment of several chronic inflammatory disorders, including chronic obstructive pulmonary disease (COPD). Characteristics of COPD are airway obstruction, airway inflammation and airway remodelling, processes encompassed by increased airway smooth muscle mass, epithelial changes, goblet cell and submucosal gland hyperplasia. In addition to inflammatory cells, airway smooth muscle cells and (myo)fibroblasts, epithelial cells underpin a variety of key responses in the airways such as inflammatory cytokine release, airway remodelling, mucus hypersecretion and airway barrier function. Cigarette smoke, being next to environmental pollution the main cause of COPD, is believed to cause epithelial hyperpermeability by disrupting the barrier function.

Here we will focus on the most recent progress on compartmentalized signalling by cAMP.

In addition to G protein-coupled receptors, adenylyl cyclases, cAMP-specific phospho- diesterases (PDEs) maintain compartmentalized cAMP signalling. Intriguingly, spatially discrete cAMP-sensing signalling complexes seem also to involve distinct members of the A-kinase anchoring (AKAP) superfamily and IQ motif containing GTPase activating protein (IQGAPs). In this review, we will highlight the interaction between cAMP and the epithelial barrier to retain proper lung function and to alleviate COPD symptoms and focus on the possible molecular mechanisms involved in this process. Future studies should include the development of cAMP-sensing multiprotein complex specific disruptors and/or

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stabilizers to orchestrate cellular functions. Compartmentalized cAMP signalling regulates important cellular processes in the lung and may serve as a therapeutic target.

Keywords: cAMP compartmentalization; barrier function; COPD; A-kinase anchoring proteins (AKAPs); Epac

1. Introduction Cyclic adenosine monophosphate (cAMP), the most common and universal secondary messenger, regulates physiological processes as diverse as calcium handling, secretion, ion channel conductance, learning and memory, metabolic events, cardiac and smooth muscle contraction, cell growth and differentiation, apoptosis, inflammation, and barrier functioning [1,2]. The impact and complexity of research into the molecular architecture of cAMP signalling is not only reflected by five Nobel awards since the discovery of cAMP in 1957 by Sutherland and colleagues [1], but also by a unique interplay of signalling components that tightly control the cellular content of cAMP. Next to G protein-coupled receptors, adenylyl cyclases (ACs) and cAMP-specific phosphodiesterases (PDEs) maintain the spatio-temporal nature of cAMP signalling by shaping a cAMP gradient throughout the cell [3–5].

Subcellular membrane clustering of receptors, ACs and PDEs to lipid rafts and caveolae [6–8], and cell compartment-specific (co)localization to distinct cAMP effectors [9–13] further support the maintenance of spatio-temporal compartmentalized cAMP signalling. Moreover, A-kinase anchoring proteins (AKAPs) facilitate subcellular cAMP spatio-temporal compartmentalization by generating spatially discrete signalling complexes that create local gradients of cAMP, and thereby permit and control specific cellular responses (Figure 1) [14–17]. Dysfunctions of cAMP-sensing AKAP complexes seem to contribute to the progression of a wide variety of diseases, including chronic heart failure, cardiac arrhythmia, Alzheimer’s dementia, HIV infection, diabetes mellitus and cancer [17–21], hence, current research intends to target the spatio-temporal cAMP-responsive complexes to provide novel therapeutical interventions [5,11,12,17,22].

In this review we will discuss the recent progress on spatio-temporal compartmentalized cAMP signalling from the receptors coupled to the cAMP pathway up to the subtle interplay between the distinct cAMP-sensitive effectors that maintain cAMP-sensing multiprotein complexes. In particular, we will focus on the impact of perturbation of cAMP-sensing signalling complexes in the development and progression of chronic obstructive pulmonary disease (COPD), a chronic inflammatory lung disease characterized by airway obstruction, emphysema and airway remodelling. Remodelling processes encompass increased airway smooth muscle mass, epithelial changes, goblet cell and submucosal gland hyperplasia—leading to mucus hypersecretion [23–30]. In addition to inflammatory cells, airway smooth muscle cells and (myo)fibroblasts, epithelial cells underpin a variety of key responses in the airways such as inflammatory cytokine release, airway remodelling, mucus hypersecretion and the barrier function [23–30]. Cigarette smoke—together with environmental pollution—is the main risk factor for COPD and induces inflammatory processes, alveolar destruction (emphysema), fibrosis and epithelial hyperpermeability by disrupting the barrier function, releasing proteases and inducing multiple inflammatory genes [27–29,31]. Disruption of the epithelial barrier is 1293 Pharmaceuticals 2012, 5 associated with epithelial remodelling that also accounts for goblet cell metaplasia and mucus gland hypertrophy in COPD [32,33]. Mucus hypersecretion contributes to the morbidity and mortality of COPD, particularly in those patients with more severe disease [27,28,34]. In the treatment of obstructive lung diseases, including COPD, cAMP elevating drugs are widely used. Already in the early eighties it has been reported that cAMP elevating agents, such as β2-agonists, prostanoids and the direct AC activator forskolin (Figure 1), temper oedema in whole animal, isolated lung, and clinical studies of lung injury, phenomena which could be linked to an increase in barrier function in pulmonary endothelial cells [2].

Figure 1. Overview of compartmentalization of cAMP signalling.

Gs-protein coupled receptors are stimulated by their appropriate ligands such as β2-agonists and prostanoids.

Subsequently, activation of adenylyl cyclase (AC) will lead to the production of the second messenger cyclic AMP (cAMP), whereas cAMP-specific phosphodiesterases (PDEs) will shape the cAMP gradient throughout the cell. Alternatively, AC can be directly activated by the cell membrane-permeable diterpene forskolin from the Indian plant Coleus forskolhlii. Elevation of cellular cAMP will simultaneously induce the activation of protein kinase A (PKA) and of the exchange protein directly activated by cAMP (Epac). Members of the A-kinase anchoring protein (AKAP) family will support the maintenance of cAMP compartmentalization upon binding to the cAMP-producing receptors, the cAMP effectors PKA and/or Epac as well as PDEs. The generation of cAMP-sensing multiprotein complexes by AKAPs is of tremendous importance to maintain spatio-temporal cAMP signalling at specific and discrete locations within the cell to regulate specific cellular responses upon signalling to several distinct effector proteins including vasodilatorstimulated phosphoprotein (VASP), a subset of small GTPases, and phospholipase C-ε (PLC-ε). Shown are tools being used to study the functioning of the cAMP-sensing multiprotein complexes: st-Ht31, the PKA binding blocking peptide known to act as a generic AKAP inhibitor [14–16]; 8-pCPT-2'-O-Me-cAMP and/or Sp-8-pCPT-2'-O-MecAMP, activator of Epac; 6-Bnz-cAMP, activator of PKA; Rp-8-CPT-cAMP, Rp-cAMPs, Rp-8-Bromo-cAMPs inhibitors of PKA.

1294 Pharmaceuticals 2012, 5 Our current knowledge, however, about the molecular mechanisms underlying proper epithelial barrier functioning in the airways is mainly based on studies with focus on the endothelial barrier in the vasculature [2]. For the purpose of this review, we will outline our current knowledge about compartmentalized cAMP signalling. We will highlight the role of the epithelial barrier to maintain proper lung functioning and to alleviate COPD symptoms. The regulation of the endothelial barrier will serve as a starting point, and whenever appropriate, we will focus on the epithelial barrier function.

2. Spatio-Temporal Nature of Compartmentalized cAMP Signalling: Paradigm Shifts

The formation of cAMP is initiated by the stimulation of Gs-protein-coupled receptors, such as the β2-adrenoceptor and distinct prostanoid receptor subtypes. As members of the largest superfamily of cell surface signalling molecules, cAMP-elevating Gs-protein-coupled receptors represent the most prominent family of validated pharmacological targets in biomedicine [1,35,36]. In obstructive airways diseases short- and long-acting β2-agonists, such as salbutamol/albuterol, fenoterol, formoterol and indaceterol, are clinically widely used and act via stimulation of Gs-protein-coupled receptors [37–40].

In addition, recent studies emphasize also substantial progress to pharmacologically target the prostanoid PGE2-receptors to alleviate symptoms of obstructive lung diseases [41–45]. Over the last years substantial progress has been made to decipher the distinct signalling properties of cAMP.

Initially, elevation of cellular cAMP by β2-agonists and prostanoids were expected to simultaneously stimulate both protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac) [1,46,47]. Meanwhile, it is generally accepted that spatio-temporal compartmentalization of cAMP maintained by cAMP-sensing AKAP-bearing multiprotein complexes and PDEs is of utmost importance to gain signalling specificity of cAMP [4,9–17].

Generally, G protein coupled receptors are considered as cell surface recognition sites sensing ions, hormones, neurotransmitters, autocoids and extracellular matrix components [36,38,48–50]. More recent studies showed that also internalized G protein-coupled receptors—until now believed to act as a ‘loss-of-function’ receptor signal—maintain signalling properties [18,51–53]. Using fluorescence resonance energy transfer to track intracellular cAMP fluctuations following activation of typically Gs-protein-coupled receptors [51,52], it has been reported that AC signalling is not necessarily restricted to the plasma membrane, but could be also detected in the endosome compartment. Indeed, endosomes, in which internalized receptors may end up, are now recognized as essential sites of cellular signalling [54,55], In addition, actin-stabilized endosomal microdomains profoundly affect the endosomal recycling and thereby the signalling properties of the β2-adrenoceptor [56]. Strikingly, Nikolaev and colleagues demonstrated that the β2-adrenoceptor its redistributed in heart failure, thereby compartmentalizing cAMP, a process proposed to contribute to the failing myocardial phenotype [18]. While the novel concept of cAMP signalling by internalized G protein-coupled receptors has recently been adapted to the signalling properties of the β2-adrenoceptor in human small airways [37], evidence that such mechanisms are operational in distinct structural airway cell subtypes, including bronchial epithelial cells, still has to be provided.

Intriguingly, ligand-directed signalling or biased agonism, referring to Gs-induced cAMP- versus β-arrestin-mediated signalling in response to different agonists [48,49,57–59], adds another level of 1295 Pharmaceuticals 2012, 5 complexity of Gs-protein-coupled receptor signalling, and has recently been reviewed within the context of obstructive lung diseases and the β2-adrenoceptor [38,40,60–62]. In mice, genetic ablation of either β-arrestin-1 or -2 prevented against bleomycin-induced pulmonary fibrosis and fibroblast invasion, suggesting a role for β-arrestin in fibrosis [63]. In support, β-arrestin-2 expression in increased in cell models of cystic fibrosis as well as in nasal tissue from patients [64]. In human bronchial epithelial cells, β-arrestin is necessary for the transcription of matrix metalloproteinases (MMPs) by diesel exhaust particles, a risk factor for COPD [65]. In addition to modulation of remodelling processes, β-arrestin is involved in agonist-induced desensitisation of the β2-receptor by inducing the internalization of this receptor [48]. Lefkowitz and colleagues reported that β-arrestinmediated signalling exerts an even higher degree of regulation that relies on distinct phosphorylation sites of seven transmembrane receptors [66–68]. Likewise, β-arrestin-dependent signalling and trafficking of the β2-adrenoceptor also involve an unique deubiquitinase-ligase interplay [69,70].

Although recent studies indicate that ligand-directed signalling contributes to the functional responses of airway smooth muscle cells and lung fibroblasts [71,72], comparable studies in airway epithelial cells are still lacking. Further regulation of Gs signalling is mediated by the AKAP family members AKAP5 (aka AKAP79/150) and AKAP12 (aka AKAP250/Gravin), which regulate the de- and resensitization of the β2-adrenoceptor, respectively, and interact next to cAMP signalling proteins also with β-arrestin [14–17,73–75]. Thus, it is tempting to speculate that biased agonism might also profoundly alter the functional responses of AKAP-bearing multiprotein complexes. Moreover, receptors that ‘typically’ signal via Gs, including the β2-adrenoceptors, have also been shown to couple to other G-proteins, including Gi and G12/13, adding another layer of complexity to the regulatory pathways [76].

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