cAMP regulation of airway smooth muscle function

Abstract

Agonists activating β₂-adrenoceptors (β₂ARs) on airway smooth muscle (ASM) are the drug of choice for rescue from acute bronchoconstriction in patients with both asthma and chronic obstructive pulmonary disease (COPD). Moreover, the use of long-acting β-agonists combined with inhaled corticosteroids constitutes an important maintenance therapy for these diseases. β-Agonists are effective bronchodilators due primarily to their ability to antagonize ASM contraction. The presumed cellular mechanism of action involves the generation of intracellular cAMP, which in turn can activate the effector molecules cAMP-dependent protein kinase (PKA) and Epac. Other agents such as prostaglandin E₂ and phosphodiesterase inhibitors that also increase intracellular cAMP levels in ASM, can also antagonize ASM contraction, and inhibit other ASM functions including proliferation and migration. Therefore, β₂ARs and cAMP are key players in combating the pathophysiology of airway narrowing and remodeling. However, limitations of β-agonist therapy due to drug tachyphylaxis related to β₂AR desensitization, and recent findings regarding the manner in which β₂ARs and cAMP signal, have raised new and interesting questions about these well-studied molecules. In this review we discuss current concepts regarding β₂ARs and cAMP in the regulation of ASM cell functions and their therapeutic roles in asthma and COPD.

Introduction

3′-5′-Cyclic adenosine monophosphate (cAMP) is the archetypal second messenger whose specific biochemical and signaling properties in numerous cell types have been intensively researched for more than half a century. The resulting wealth of data clearly highlights the importance of cAMP in diverse physiological and pathophysiological processes via its modulation of diverse cellular events. cAMP plays a key role in the functions of many airway cells including controlling ciliary beat frequency (critical for mucus clearance) in airway epithelial cells [1] and suppressing the pro-inflammatory activity of various immune and inflammatory cells. However it is arguably the inhibitory effect of increased cytosolic cAMP levels on the contraction of airway smooth muscle (ASM) which constitutes the most profound cAMP-mediated effect in the lung.

As discussed in greater detail below, cAMP-mediated pathways are most commonly initiated following the binding of specific ligands to G protein-coupled receptors (GPCRs) of the G_s family. Perhaps the most exhaustively studied GPCR is the β₂-adrenoceptor (β₂AR) and it is specifically the β₂ARs on ASM cells which, due to their ability to rapidly promote bronchorelaxation, constitute the frontline target for asthma therapy. In addition to driving this clinically critical effect, cAMP also modulates many other aspects of ASM function including proliferation, migration, secretion of inflammatory mediators, and deposition of extracellular matrix (ECM). Beyond these acute effects, cAMP also appears to influence the “phenotype” of ASM cells; i.e., properties relating to their capacity to function as a contractile cell or one more capable of proliferation and secretory/immune-modulatory functions.

Whilst the molecular events occurring between β₂AR activation and bronchorelaxation were thought to be well understood, several recent studies have introduced layers of complexity which have the potential to profoundly alter our understanding of the β₂AR signaling pathway and how asthma is treated clinically.

In this review we aim to explore some of the myriad ways in which cAMP regulates ASM function with an emphasis placed on novel or controversial observations. A brief overview of cAMP regulation will be given encompassing modulation via GPCRs, phosphodiesterases (PDEs), and two direct downstream effectors of cAMP namely protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac). We shall then consider the ways in which diverse ASM functions are mediated via cAMP and, where possible, address whether these effects are PKA- or Epac-driven. Finally we will consider the therapeutic implications both in terms of future targets and problems with current therapy and ask “What Next?”