By interacting with specific domains in the PKA regulatory subunits, cAMP releases the two catalytic PKA subunits to phosphorylate serine and/or threonine residues in target proteins ( 11). cAMP-dependent protein kinase (PKA) is by far the best studied effector of cAMP signaling and regulates many cellular processes including cell proliferation and differentiation, among others ( 10). A 1 and A 3 receptors are preferentially coupled to the inhibitory Gα (Gi/o) subunit that inhibits AC1, AC5 and AC6, decreasing 3’,5’-cAMP (from here forward referred to as simply cAMP) production, whereas A 2A and A 2B are strongly coupled to stimulatory Gα (Gs) subunits, which can activate all nine membrane-bound AC isoforms, increasing intracellular cAMP concentrations ( 7, 8) and triggering one or more cAMP-dependent intracellular signaling pathways ( 9). These four receptors are encoded by different genes and present high affinities for the α subunit (Gα) of heterotrimeric G-proteins that regulate adenylyl cyclase (AC) activity ( 6). Adenosine receptors are seven transmembrane G-protein coupled receptors (GPCRs) ( 4, 5), and consist of a family of four adenosine receptor subtypes called A 1, A 2A, A 2B and A 3.

Finally, we will discuss therapeutic possibilities targeting the extracellular cAMP-adenosine pathway for treatment of these respiratory diseases.Īdenosine is an endogenous purine nucleoside that, via activation of specific adenosine receptors, modulates inflammation and immune responses ( 1– 3). In this mini-review, we will highlight the potential role of the extracellular cAMP-adenosine pathway in chronic respiratory inflammatory disorders, and we will explore how extracellular cAMP could interfere with the regulatory effects of intracellular cAMP on airway smooth muscle and innate immune cell function. Indeed, our recent findings support this view. These considerations lead to the hypothesis that the cAMP-adenosine pathway attenuates the efficacy of β 2-adrenoceptor agonists. In the airways, extracellular adenosine exerts pro-inflammatory effects and induces bronchoconstriction in patients with asthma and chronic obstructive pulmonary diseases. In airways, β 2-adrenoceptor agonists, which are used as bronchodilators for treatment of asthma and chronic respiratory diseases, stimulate cAMP efflux and thus trigger the extracellular cAMP-adenosine pathway leading to increased concentrations of extracellular adenosine in airways. Importantly, the cAMP-adenosine pathway is operative in many cell types, including those of the airways. However, studies over the past 30 years provide strong evidence for another source of extracellular adenosine, namely the “cAMP-adenosine pathway.” The cAMP-adenosine pathway is a biochemical mechanism mediated by ATP-binding cassette transporters that facilitate cAMP efflux and by specific ectoenzymes that convert cAMP to AMP (ecto-PDEs) and AMP to adenosine (ecto-nucleotidases such as CD73).

Under pathological conditions and in response to inflammatory stimuli, extracellular ATP is released from damaged cells and is metabolized to extracellular adenosine. 2Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesĪdenosine is a purine nucleoside that, via activation of distinct G protein-coupled receptors, modulates inflammation and immune responses.1Division of Cellular Pharmacology, Department of Pharmacology, Universidade Federal de São Paulo, São Paulo, Brazil.Enio Setsuo Arakaki Pacini 1, Naiara Ayako Satori 1, Edwin Kerry Jackson 2 and Rosely Oliveira Godinho 1*

Becker satori x 100