Validation of the "Extracellular cyclic AMP-Adenosine pathway" as a therapeutic target for chronic respiratory diseases.

Abstract

The intracellular cyclic AMP (cAMP) regulates several processes including contraction, metabolism, protein expression and function of striated and smooth muscle. Previous studies from our lab have shown that the increment in cAMP production in skeletal muscle induced by activation of stimulatory (Gs) protein coupled receptor (GsPCR) or adenylyl cyclase is followed by efflux of this cyclic nucleotide (Godinho & Costa-Jr, 2003). Once outside the cell, cAMP exerts its effects via its metabolite adenosine, generated by sequential action of ecto-phosphodiesterases and ecto-5'-nucleotidases (Chiavegatti et al., 2008). Our results also showed that the extracellular cAMP-adenosine pathway modulates skeletal muscle contraction, being responsible for indirect coupling of ²2 adrenoceptors to inhibitory G (Gi) protein (Duarte et al., 2012). Taking into account the involvement of the intracellular cAMP on the relaxation of bronchiolar smooth muscle induced by catecholamines and ²2 adrenoceptor agonists (Cazzola et al., 2013) used for treatment of pulmonary obstructive chronic diseases and the contracting effects of extracellular cAMP on tracheal smooth muscle (Pacini et al., 2018), the major aim of the present study is to evaluate the contribution of extracellular cAMP-adenosine pathway on the reactivity of tracheal smooth muscle and on pathophysiology of the respiratory tract in an ovalbumin-induced model of allergic lung inflammation. Assuming that the accessory respiratory skeletal muscles are also affected by DPOC, in the present study the influence of extracellular cAMP on the trophism of respiratory skeletal muscle physiology will be accessed.References1.Cazzola, M, Page, CP, Rogliani, P & Matera, MG. (2013). beta2-agonist therapy in lung disease. Am J Respir Crit Care Med, 187, 690-696.2.Chiavegatti, T, Costa, VL, Araujo, MS & Godinho, RO. (2008). Skeletal muscle expresses the extracellular cyclic AMP-adenosine pathway. Br J Pharmacol, 153, 1331-1340.3.Duarte, T, Menezes-Rodrigues, FS & Godinho, RO. (2012). Contribution of the extracellular cAMP-adenosine pathway to dual coupling of beta2-adrenoceptors to Gs and Gi proteins in mouse skeletal muscle. J Pharmacol Exp Ther, 341, 820-828.4.Godinho, RO & Costa-Jr, VL. (2003). Regulation of intracellular cyclic AMP in skeletal muscle cells involves the efflux of cyclic nucleotide to the extracellular compartment. Br J Pharmacol, 138, 995-1003.5.Pacini, ESA, Sanders-Silveira, S & Godinho, RO. (2018). The Extracellular cAMP-Adenosine Pathway in Airway Smooth Muscle. J Pharmacol Exp Ther, 366, 75-83. (AU)