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Impact of the extracellular cAMP-adenosine pathway on cAMP signaling

Grant number: 23/03689-1
Support Opportunities:Regular Research Grants
Duration: September 01, 2023 - August 31, 2025
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Rosely Oliveira Godinho
Grantee:Rosely Oliveira Godinho
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated researchers: Enio Setsuo Arakaki Pacini

Abstract

cAMP (3',5'-cyclic adenosine monophosphate, cyclic AMP) is a universal intracellular second messenger to a wide variety of hormones and neurotransmitters, especially those that activate the stimulatory G protein-coupled receptors (GPCRs). Over the past 20 years, studies from our group have redesigned this concept by identifying an extracellular cAMP signaling function in both skeletal muscle and airway smooth muscle. In these tissues, part of the newly synthesized cAMP is transported to the extracellular milieu where it undergoes the sequential action of ectoenzymes, becoming a source of extracellular adenosine (Godinho & Costa-Jr, 2003, Br J Pharmacol, 138, 995-1003; Chiavegatti et al., 2008, 153, 1331-1340; Pacini et al., 2021, Biochem Pharmacol, 192:114713). This pathway known as the "extracellular cAMP-adenosine pathway" attenuates both skeletal muscle contraction (Duarte et al., 2012, J Pharmacol Exp Ther, 341, 820-828) and the bronchodilator effect of ²2-adrenoceptor agonists (Pacini et al. 2018). Despite the expression in many tissues of MRP/ABCC transporters, responsible for cAMP efflux, few studies have addressed the contribution of cAMP efflux and the extracellular cAMP-adenosine pathway in signaling mediated by stimulatory G protein-coupled receptors. Thus, one of the objectives of this project is to assess whether cAMP efflux can be considered a universal physiological process. In the present study, cAMP efflux will be evaluated in various tissues such as prostate, vas deferens, aorta and bladder. Considering that, differently from what happens intracellularly, extracellular cAMP promotes airway smooth muscle contraction, our second objective will be to evaluate the mechanisms involved in extracellular cAMP-induced bronchoconstriction and its role in the airway inflammatory response, using the model of ovalbumin-induced allergic inflammation. Finally, considering that chronic pulmonary inflammatory diseases also lead to accessory skeletal muscle atrophy, the impact of the extracellular cAMP-adenosine pathway on skeletal muscle trophism will also be addressed. (AU)

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