Epac Function and cAMP Scaffolds in the Heart and Lung

Abstract

Evidence collected over the last ten years indicates that Epac and cAMP scaffold proteins play a critical role in integrating and transducing multiple signaling pathways at the basis of cardiac and lung physiopathology. Some of the deleterious effects of Epac, such as cardiomyocyte hypertrophy and arrhythmia, initially described in vitro, have been confirmed in genetically modified mice for Epac1 and Epac2. Similar recent findings have been collected in the lung. The following sections will describe how Epac and cAMP signalosomes in different subcellular compartments may contribute to cardiac and lung diseases.

Functional Significance of the Adcy10-Dependent Intracellular cAMP Compartments

“…Though PKA has long been considered the most active kinase in the matrix and the main effector of intra-mitochondrial cAMP [ 12 ], another cAMP downstream target involved in the regulation of mitochondrial function—EPAC—has also been described [ 117 ]. The mitochondrial sAC-cAMP-EPAC pathway regulates coupling efficiency and the structural organization of F 0 F 1 ATP synthase in mammalian mitochondria [ 118 ].…”

Axelrod Symposium 2019: Phosphoproteomic Analysis of G-Protein–Coupled Pathways

“…This is an important observation as it suggests that at least some of the subcellular cAMP signalling domains may not be detectable by optical microscopy unless a cAMP sensor is strategically targeted within that nanodomain. cAMP effector proteins often cluster together with their targets and cAMP regulatory proteins to form discrete cAMP signalling hubs termed signalosomes (Maurice et al, 2014;Laudette et al, 2018). This is of considerable importance for cAMP compartmentalisation, because it leads to local concentration and amplification of cAMP effects.…”

Function of cAMP scaffolds in obstructive lung disease: Focus on epithelial‐to‐mesenchymal transition and oxidative stress

“…In this regard, there is increasing interest in understanding the role of EMT in COPD as well. COPD represents a major global health problem with the ailment estimated to become the third leading cause of death and the fifth leading cause of disability by 2030 (Barnes et al, 2015;Laudette, Zuo, Lezoualc'h, & Schmidt, 2018). Cigarette smoke is implicated as the primary cause of COPD.…”

“…It will therefore be of interest in the future to study the extent to which distinct ACs (Halls & Cooper, 2017), acting in concert with a distinct subset of PDEs, PKA, and Epac, may contribute to the differential regulation of ECM deposition. Even though such cAMP microdomains have been extensively studied in the cardiovascular system (Laudette et al, 2018;Musheshe, Schmidt, & Zaccolo, 2018), they still have to be defined in more detail in the pulmonary system.…”