Abstract
The 5′-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a natural energy sensor in mammalian cells that plays a key role in cellular and systemic energy homeostasis. At the cellular level, AMPK supports numerous processes required for energy and redox homeostasis, including mitochondrial biogenesis, autophagy, and glucose and lipid metabolism. Thus, understanding the pathways regulating AMPK activity is crucial for developing strategies to treat metabolic disorders. Mounting evidence suggests the presence of a link between cyclic AMP (cAMP) and AMPK signaling. cAMP signaling is known to be activated in circumstances of physiological and metabolic stress due to the release of stress hormones, such as adrenaline and glucagon, which is followed by activation of membrane-bound adenylyl cyclase and elevation of cellular cAMP. Because the majority of physiological stresses are associated with elevated energy consumption, it is not surprising that activation of cAMP signaling may promote AMPK activity. Aside from the physiological role of the cAMP/AMPK axis, numerous reports have suggested its role in several pathologies, including inflammation, ischemia, diabetes, obesity, and aging. Furthermore, novel reports have provided more mechanistic insight into the regulation of the cAMP/AMPK axis. In particular, the role of distinct cAMP microdomains generated by soluble adenylyl cyclase in regulating basal and induced AMPK activity has recently been demonstrated. In the present review, we discuss current advances in the understanding of the regulation of the cAMP/AMPK axis and its role in cellular homeostasis and explore some translational aspects.
Highlights
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TmACs are sensitive to G proteins and their activity is regulated by hormones and neurotransmitters. soluble adenylyl cyclase (sAC) is insensitive to G proteins but can be activated by bicarbonate (HCO3−), making sAC a unique bicarbonate sensor with enzymatic activity [1]
In rat cardiac and endothelial cells, we found that sAC knockdown reduced AMPK phosphorylation and activity under basal conditions, which was accompanied by the impairment of mitophagy, mitochondrial depolarization, and mitochondrial reactive oxygen species formation
Summary
Cyclic adenosine 3 ,5 -monophosphate (cAMP) is a ubiquitous and essential intracellular second messenger molecule involved in a wide range of physiological and pathological processes. cAMP signaling pathways consist of (i) cAMP synthesizing cyclases, (ii) cAMP degrading phosphodiesterases (PDEs), and (iii) cAMP effectors. The specificity and selectivity of cAMP signaling is maintained by the formation of multiple intracellular cAMP functional compartments within the cell and organelles This compartmentalization is achieved, first, by distinct spatial distribution of the two main cAMP-generating enzymes, i.e., tmAC and sAC. The compartmentalization of cAMP signaling within the cell is further supported by the activity of PDEs that restrict cAMP diffusion from its origin [10,11] Scaffolding proteins, such as A-kinase anchoring proteins (AKAPs) play a key role in coupling cAMP synthesis to functional effectors, such as PKA and EPAC. AKAPs bind other kinases, cyclases, PDEs, G-protein-coupled receptors, and phosphatases (for review, see [4]) Due to their localization at specific subcellular sites, AKAPs play a critical role in maintaining the subcellular compartmentalization of cAMP signaling
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