![]() ![]() doi: 10.1038/s41467-2.System of signaling molecules within a cell Internalized TSH receptors en route to the TGN induce local Gs-protein signaling and gene transcription. Godbole A., Lyga S., Lohse M.J., Calebiro D. ![]() Subcellular Organization of the cAMP Signaling Pathway. Cardiac cAMP: Production, hydrolysis, modulation and detection. Compartmentalization of bicarbonate-sensitive adenylyl cyclase in distinct signaling microdomains. Zippin J.H., Chen Y., Nahirney P., Kamenetsky M., Wuttke M.S., Fischman D.A., Levin L.R., Buck J. ![]() ![]() Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor. AMP: adenosine monophosphate ATP: adenosine 5’-triphosphate cAMP: cyclic AMP CaMKKβ: Ca 2+/calmodulin regulated kinase kinase beta EPAC: exchange protein directly activated by cAMP LKB1: liver kinase b1 PDEs: phosphodiesterases PKA: protein kinase A PPs: protein phosphatases.Ĭhen Y., Cann M.J., Litvin T.N., Iourgenko V., Sinclair M.L., Levin L.R., Buck J. Furthermore, cAMP elevation may lead to the simultaneous elevation of AMP, a degradation product of cAMP resulting from PDE activity, which, via an increasing AMP/ATP ratio, may promote AMPK activity. On the other hand, both PKA and Akt can also directly phosphorylate AMPK at inhibitory Ser485, thus negatively regulating its activity. cAMP, either via EPAC-dependent activation of CaMKK2 or PKA-dependent activation of LKB1, may promote AMPK activity. At a high AMP/ATP ratio, ATP bound to the γ-subunit is exchanged for AMP, causing an allosteric modification of AMPK that leads to reduced access of Thr172 to phosphatases, but easy access to LKB1 and CaMKKβ, resulting in enhanced AMPK phosphorylation and activation. AMPK consists of three subunits: one catalytic subunit alpha and two regulatory subunits, beta and gamma. Schematic presentation of the cAMP-dependent regulation of AMPK activity. 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.ĪMPK EPAC PKA adenylyl cyclase autophagy cAMP mitophagy. In particular, the role of distinct cAMP microdomains generated by soluble adenylyl cyclase in regulating basal and induced AMPK activity has recently been demonstrated. Furthermore, novel reports have provided more mechanistic insight into the regulation of the cAMP/AMPK axis. 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. 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. 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. Mounting evidence suggests the presence of a link between cyclic AMP (cAMP) and AMPK signaling. Thus, understanding the pathways regulating AMPK activity is crucial for developing strategies to treat metabolic disorders. At the cellular level, AMPK supports numerous processes required for energy and redox homeostasis, including mitochondrial biogenesis, autophagy, and glucose and lipid metabolism. 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. ![]()
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