Cyclic Amp
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2021 ◽  
Vol 12 (9) ◽  
Marion Laudette ◽  
Yannis Sainte-Marie ◽  
Grégoire Cousin ◽  
Dorian Bergonnier ◽  
Ismahane Belhabib ◽  

AbstractCyclic adenosine monophosphate (cAMP) is a master regulator of mitochondrial metabolism but its precise mechanism of action yet remains unclear. Here, we found that a dietary saturated fatty acid (FA), palmitate increased intracellular cAMP synthesis through the palmitoylation of soluble adenylyl cyclase in cardiomyocytes. cAMP further induced exchange protein directly activated by cyclic AMP 1 (Epac1) activation, which was upregulated in the myocardium of obese patients. Epac1 enhanced the activity of a key enzyme regulating mitochondrial FA uptake, carnitine palmitoyltransferase 1. Consistently, pharmacological or genetic Epac1 inhibition prevented lipid overload, increased FA oxidation (FAO), and protected against mitochondrial dysfunction in cardiomyocytes. In addition, analysis of Epac1 phosphoproteome led us to identify two key mitochondrial enzymes of the the β-oxidation cycle as targets of Epac1, the long-chain FA acyl-CoA dehydrogenase (ACADL) and the 3-ketoacyl-CoA thiolase (3-KAT). Epac1 formed molecular complexes with the Ca2+/calmodulin-dependent protein kinase II (CaMKII), which phosphorylated ACADL and 3-KAT at specific amino acid residues to decrease lipid oxidation. The Epac1-CaMKII axis also interacted with the α subunit of ATP synthase, thereby further impairing mitochondrial energetics. Altogether, these findings indicate that Epac1 disrupts the balance between mitochondrial FA uptake and oxidation leading to lipid accumulation and mitochondrial dysfunction, and ultimately cardiomyocyte death.

2021 ◽  
Vol 14 (3) ◽  
pp. 214-221
Rafina Syfridiana ◽  
Fauna Herawati

Asthma is a heterogeneous disease characterized by chronic inflammation of the airways induced reversible obstruction resulting in mortality and morbidity. Roflumilast is a second-generation selective inhibitor of phosphodiesterase-4  targeting PDE type 4 isoenzymes, disturbing the breakdown of cyclic AMP (cAMP) and reducing inflammation. However, it has not been recommended for asthma patients because of insufficient evidence from trial results. The search was carried out using the PUBMED online database from 2011 to May 2021. The keywords used in this study were "Asthma" and "Roflumilast" using the Boolean Operator "AND." All articles were published until May 7, 2021. The design of the articles involved in this study was randomized. Selection of research articles was obtained to avoid duplication of articles through title and abstract screening. Next, eligible articles were extracted by reviewing the full text according to the inclusion criteria. Finally, Five articles were used in this paper. Roflumilast can be given per-oral as a single dose or combine with ICS or montelukast. Roflumilast can increase FEV1 and reduce eosinophils, a pathological cause of asthma that induces inflammation in the airways. The side effects of roflumilast are well tolerated in asthma patients, the most common of which include headache, diarrhea, nausea, weight loss, and insomnia

Kevin R. Coffey ◽  
Atom J. Lesiak ◽  
Russell G. Marx ◽  
Emily K. Vo ◽  
Gwenn A. Garden ◽  

Function ◽  
2021 ◽  
Pulak Kar ◽  
Pradeep Barak ◽  
Anna Zerio ◽  
Yu-Ping Lin ◽  
Amy J Parekh ◽  

Abstract To avoid conflicting and deleterious outcomes, eukaryotic cells often confine signalling molecules to spatially restricted sub-compartments. The smallest signalling unit is the Ca2+ nanodomain, forming near open Ca2+ channels. Ca2+ nanodomains near store-operated Orai1 channels stimulate calcineurin, which activates the transcription factor NFAT1, and both enzyme and target are initially attached to the plasma membrane through the scaffolding protein AKAP79. Here we show that a cAMP signalling nexus also forms adjacent to Orai1. Protein kinase A and phosphodiesterase 4, an enzyme that rapidly breaks down cAMP, both associate with AKAP79 and realign close to Orai1 after stimulation. PCR and mass spectrometry failed to show expression of Ca2+-activated adenylyl cyclase 8 in HEK293 cells, whereas the enzyme was observed in neuronal cell lines. FRET and biochemical measurements of bulk cAMP and protein kinase A activity consistently failed to show an increase in adenylyl cyclase activity following even a large rise in cytosolic Ca2+. Furthermore, expression of AKAP79-CUTie, a cAMP FRET sensor tethered to AKAP79, did not report a rise in cAMP after stimulation, despite AKAP79 association with Orai1. Hence HEK293 cells do not express functionally active Ca2+-activated adenylyl cyclases including adenylyl cyclase 8. Our results show that two ancient second messengers are independently generated in nanodomains close to Orai1 Ca2+ channels.

Ian Rochford ◽  
Jagdish Chandra Joshi ◽  
Rayees Sheikh ◽  
Mumtaz Anwar ◽  
Md Zahid Akhter ◽  

Increased lung vascular permeability and neutrophilic inflammation are hallmarks of acute lung injury. Alveolar macrophages (AMϕ), the predominant sentinel cell type in the airspace, die in massive numbers while fending off pathogens. Recent studies indicate that the AMϕ pool is replenished by airspace-recruited monocytes, but the mechanisms instructing the conversion of recruited monocytes into reparative AMϕ remain elusive. Cyclic AMP (cAMP) is a vascular barrier protective and immunosuppressive second messenger in the lung. Here, we subjected mice expressing GFP under the control of the Lysozyme-M promoter (LysM-GFP mice) to the LPS model of rapidly resolving lung injury to address the impact of mechanisms determining cAMP levels in AMϕ and regulation of mobilization of the reparative AMϕ-pool. RNA-seq analysis of flow-sorted Mϕ identified phosphodiesterase 4b (PDE4b) as the top LPS-responsive cAMP-regulating gene. We observed that PDE4b expression markedly increased at the time of peak injury (4 h) and then decreased to below the basal level during the resolution phase (24 h). Activation of transcription factor NFATc2 was required for transcription of PDE4b in Mϕ. Inhibition of PDE4 activity at the time of peak injury, using i.t. rolipram, increased cAMP levels, augmented the reparative AMϕ pool, and resolved lung injury. This response was not seen following conditional depletion of monocytes, thus establishing airspace-recruited PDE4b-sensitive monocytes as the source of reparative AMϕ. Interestingly, adoptive transfer of rolipram-educated AMϕ into injured mice resolved lung edema. We propose suppression of PDE4b as an effective approach to promote reparative AMϕ generation from monocytes for lung repair.

2021 ◽  
Vol 22 (15) ◽  
pp. 7871
Taner Duysak ◽  
Thanh Tuyen Tran ◽  
Aqeel Rana Afzal ◽  
Che-Hun Jung

The cyclic AMP receptor protein (CRP) is one of the best-known transcription factors, regulating about 400 genes. The histone-like nucleoid structuring protein (H-NS) is one of the nucleoid-forming proteins and is responsible for DNA packaging and gene repression in prokaryotes. In this study, the binding of ppGpp to CRP and H-NS was determined by fluorescence spectroscopy. CRP from Escherichia coli exhibited intrinsic fluorescence at 341 nm when excited at 280 nm. The fluorescence intensity decreased in the presence of ppGpp. The dissociation constant of 35 ± 3 µM suggests that ppGpp binds to CRP with a similar affinity to cAMP. H-NS also shows intrinsic fluorescence at 329 nm. The fluorescence intensity was decreased by various ligands and the calculated dissociation constant for ppGpp was 80 ± 11 µM, which suggests that the binding site was occupied fully by ppGpp under starvation conditions. This study suggests the modulatory effects of ppGpp in gene expression regulated by CRP and H-NS. The method described here may be applicable to many other proteins.

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