scholarly journals Regulation of Mitochondrial Homeostasis by sAC-Derived cAMP Pool: Basic and Translational Aspects

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 473
Author(s):  
Muhammad Aslam ◽  
Yury Ladilov
Keyword(s):  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Basic Mechanism ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Matrix ◽  
Synthesis System ◽  
Cellular Energy ◽  
Cellular Processes ◽  
Mitochondrial Homeostasis

In contrast to the traditional view of mitochondria being solely a source of cellular energy, e.g., the “powerhouse” of the cell, mitochondria are now known to be key regulators of numerous cellular processes. Accordingly, disturbance of mitochondrial homeostasis is a basic mechanism in several pathologies. Emerging data demonstrate that 3′–5′-cyclic adenosine monophosphate (cAMP) signalling plays a key role in mitochondrial biology and homeostasis. Mitochondria are equipped with an endogenous cAMP synthesis system involving soluble adenylyl cyclase (sAC), which localizes in the mitochondrial matrix and regulates mitochondrial function. Furthermore, sAC localized at the outer mitochondrial membrane contributes significantly to mitochondrial biology. Disturbance of the sAC-dependent cAMP pools within mitochondria leads to mitochondrial dysfunction and pathology. In this review, we discuss the available data concerning the role of sAC in regulating mitochondrial biology in relation to diseases.

Mechanisms of ATP to cAMP Conversion Catalyzed by the Mammalian Adenylyl Cyclase: A Role of Magnesium Coordination Shells and Proton Wires

2019 ◽  
Author(s):  
Bella Grigorenko ◽  
Igor Polyakov ◽  
Alexander Nemukhin
Keyword(s):  
Adenylyl Cyclase ◽  
Bond Cleavage ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Md Simulations ◽  
Coordination Shell ◽  
Energy Profile ◽  
One Step ◽  
Type V

<p>We report a mechanism of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) conversion by the mammalian type V adenylyl cyclase revealed in molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) simulations. We characterize a set of computationally derived enzyme-substrate (ES) structures showing an important role of coordination shells of magnesium ions in the solvent accessible active site. Several stable six-fold coordination shells of Mg<sub>A</sub><sup>2+ </sup>are observed in MD simulations of ES complexes. In the lowest energy ES conformation, the coordination shell of Mg<sub>A</sub><sup>2+ </sup>does not include the O<sub>δ1</sub> atom of the conserved Asp440 residue. Starting from this conformation, a one-step reaction mechanism is characterized which includes proton transfer from the ribose O<sup>3'</sup>H<sup>3' </sup>group in ATP to Asp440 via a shuttling water molecule and P<sup>A</sup>-O<sup>3A</sup> bond cleavage and O<sup>3'</sup>-P<sup>A</sup> bond formation. The energy profile of this route is consistent with the observed reaction kinetics. In a higher energy ES conformation, Mg<sub>A</sub><sup>2+</sup> is bound to the O<sub>δ1</sub>(Asp440) atom as suggested in the relevant crystal structure of the protein with a substrate analog. The computed energy profile initiated by this ES is characterized by higher energy expenses to complete the reaction. Consistently with experimental data, we show that the Asp440Ala mutant of the enzyme should exhibit a reduced but retained activity. All considered reaction pathways include proton wires from the O<sup>3'</sup>H<sup>3' </sup>group via shuttling water molecules. </p>

scholarly journals Role of Long Non-Coding RNAs and the Molecular Mechanisms Involved in Insulin Resistance

2021 ◽  
Vol 22 (14) ◽  
pp. 7256
Author(s):  
Vianet Argelia Tello-Flores ◽  
Fredy Omar Beltrán-Anaya ◽  
Marco Antonio Ramírez-Vargas ◽  
Brenda Ely Esteban-Casales ◽  
Napoleón Navarro-Tito ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Biological Species ◽  
Necrosis Factor Alpha ◽  
Polypyrimidine Tract Binding Protein ◽  
Non Coding Rnas

Long non-coding RNAs (lncRNAs) are single-stranded RNA biomolecules with a length of >200 nt, and they are currently considered to be master regulators of many pathological processes. Recent publications have shown that lncRNAs play important roles in the pathogenesis and progression of insulin resistance (IR) and glucose homeostasis by regulating inflammatory and lipogenic processes. lncRNAs regulate gene expression by binding to other non-coding RNAs, mRNAs, proteins, and DNA. In recent years, several mechanisms have been reported to explain the key roles of lncRNAs in the development of IR, including metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), imprinted maternal-ly expressed transcript (H19), maternally expressed gene 3 (MEG3), myocardial infarction-associated transcript (MIAT), and steroid receptor RNA activator (SRA), HOX transcript antisense RNA (HOTAIR), and downregulated Expression-Related Hexose/Glucose Transport Enhancer (DREH). LncRNAs participate in the regulation of lipid and carbohydrate metabolism, the inflammatory process, and oxidative stress through different pathways, such as cyclic adenosine monophosphate/protein kinase A (cAMP/PKA), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), polypyrimidine tract-binding protein 1/element-binding transcription factor 1c (PTBP1/SREBP-1c), AKT/nitric oxide synthase (eNOS), AKT/forkhead box O1 (FoxO1), and tumor necrosis factor-alpha (TNF-α)/c-Jun-N-terminal kinases (JNK). On the other hand, the mechanisms linked to the molecular, cellular, and biochemical actions of lncRNAs vary according to the tissue, biological species, and the severity of IR. Therefore, it is essential to elucidate the role of lncRNAs in the insulin signaling pathway and glucose and lipid metabolism. This review analyzes the function and molecular mechanisms of lncRNAs involved in the development of IR.

scholarly journals The protective effect of the PDE-4 inhibitor rolipram on intracerebral haemorrhage is associated with the cAMP/AMPK/SIRT1 pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiao-Liu Dong ◽  
Yan-Hui Wang ◽  
Jing Xu ◽  
Nan Zhang
Keyword(s):  
Mouse Model ◽  
Protective Effect ◽  
Intracerebral Haemorrhage ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Pathological Process ◽  
Silent Information Regulator 1 ◽  
Sirt1 Inhibitor ◽  
Amp Activated Protein Kinase

AbstractRolipram specifically inhibits phosphodiesterase (PDE) 4, thereby preventing inactivation of the intracellular second messenger cyclic adenosine monophosphate (cAMP). Rolipram has been shown to play a neuroprotective role in some central nervous system (CNS) diseases. However, the role of PDE4 and the potential protective effect of rolipram on the pathophysiological process of intracerebral haemorrhage (ICH) are still not entirely clear. In this study, a mouse model of ICH was established by the collagenase method. Rolipram reduced brain oedema, blood–brain barrier (BBB) leakage, neuronal apoptosis and inflammatory cytokine release and improved neurological function in our mouse model of ICH. Moreover, rolipram increased the levels of cAMP and silent information regulator 1 (SIRT1) and upregulated the phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, these effects of rolipram could be reversed by the SIRT1 inhibitor sirtinol. In conclusion, rolipram can play a neuroprotective role in the pathological process of ICH by activating the cAMP/AMPK/SIRT1 pathway.

scholarly journals Cytochemical methods for the localization of adenylate cyclase. A review and evaluation of the efficacy of the procedures.

1983 ◽  
Vol 31 (1) ◽  
pp. 85-93 ◽  
Author(s):  
L S Cutler
Keyword(s):  
Adenylate Cyclase ◽  
Cyclic Nucleotides ◽  
Cell Biology ◽  
Enzyme System ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cellular Functions ◽  
Cytochemical Localization ◽  
Biochemical Evaluation

The cytochemical procedures for localizing adenylate cyclase have been a source of controversy since their introduction. The importance of cyclic adenosine monophosphate (AMP), the product of adenylate cyclase's action on adenosine triphosphate (ATP), in cell biology is clear. Thus, the ability to localize this enzyme system reliably is an important tool in the study of various cellular functions. This report reviews the literature and presents a biochemical evaluation of the methods for localizing adenylate cyclase. The review and data presented serve to clarify many of the controversies surrounding this important cytochemical procedure. It is evident that although there are problems associated with localizing the enzyme, several valid procedures are currently available for the cytochemical localization of adenylate cyclase. In using these procedures, the effects of fixation and the capture agent on adenylate cyclase activity in the particular tissue being studied should be considered. Only repurified adenylyl imidodiphosphate [App(NH)p] should be used in the incubation medium. If care is taken, the use of these techniques can be of great value in the continued study of the role of cyclic nucleotides in cell biology.

scholarly journals Integration of Rap1 and Calcium Signaling

2020 ◽  
Vol 21 (5) ◽  
pp. 1616 ◽  
Author(s):  
Ramoji Kosuru ◽  
Magdalena Chrzanowska
Keyword(s):  
Intracellular Signaling ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Cardiac Excitation

Ca2+ is a universal intracellular signal. The modulation of cytoplasmic Ca2+ concentration regulates a plethora of cellular processes, such as: synaptic plasticity, neuronal survival, chemotaxis of immune cells, platelet aggregation, vasodilation, and cardiac excitation–contraction coupling. Rap1 GTPases are ubiquitously expressed binary switches that alternate between active and inactive states and are regulated by diverse families of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Active Rap1 couples extracellular stimulation with intracellular signaling through secondary messengers—cyclic adenosine monophosphate (cAMP), Ca2+, and diacylglycerol (DAG). Much evidence indicates that Rap1 signaling intersects with Ca2+ signaling pathways to control the important cellular functions of platelet activation or neuronal plasticity. Rap1 acts as an effector of Ca2+ signaling when activated by mechanisms involving Ca2+ and DAG-activated (CalDAG-) GEFs. Conversely, activated by other GEFs, such as cAMP-dependent GEF Epac, Rap1 controls cytoplasmic Ca2+ levels. It does so by regulating the activity of Ca2+ signaling proteins such as sarcoendoplasmic reticulum Ca2+-ATPase (SERCA). In this review, we focus on the physiological significance of the links between Rap1 and Ca2+ signaling and emphasize the molecular interactions that may offer new targets for the therapy of Alzheimer’s disease, hypertension, and atherosclerosis, among other diseases.

scholarly journals Rottlerin Reduces cAMP/CREB-Mediated Melanogenesis via Regulation of Autophagy

2019 ◽  
Vol 20 (9) ◽  
pp. 2081 ◽  
Author(s):  
Nurinanda Prisky Qomaladewi ◽  
Mi-Yeon Kim ◽  
Jae Youl Cho
Keyword(s):  
Signaling Pathway ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Sequential Process ◽  
Camp Response Element ◽  
Melanin Production ◽  
Melanocyte Stimulating Hormone ◽  
Cellular Autophagy

Melanogenesis is the sequential process of melanin production by melanocytes in order to protect the skin from harmful stimuli. Melanogenesis is disrupted by radiation exposure, which results in the differentiation of melanocytes into melanoma. Recently, some methods have been developed to maintain the instability of melanogenesis in melanoma by activating cellular autophagy. However, there is still a lack of knowledge about how autophagy is involved in the regulation of melanogenesis in melanoma cells. Here, we used rottlerin as an autophagy inducer to investigate the role of the cyclic adenosine monophosphate (cAMP)/cAMP response element binding (CREB) signaling pathway in melanogenesis. We found that rottlerin can inhibit melanin production by targeting cAMP, which is initially activated by alpha-melanocyte stimulating hormone (α-MSH). Our findings suggest that rottlerin has a pivotal role as an autophagy inducer in the regulation of melanogenesis by targeting the cAMP/CREB signaling pathway.

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