scholarly journals Inhibition of cloned adenylyl cyclases by mutant-activated Gi-alpha and specific suppression of type 2 adenylyl cyclase inhibition by phorbol ester treatment

1993 ◽  
Vol 268 (17) ◽  
pp. 12253-12256 ◽  
Author(s):  
J. Chen ◽  
R. Iyengar
Keyword(s):  
Adenylyl Cyclase ◽  
Phorbol Ester ◽  
Adenylyl Cyclases ◽  
Specific Suppression

scholarly journals Functional Characterization of the Adenylyl Cyclase Genesgs-1by Analysis of a Mutational Spectrum inCaenorhabditis elegans

Genetics ◽  
2002 ◽  
Vol 161 (1) ◽  
pp. 133-142 ◽  
Author(s):  
Celine Moorman ◽  
Ronald H A Plasterk
Keyword(s):  
Life Span ◽  
Adenylyl Cyclase ◽  
Neuronal Degeneration ◽  
Functional Characterization ◽  
Adenylyl Cyclases ◽  
Loss Of Function ◽  
C Elegans ◽  
Larval Stages ◽  
Pharyngeal Pumping

AbstractThe sgs-1 (suppressor of activated Gαs) gene encodes one of the four adenylyl cyclases in the nematode C. elegans and is most similar to mammalian adenylyl cyclase type IX. We isolated a complete loss-of-function mutation in sgs-1 and found it to result in animals with retarded development that arrest in variable larval stages. sgs-1 mutant animals exhibit lethargic movement and pharyngeal pumping and (while not reaching adulthood) have a mean life span that is >50% extended compared to wild type. An extensive set of reduction-of-function mutations in sgs-1 was isolated in a screen for suppressors of a neuronal degeneration phenotype induced by the expression of a constitutively active version of the heterotrimeric Gαs subunit of C. elegans. Although most of these mutations change conserved residues within the catalytic domains of sgs-1, mutations in the less-conserved transmembrane domains are also found. The sgs-1 reduction-of-function mutants are viable and have reduced locomotion rates, but do not show defects in pharyngeal pumping or life span.

scholarly journals Signaling through Adenylyl Cyclase Is Essential for Hyphal Growth and Virulence in the Pathogenic FungusCandida albicans

2001 ◽  
Vol 12 (11) ◽  
pp. 3631-3643 ◽  
Author(s):  
Cintia R. C. Rocha ◽  
Klaus Schröppel ◽  
Doreen Harcus ◽  
Anne Marcil ◽  
Daniel Dignard ◽  
...  
Keyword(s):  
Mouse Model ◽  
Adenylyl Cyclase ◽  
Sequence Similarity ◽  
Hyphal Growth ◽  
Antifungal Drugs ◽  
Growth Defect ◽  
Adenylyl Cyclases ◽  
Gene Encoding ◽  
Mutant Cells

The human fungal pathogen Candida albicans switches from a budding yeast form to a polarized hyphal form in response to various external signals. This morphogenetic switching has been implicated in the development of pathogenicity. We have cloned theCaCDC35 gene encoding C. albicansadenylyl cyclase by functional complementation of the conditional growth defect of Saccharomyces cerevisiae cells with mutations in Ras1p and Ras2p. It has previously been shown that these Ras homologues regulate adenylyl cyclase in yeast. The C. albicans adenylyl cyclase is highly homologous to other fungal adenylyl cyclases but has less sequence similarity with the mammalian enzymes. C. albicans cells deleted for both alleles ofCaCDC35 had no detectable cAMP levels, suggesting that this gene encodes the only adenylyl cyclase in C. albicans. The homozygous mutant cells were viable but grew more slowly than wild-type cells and were unable to switch from the yeast to the hyphal form under all environmental conditions that we analyzed in vitro. Moreover, this morphogenetic switch was completely blocked in mutant cells undergoing phagocytosis by macrophages. However, morphogenetic switching was restored by exogenous cAMP. On the basis of epistasis experiments, we propose that CaCdc35p acts downstream of the Ras homologue CaRas1p. These epistasis experiments also suggest that the putative transcription factor Efg1p and components of the hyphal-inducing MAP kinase pathway depend on the function of CaCdc35p in their ability to induce morphogenetic switching. Homozygouscacdc35Δ cells were unable to establish vaginal infection in a mucosal membrane mouse model and were avirulent in a mouse model for systemic infections. These findings suggest that fungal adenylyl cyclases and other regulators of the cAMP signaling pathway may be useful targets for antifungal drugs.

scholarly journals Non-canonical regulation of glycogenolysis and the Warburg phenotype by soluble adenylyl cyclase

2020 ◽  
Author(s):  
Jung-Chin Chang ◽  
Simei Go ◽  
Eduardo H. Gilglioni ◽  
Hang Lam Li ◽  
Hsu-Li Huang ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Adenylyl Cyclase ◽  
Energy Homeostasis ◽  
Aerobic Glycolysis ◽  
Glycogen Metabolism ◽  
Adenylyl Cyclases ◽  
Soluble Adenylyl Cyclase ◽  
Atp Level ◽  
Downstream Effectors ◽  
Different Types

AbstractCyclic AMP is produced in cells by two very different types of adenylyl cyclases: the canonical transmembrane adenylyl cyclases (tmACs, ADCY1∼9) and the evolutionarily more conserved soluble adenylyl cyclase (sAC, ADCY10). While the role and regulation of tmACs is well documented, much less is known of sAC in cellular metabolism. We demonstrate here that sAC is an acute regulator of glycolysis, oxidative phosphorylation and glycogen metabolism, tuning their relative bioenergetic contributions. Suppression of sAC activity leads to aerobic glycolysis, enhanced glycogenolysis, decreased oxidative phosphorylation, and an elevated cytosolic NADH/NAD+ ratio, resembling the Warburg phenotype. Importantly, we found that glycogen metabolism is regulated in opposite directions by cAMP depending on its location of synthesis and downstream effectors. While the canonical tmAC-cAMP-PKA axis promotes glycogenolysis, we identify a novel sAC-cAMP-Epac1 axis that suppresses glycogenolysis. These data suggest that sAC is an autonomous bioenergetic sensor that suppresses aerobic glycolysis and glycogenolysis when ATP levels suffice. When the ATP level falls, diminished sAC activity induces glycogenolysis and aerobic glycolysis to maintain energy homeostasis.

scholarly journals Soluble adenylyl cyclase-dependent microtubule disassembly reveals a novel mechanism of endothelial cell retraction

2009 ◽  
Vol 297 (1) ◽  
pp. L73-L83 ◽  
Author(s):  
Nutan Prasain ◽  
Mikhail Alexeyev ◽  
Ron Balczon ◽  
Troy Stevens
Keyword(s):  
Endothelial Cell ◽  
Adenylyl Cyclase ◽  
Fluorescent Protein ◽  
Fiber Formation ◽  
Stress Fibers ◽  
Actin Stress Fiber ◽  
Adenylyl Cyclases ◽  
Gap Formation ◽  
Soluble Adenylyl Cyclase ◽  
Cell Retraction

Soluble adenylyl cyclase toxins, such as Pseudomonas aeruginosa exoY, generate a cAMP pool that retracts cell borders. However, the cytoskeletal basis by which this cAMP signal retracts cell borders is not known. We sought to determine whether activation of chimeric, soluble adenylyl cyclase I/II (sACI/II) reorganizes either microtubules or peripheral actin. Endothelial cells were stably transfected with either green fluorescent protein-labeled α-tubulin or β-actin, and then infected with adenovirus to express sACI/II. Forskolin, which stimulates both the endogenously expressed transmembrane adenylyl cyclases and sACI/II, induced cell retraction accompanied by the reorganization of peripheral microtubules. However, cortical filamentous-actin (f-actin) did not reorganize into stress fibers, and myosin light-chain-20 phosphorylation was decreased. Isoproterenol, which activates endogenous adenylyl cyclases but does not activate sACI/II, did not induce endothelial cell gaps and did not influence microtubule or f-actin architecture. Thus, sACI/II generates a cAMP signal that reorganizes microtubules and induces cell retraction, without inducing f-actin stress fibers. These findings illustrate that endothelial cell gap formation can proceed without f-actin stress fiber formation, and provide mechanistic insight how bacterial adenylyl cyclase toxins reorganize the cytoskeleton to induce cell rounding.

scholarly journals Capacitative Ca2+ entry regulates Ca2+-sensitive adenylyl cyclases

1994 ◽  
Vol 297 (3) ◽  
pp. 437-440 ◽  
Author(s):  
D M Cooper ◽  
M Yoshimura ◽  
Y Zhang ◽  
M Chiono ◽  
R Mahey
Keyword(s):  
Adenylyl Cyclase ◽  
In Vitro Assays ◽  
Adenylyl Cyclases ◽  
Intact Cells ◽  
Specific Effects ◽  
Kinase C ◽  
293 Cells ◽  
Gamma Subunits ◽  
Regulatory Significance

A number of the currently described adenylyl cyclase species can be regulated by Ca2+ in the submicromolar concentration range in in vitro assays. The regulatory significance of these observations hinges on whether a physiological elevation in intracellular Ca2+ can regulate these cyclase activities in intact cells. However, achieving a physiological elevation in cytosolic Ca2+ is complicated by the fact that hormonal increases in cytosolic Ca2+ can be accompanied by additional effects, such as liberation of beta gamma-subunits of G-proteins and activation of protein kinase C, which can have disparate type-specific effects on cyclase activities. Therefore we have devised a strategy based on capacitative Ca2+ entry to show that, when types I and VI adenylyl cyclase are expressed in human embryonic kidney 293 cells, they are stimulated and inhibited respectively by Ca2+ entry. Blockade of Ca2+ entry by La3+ ions blocks the effects of Ca2+ entry on cyclic AMP synthesis. These studies establish that adenylyl cyclases deemed to be sensitive to Ca2+ in in vitro assays can be regulated by physiological Ca2+ entry, and therefore, such cyclases are poised to respond to changes in intracellular Ca2+ in tissues in which they are expressed.

scholarly journals Adenylyl cyclases (ACs) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Carmen W. Dessauer ◽  
Rennolds Ostrom ◽  
Roland Seifert ◽  
Val J. Watts
Keyword(s):  
Cyclic Amp ◽  
Adenylyl Cyclase ◽  
G Protein ◽  
Adenylyl Cyclases ◽  
Adenylyl Cyclase Activity ◽  
Α Subunit ◽  
Soluble Adenylyl Cyclase ◽  
Catalytic Domains ◽  
Stimulatory G Protein ◽  
Membrane Spanning

Adenylyl cyclase, E.C. 4.6.1.1, converts ATP to cyclic AMP and pyrophosphate. Mammalian membrane-delimited adenylyl cyclases (nomenclature as approved by the NC-IUPHAR Subcommittee on Adenylyl cyclases [9]) are typically made up of two clusters of six TM domains separating two intracellular, overlapping catalytic domains that are the target for the nonselective activators Gαs (the stimulatory G protein α subunit) and forskolin (except AC9, [21]). adenosine and its derivatives (e.g. 2',5'-dideoxyadenosine), acting through the P-site,are inhibitors of adenylyl cyclase activity [27]. Four families of membranous adenylyl cyclase are distinguishable: calmodulin-stimulated (AC1, AC3 and AC8), Ca2+- and Gβγ-inhibitable (AC5, AC6 and AC9), Gβγ-stimulated and Ca2+-insensitive (AC2, AC4 and AC7), and forskolin-insensitive (AC9) forms. A soluble adenylyl cyclase (AC10) lacks membrane spanning regions and is insensitive to G proteins.It functions as a cytoplasmic bicarbonate (pH-insensitive) sensor [5].

Adenylyl cyclase P-site ligands accelerate differentiation in Ob1771 preadipocytes

1999 ◽  
Vol 276 (2) ◽  
pp. C487-C496 ◽  
Author(s):  
Azeddine Ibrahimi ◽  
Nada Abumrad ◽  
Hengameh Maghareie ◽  
Michael Golia ◽  
Ilana Shoshani ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Morphological Changes ◽  
Intracellular Camp ◽  
Specific Marker ◽  
Marker Enzyme ◽  
Adenylyl Cyclases ◽  
Consequent Reduction ◽  
Elevated Expression ◽  
Glycerol 3 Phosphate Dehydrogenase ◽  
Camp Levels

Differentiation of Ob1771 preadipocytes to adipocytes was characterized by morphological changes and elevated expression of the specific marker enzyme, glycerol-3-phosphate dehydrogenase. A differentiation response substantially more complete and rapid than that obtained with insulin and 3,5,3′-triiodothyronine was observed with established inhibitors of adenylyl cyclases: 2′,5′-dideoxyadenosine (2′,5′-dd-Ado), 9-(cyclopentyl)adenine (9-CP-Ade), and 9-(arabinofuranosyl)adenine (9-Ara-Ade), coincident with decreased cellular cAMP levels. These ligands inhibit adenylyl cyclases noncompetitively, via a domain referred to as the P-site because of its requirement for an intact purine moiety. Differentiation was not induced by inosine, a nucleoside known not to act at the P-site, or by N 6-(2-phenylisopropyl)adenosine or 1,3-diethyl-8-phenylxanthine, agonist and antagonist, respectively, for adenosine A1 receptors. Also ineffective were IBMX or forskolin, agents that can raise intracellular cAMP levels. Potency of the differentiation response followed the order 2′,5′-dd-Ado (1–20 μM) > 9-CP-Ade (10–100 μM) = 9-Ara-Ade (10–100 μM) >> inosine, consistent with their potencies to inhibit adenylyl cyclases. The data suggest that inhibition of adenylyl cyclase via the P-site and the consequent reduction in cell cAMP levels facilitate the induction of differentiation in Ob1771 cells. The findings raise the question whether the known endogenous P-site ligands participate in the differentiation response induced by hormones.

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