On the Modes of Regulation of Intracellular Cyclic AMP: Desensitization of Adenylyl Cyclases to Hormonal Stimulation and Compartmentalization of Cyclic AMP

1976 ◽  
pp. 43-66
Author(s):  
L. Birnbaumer ◽  
J. Bockaert ◽  
M. Hunzicker-Dunn ◽  
V. Pliška ◽  
A. Glattfelder
Keyword(s):  
Cyclic Amp ◽  
Adenylyl Cyclases ◽  
Hormonal Stimulation

Elucidating cyclic AMP signaling in subcellular domains with optogenetic tools and fluorescent biosensors

2019 ◽  
Vol 47 (6) ◽  
pp. 1733-1747 ◽  
Author(s):  
Christina Klausen ◽  
Fabian Kaiser ◽  
Birthe Stüven ◽  
Jan N. Hansen ◽  
Dagmar Wachten
Keyword(s):  
Cyclic Amp ◽  
Adenosine Monophosphate ◽  
Adenylyl Cyclases ◽  
Temporal Precision ◽  
Fluorescent Biosensors ◽  
Subcellular Domains ◽  
Spatio Temporal ◽  
Hydrolysis Of ◽  
Shed Light ◽  
Cyclic Amp Signaling

The second messenger 3′,5′-cyclic nucleoside adenosine monophosphate (cAMP) plays a key role in signal transduction across prokaryotes and eukaryotes. Cyclic AMP signaling is compartmentalized into microdomains to fulfil specific functions. To define the function of cAMP within these microdomains, signaling needs to be analyzed with spatio-temporal precision. To this end, optogenetic approaches and genetically encoded fluorescent biosensors are particularly well suited. Synthesis and hydrolysis of cAMP can be directly manipulated by photoactivated adenylyl cyclases (PACs) and light-regulated phosphodiesterases (PDEs), respectively. In addition, many biosensors have been designed to spatially and temporarily resolve cAMP dynamics in the cell. This review provides an overview about optogenetic tools and biosensors to shed light on the subcellular organization of cAMP signaling.

scholarly journals Brief Note: Effects of Prostaglandins, Epinephrine and NaF on Human Leukocyte, Platelet and Liver Adenyl Cyclase

Blood ◽  
1970 ◽  
Vol 35 (4) ◽  
pp. 514-516 ◽  
Author(s):  
ROBERT E. SCOTT
Keyword(s):  
Cyclic Amp ◽  
Phagocytic Activity ◽  
Prostaglandin E1 ◽  
Human Leukocyte ◽  
Adenyl Cyclase ◽  
Hormonal Stimulation ◽  
Human Leukocytes ◽  
Prostaglandin F ◽  
Limited Scope

Abstract Despite the limited scope of this study, the data show that homogenates of human leukocytes, platelets and liver are capable of synthesizing cyclic AMP, and that such preparations are responsive to hormonal stimulation. Epinephrine stimulates cyclic AMP production in liver and leukocyte homogenates, and NaF shows a stimulatory effect in each tissue.1,8 The data confirm the previous reports10,11 that prostaglandin E1 stimulates platelet adenyl cyclase, but further shows a lack of stimulation by prostaglandin F/1β. Incubation of leukocytes with the prostaglandins showed a similar effect. It is suggested that further study may establish a relationship between adenyl cyclase stimulation and chemotaxis or phagocytic activity of circulating leukocytes as has been reported in amebae.12 Since systemic enzyme deficiencies such as phosphorylase in Hers’ Disease13 and amylo-1.4→1.6-transglucosidase in Andersens’ Disease14 are evident in leukocytes, it is suggested that further study of circulating leukocytes may also detect an abnormal responsiveness or a deficiency of adenyl cyclase.

scholarly journals Characterization of motifs which are critical for activity of the cyclic AMP-responsive transcription factor CREB.

1991 ◽  
Vol 11 (3) ◽  
pp. 1306-1312 ◽  
Author(s):  
G A Gonzalez ◽  
P Menzel ◽  
J Leonard ◽  
W H Fischer ◽  
M R Montminy
Keyword(s):  
Transcription Factor ◽  
Cyclic Amp ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Transactivation Domain ◽  
Hormonal Stimulation ◽  
Eukaryotic Genes ◽  
Teratocarcinoma Cells ◽  
A Site ◽  
F9 Teratocarcinoma

Cyclic AMP mediates the hormonal stimulation of a number of eukaryotic genes by directing the protein kinase A (PK-A)-dependent phosphorylation of transcription factor CREB. We have previously determined that although phosphorylation at Ser-133 is critical for induction, this site does not appear to participate directly in transactivation. To test the hypothesis that CREB ultimately activates transcription through domains that are distinct from the PK-A site, we constructed a series of CREB mutants and evaluated them by transient assays in F9 teratocarcinoma cells. Remarkably, a glutamine-rich region near the N terminus appeared to be important for PK-A-mediated induction of CREB since removal of this domain caused a marked reduction in CREB activity. A second region consisting of a short acidic motif (DLSSD) C terminal to the PK-A site also appeared to synergize with the phosphorylation motif to permit transcriptional activation. Biochemical experiments with purified recombinant CREB protein further demonstrate that the transactivation domain is more sensitive to trypsin digestion than are the DNA-binding and dimerization domains, suggesting that the activator region may be structured to permit interactions with other proteins in the RNA polymerase II complex.

scholarly journals N 6-(Phenylisopropyl)adenosine prevents glucagon both blocking insulin's activation of the plasma-membrane cyclic AMP phosphodiesterase and uncoupling hormonal stimulation of adenylate cyclase activity in hepatocytes

1984 ◽  
Vol 222 (1) ◽  
pp. 177-182 ◽  
Author(s):  
A V Wallace ◽  
C M Heyworth ◽  
M D Houslay
Keyword(s):  
Plasma Membrane ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Phosphodiesterase Inhibitor ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Maximal Effect ◽  
Hormonal Stimulation ◽  
Cyclic Amp Phosphodiesterase ◽  
Phenylisopropyl Adenosine

Glucagon (10nM) prevented insulin (10nM) from activating the plasma-membrane cyclic AMP phosphodiesterase. This effect of glucagon was abolished by either PIA [N6-(phenylisopropyl)adenosine] (100nM) or adenosine (10 microM). Neither PIA nor adenosine exerted any effect on the plasma-membrane cyclic AMP phosphodiesterase activity either alone or in combination with glucagon. Furthermore, PIA and adenosine did not potentiate the action of insulin in activating this enzyme. 2-Deoxy-adenosine (10 microM) was ineffective in mimicking the action of adenosine. The effect of PIA in preventing the blockade by glucagon of insulin's action was inhibited by low concentrations of theophylline. Half-maximal effects of PIA were elicited at around 6nM-PIA. It is suggested that adenosine is exerting its effects on this system through an R-type receptor. This receptor does not appear to be directly coupled to adenylate cyclase, however, as PIA did not affect either the activity of adenylate cyclase or intracellular cyclic AMP concentrations. Insulin's activation of the plasma-membrane cyclic AMP phosphodiesterase, in the presence of both glucagon and PIA, was augmented by increasing intracellular cyclic AMP concentrations with either dibutyryl cyclic AMP or the cyclic AMP phosphodiesterase inhibitor Ro-20-1724. PIA also inhibited the ability of glucagon to uncouple (desensitize) adenylate cyclase activity in intact hepatocytes. This occurred at a half-maximal concentration of around 3 microM-PIA. However, if insulin (10 nM) was also present in the incubation medium, PIA exerted its action at a much lower concentration, with a half-maximal effect occurring at around 4 nM.

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].

scholarly journals Effects of growth factors on hormonal stimulation of amino acid transport in primary cultures of rat hepatocytes

1983 ◽  
Vol 210 (2) ◽  
pp. 361-366 ◽  
Author(s):  
P Auberger ◽  
M Samson ◽  
A Le Cam
Keyword(s):  
Growth Factors ◽  
Amino Acid ◽  
Growth Factor ◽  
Cyclic Amp ◽  
Primary Cultures ◽  
Rat Hepatocytes ◽  
Acid Transport ◽  
Hormonal Stimulation ◽  
Hormonal Effect ◽  
Stimulation Of

In primary cultures of rat hepatocytes, epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and foetal-calf serum (FCS) prevented the stimulation of amino acid transport by glucagon (cyclic AMP-dependent) and by catecholamines (cyclic AMP-independent), but not by insulin. The insulin effect, as well as the effect of other hormones, were totally inhibited by thrombin through a mechanism independent of its proteolytic activity. The inhibitory effect of growth factors, not found in freshly isolated hepatocytes, was expressed very early in culture (4h). Induction of tyrosine aminotransferase by glucagon or dexamethasone, which, like stimulation of transport, represents a late hormonal effect, was not affected by EGF, PDGF or FCS, but was inhibited by thrombin. In contrast, none of the rapid changes in protein phosphorylation caused by hormones was altered by growth factors. Thus the inhibition by growth factors of hormonal stimulation of transport presumably involves late step(s) in the cascade of events implicated in this hormonal effect.

scholarly journals CREB Binds to Multiple Loci on Human Chromosome 22

2004 ◽  
Vol 24 (9) ◽  
pp. 3804-3814 ◽  
Author(s):  
Ghia Euskirchen ◽  
Thomas E. Royce ◽  
Paul Bertone ◽  
Rebecca Martone ◽  
John L. Rinn ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Human Chromosome ◽  
Binding Sites ◽  
Global Analysis ◽  
Active Regions ◽  
Chromosome 22 ◽  
Neuronal Function ◽  
Hormonal Stimulation ◽  
Multiple Loci ◽  
Element Binding Protein

ABSTRACT The cyclic AMP-responsive element-binding protein (CREB) is an important transcription factor that can be activated by hormonal stimulation and regulates neuronal function and development. An unbiased, global analysis of where CREB binds has not been performed. We have mapped for the first time the binding distribution of CREB along an entire human chromosome. Chromatin immunoprecipitation of CREB-associated DNA and subsequent hybridization of the associated DNA to a genomic DNA microarray containing all of the nonrepetitive DNA of human chromosome 22 revealed 215 binding sites corresponding to 192 different loci and 100 annotated potential gene targets. We found binding near or within many genes involved in signal transduction and neuronal function. We also found that only a small fraction of CREB binding sites lay near well-defined 5′ ends of genes; the majority of sites were found elsewhere, including introns and unannotated regions. Several of the latter lay near novel unannotated transcriptionally active regions. Few CREB targets were found near full-length cyclic AMP response element sites; the majority contained shorter versions or close matches to this sequence. Several of the CREB targets were altered in their expression by treatment with forskolin; interestingly, both induced and repressed genes were found. Our results provide novel molecular insights into how CREB mediates its functions in humans.

scholarly journals The control of glucose 1,6-bisphosphate by developmental state and hormonal stimulation in cultured muscle tissue

1982 ◽  
Vol 204 (3) ◽  
pp. 765-769 ◽  
Author(s):  
M J Wakelam ◽  
D Pette
Keyword(s):  
Glucose Metabolism ◽  
Cyclic Amp ◽  
Muscle Cells ◽  
Developmental State ◽  
Ionophore A23187 ◽  
Dibutyryl Cyclic Amp ◽  
Hormonal Stimulation ◽  
Phosphofructokinase Activity ◽  
Embryonic Muscle ◽  
Fructose 1,6 Bisphosphate

1. The concentration of glucose 1,6-bisphosphate, a potent regulator of muscle glucose metabolism, was examined in embryonic muscle cells in culture. 2. The concentration in fused myotubes was twice that in unfused myoblasts. 3. The effect of various hormones and agonists on the glucose 1,6-bisphosphate concentration in both pre- and post-fusion muscle cells was examined. In pre-fusion cells no effect of adrenaline or cyclic AMP was observed, but stimulation by vasopressin, adrenaline + propranolol, ionophore A23187 and dibutyryl cyclic GMP significantly decreased glucose 1,6-bisphosphate. In post-fusion cells similar effects were observed, except that stimulation by adrenaline and by dibutyryl cyclic AMP significantly increased metabolite concentration. 4. All effects increased with time (over a 1 h period), except for that of vasopressin, which was transient. 5. The changes in glucose 1,6-bisphosphate concentration were accompanied by changes in the fructose 1,6-bisphosphate/fructose 6-phosphate ratio, implying an effect on phosphofructokinase activity.

Characterization of motifs which are critical for activity of the cyclic AMP-responsive transcription factor CREB

1991 ◽  
Vol 11 (3) ◽  
pp. 1306-1312
Author(s):  
G A Gonzalez ◽  
P Menzel ◽  
J Leonard ◽  
W H Fischer ◽  
M R Montminy
Keyword(s):  
Transcription Factor ◽  
Cyclic Amp ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Transactivation Domain ◽  
Hormonal Stimulation ◽  
Eukaryotic Genes ◽  
Teratocarcinoma Cells ◽  
A Site ◽  
F9 Teratocarcinoma

Cyclic AMP mediates the hormonal stimulation of a number of eukaryotic genes by directing the protein kinase A (PK-A)-dependent phosphorylation of transcription factor CREB. We have previously determined that although phosphorylation at Ser-133 is critical for induction, this site does not appear to participate directly in transactivation. To test the hypothesis that CREB ultimately activates transcription through domains that are distinct from the PK-A site, we constructed a series of CREB mutants and evaluated them by transient assays in F9 teratocarcinoma cells. Remarkably, a glutamine-rich region near the N terminus appeared to be important for PK-A-mediated induction of CREB since removal of this domain caused a marked reduction in CREB activity. A second region consisting of a short acidic motif (DLSSD) C terminal to the PK-A site also appeared to synergize with the phosphorylation motif to permit transcriptional activation. Biochemical experiments with purified recombinant CREB protein further demonstrate that the transactivation domain is more sensitive to trypsin digestion than are the DNA-binding and dimerization domains, suggesting that the activator region may be structured to permit interactions with other proteins in the RNA polymerase II complex.

scholarly journals Hepatic inositol release upon hormonal stimulation of perfused rat liver

1988 ◽  
Vol 251 (3) ◽  
pp. 843-848 ◽  
Author(s):  
S vom Dahl ◽  
P Graf ◽  
H Sies
Keyword(s):  
Cyclic Amp ◽  
Rat Liver ◽  
Radioactive Material ◽  
Perfused Rat Liver ◽  
Dibutyryl Cyclic Amp ◽  
Hormonal Stimulation ◽  
Metabolic Difference ◽  
Basal Release ◽  
Stimulation Of ◽  
Sustained Increase

A sustained increase in the hepatic release of 3H radioactivity was shown to occur upon hormonal stimulation of perfused rat liver 15-20 h after intraperitoneal injection of 100 microCi of myo-[2-3H]inositol. Hormone-released radioactive material was analysed by t.l.c. and was found to consist predominantly of [3H]inositol, without further metabolites. Vasopressin (14 nM), phenylephrine (1.7 microM), angiotensin II (15 nM), glucagon (0.5 nM) and dibutyryl cyclic AMP (5 microM) exert maximal effects on hepatic inositol efflux after 10-15 min of stimulation. Omission of Ca2+ from the perfusion medium abolishes the hormone-dependent inositol release. LiCl (10 mM) does not significantly affect the basal release of [3H]inositol, but suppresses vasopressin- and angiotensin-triggered inositol release. Inositol efflux induced by glucagon, dibutyryl cyclic AMP and phenylephrine, however, remains essentially unchanged by LiCl infusion. This establishes a further metabolic difference between these two groups of agonists in that stimuli that act through cyclic AMP produce a stimulated outflow of inositol, but apparently without a Li+-sensitive phosphatase being involved in the overall process.

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