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Cells Jan 2020Compartmentalization of diverse types of signaling molecules contributes to the precise coordination of signal propagation. The primary cilium fulfills this function by... (Review)
Review
Compartmentalization of diverse types of signaling molecules contributes to the precise coordination of signal propagation. The primary cilium fulfills this function by acting as a spatiotemporally confined sensory signaling platform. For the integrity of ciliary signaling, it is mandatory that the ciliary signaling pathways are constantly attuned by alterations in both oscillating small molecules and the presence or absence of their sensor/effector proteins. In this context, ciliary G protein-coupled receptor (GPCR) pathways participate in coordinating the mobilization of the diffusible second messenger molecule 3',5'-cyclic adenosine monophosphate (cAMP). cAMP fluxes in the cilium are primarily sensed by protein kinase A (PKA) complexes, which are essential for the basal repression of Hedgehog (Hh) signaling. Here, we describe the dynamic properties of underlying signaling circuits, as well as strategies for second messenger compartmentalization. As an example, we summarize how receptor-guided cAMP-effector pathways control the off state of Hh signaling. We discuss the evidence that a macromolecular, ciliary-localized signaling complex, composed of the orphan GPCR Gpr161 and type I PKA holoenzymes, is involved in antagonizing Hh functions. Finally, we outline how ciliary cAMP-linked receptor pathways and cAMP-sensing signalosomes may become targets for more efficient combinatory therapy approaches to counteract dysregulation of Hh signaling.
Topics: Cilia; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Hedgehog Proteins; Humans; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 31947770
DOI: 10.3390/cells9010118 -
The Journal of Clinical Investigation May 1974The effect of adenosine-3',5'-cyclic monophosphate (cyclic AMP) and N(6),O(2)-dibutyryl adenosine-3',5'-cyclic monophosphate (dibutyryl cyclic AMP) on renal tubular...
The effect of adenosine-3',5'-cyclic monophosphate (cyclic AMP) and N(6),O(2)-dibutyryl adenosine-3',5'-cyclic monophosphate (dibutyryl cyclic AMP) on renal tubular permeability was studied by microinjection techniques in anesthetized diuretic rats. Radioactive inulin and mannitol were microinjected simultaneously into superficial proximal and distal convolutions and recovery of the isotopes was measured in the urine.During control conditions, mannitol and inulin recovery was essentially complete. However, during infusion of cyclic AMP or dibutyryl cyclic AMP, mannitol recovery was significantly less than control after early proximal and late proximal microinjections, averaging 79 and 85%, respectively. There was no loss of mannitol from the nephron after microinjection into distal convolutions. Inulin recovery was complete after all microinjections during cyclic AMP or dibutyryl cyclic AMP infusion. Simultaneous clearances of mannitol and inulin as well as peritubular capillary microinjections studies demonstrated bidirectional fluxes of mannitol across the proximal tubular epithelium during infusion of cyclic AMP or dibutyryl cyclic AMP. Intratubular pressures were not different during control and experimental periods. These studies demonstrate a change in the permeability characteristic of the proximal convoluted tubule during infusion of cyclic AMP and dibutyryl cyclic AMP. This change in permeability of the proximal tubule could account for the effects of cyclic AMP on proximal tubular transport processes.
Topics: Animals; Bucladesine; Carbon Radioisotopes; Cyclic AMP; Diuresis; Inulin; Kidney Tubules; Kidney Tubules, Distal; Kidney Tubules, Proximal; Male; Mannitol; Permeability; Rats; Tritium
PubMed: 4363407
DOI: 10.1172/JCI107671 -
The Journal of Biological Chemistry Jul 1988
Review
Topics: Animals; Cyclic AMP; Enzymes; Gene Expression Regulation; Genes; Humans; Transcription, Genetic
PubMed: 2837474
DOI: No ID Found -
Adenylate cyclase activity and cyclic AMP levels during the development of Dictyostelium discoideum.The Journal of Biological Chemistry Oct 1979Adenylate cyclase activity and endogenous cyclic AMP levels were measured using a highly sensitive radioimmunoassay and protein binding assay during 24 h of development...
Adenylate cyclase activity and endogenous cyclic AMP levels were measured using a highly sensitive radioimmunoassay and protein binding assay during 24 h of development of Dictyostelium discoideum. Adenylate cyclase activity was not detected until the aggregation stage of development (10 h) when a sudden peak of activity was found. The enzyme was active at all subsequent stages, although a slow decline in activity was observed. Similarly, cyclic AMP levels were not detectable through the first 7 h of development and then showed a sudden peak at aggregation. Following aggregation the cyclic AMP levels decreased to approximately 1/2 the peak value and maintained that level throughout the remainder of the developmental cycle. Adenylate cyclase had a narrow range of substrate saturation with a maximum velocity at 1 to 4 mM ATP at both the aggregation stage (10 h) and the sorocarp stage (24 h). At levels of ATP higher than 6 mM the enzyme from both stages was strongly inhibited. No activity was observed in the absence of Mg2+ or dithiothreitol. The activity from 10-, 14-, and 20-h stages was found bound to a 25,000 x g pellet fraction. The sudden appearance of adenylate cyclase and its product cyclic AMP at aggregation provides additional evidence of a role for this nucleotide in chemotaxis, and the retention of enzyme activity and nucleotide level during the subsequent stages may reflect a further function of cyclic AMP during formation of the two cell types.
Topics: Adenylyl Cyclases; Cyclic AMP; Dictyostelium; Kinetics; Phosphoric Diester Hydrolases; Theophylline
PubMed: 226525
DOI: No ID Found -
The Journal of Biological Chemistry Feb 1985We have recently identified a cell surface cAMP-binding protein by specific photoaffinity labeling of intact Dictyostelium discoideum cells with 8-N3-[32P] cAMP. The...
We have recently identified a cell surface cAMP-binding protein by specific photoaffinity labeling of intact Dictyostelium discoideum cells with 8-N3-[32P] cAMP. The major photolabeled protein appears as a doublet (Mr = 40,000-43,000) in sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiography. In this study, the doublet is shown to have the characteristics of the cAMP receptor responsible for chemotaxis and cAMP signaling. Both specific photoaffinity labeling of the doublet and binding of 8-N3-[32P]cAMP are saturable (KD = 0.3 microM), the levels of both peak at 5 h, and both are inhibited by cAMP and several cAMP analogs in the same order of potency and with K1 values similar to those measured for inhibition of [3H]cAMP binding. When cAMP-binding activity was partially purified (40-fold) and then photoaffinity labeled, the same bands (Mr = 40,000-43,000) were observed. The relative intensities of the upper and lower bands of the doublet alternated at the same frequency as the spontaneous oscillations in cAMP synthesis. When oscillations were suppressed, the lower band of the doublet predominated. Following addition of cAMP, the relative intensity gradually shifted to the upper band. When cAMP was removed, there was a gradual restoration of the lower band form. We propose that the lower band form of the receptor activates chemotaxis and cAMP signaling and that the upper band form does not. This reversible receptor modification may then be the mechanism of adaptation, the process by which the physiological responses cease to be stimulated by persistent cAMP. Several developmentally regulated genes in D. discoideum have been reported to be induced or suppressed by pulses of cAMP (adaptive regulation) and others by continuous cAMP (nonadaptive regulation). These observations may be explained by the receptor modification reported here if the two forms of the receptor, which bind cAMP with the same affinity, independently influence gene expression.
Topics: Affinity Labels; Azides; Binding, Competitive; Chemotaxis; Cyclic AMP; Dictyostelium; Electrophoresis, Polyacrylamide Gel; Photochemistry; Receptors, Cyclic AMP
PubMed: 2981872
DOI: No ID Found -
Frontiers in Bioscience (Landmark... Jan 2013Breast cancer is a major cause of cancer death in women in the world. Triple-negative breast cancers, which accounts for 10-20% of all mammary tumours, are characterised... (Review)
Review
Breast cancer is a major cause of cancer death in women in the world. Triple-negative breast cancers, which accounts for 10-20% of all mammary tumours, are characterised by an aggressive phenotype, are often found in younger women and have been associated with poor prognosis. Obesity increases the risk for triple-negative breast cancer occurrence. Because triple-negative breast cancer patients are unresponsive to current targeted therapies and other treatment options are only partially effective, new pharmacological approaches are warranted. The obesity-linked adipokine, leptin, is a well known mitogen/survival factor in breast cancer cells and several studies have addressed the role of leptin in breast cancer pathogenesis and progression. Surprisingly, recent in vitro studies have shown that leptin enhances the anti-proliferative effects of cAMP elevation in triple-negative breast cancer cells by apoptosis induction. In the current review, we discuss on the role of cAMP as a growth suppressor and of leptin as a growth promoting factor in breast cancer cells and we will focus on the molecular pathways involved in the antiproliferative interaction between leptin and cAMP elevation. The rationale for the possible development of a simple, cheap and innovative approach for therapeutic intervention in triple-negative breast cancer, based on the use of cAMP elevating drugs at lower and tolerable doses, will be also discussed.
Topics: Breast Neoplasms; Cell Line, Tumor; Cyclic AMP; Drug Resistance, Neoplasm; Female; Humans; Leptin; STAT3 Transcription Factor; Signal Transduction
PubMed: 23276914
DOI: 10.2741/4092 -
British Journal of Pharmacology Mar 2003(1) This report analyses the intracellular and extracellular accumulation of cyclic AMP in primary rat skeletal muscle cultures, after direct and receptor-dependent...
(1) This report analyses the intracellular and extracellular accumulation of cyclic AMP in primary rat skeletal muscle cultures, after direct and receptor-dependent stimulation of adenylyl cyclase (AC). (2) Isoprenaline, calcitonin gene-related peptide (CGRP) and forskolin induced a transient increase in the intracellular cyclic AMP that peaked 5 min after onset stimulation. (3) Under stimulation with isoprenaline or CGRP, the intracellular cyclic AMP initial rise was followed by an exponential decline, reaching 46 and 52% of peak levels in 10 min, respectively. (4) Conversely, the forskolin-dependent accumulation of intracellular cyclic AMP decreased slowly and linearly, reaching 49% of the peak level in 30 min. (5) The loss of intracellular cyclic AMP from peak levels, induced by direct or receptor-induced activation of AC, was followed by an increase in the extracellular cyclic AMP. (6) This effect was independent on PDEs, since it was obtained in the presence of 3-isobutyl-1-methylxanthine (IBMX). (7) Besides, in isoprenaline treated cells, the beta-adrenoceptor antagonist propranolol reduced both intra- and extracellular accumulation of cyclic AMP, whereas the organic anion transporter inhibitor probenecid reduced exclusively the extracellular accumulation. (8) Together our data show that direct or receptor-dependent activation of skeletal muscle AC results in a transient increase in the intracellular cyclic AMP, despite the continuous presence of the stimulus. The temporal declining of intracellular cyclic AMP was not dependent on the cyclic AMP breakdown but associated to the efflux of cyclic nucleotide to the extracellular compartment, by an active transport since it was prevented by probenecid.
Topics: Animals; Biological Transport; Cells, Cultured; Cyclic AMP; Dose-Response Relationship, Drug; Extracellular Space; Intracellular Fluid; Muscle, Skeletal; Nucleotides, Cyclic; Rats
PubMed: 12642402
DOI: 10.1038/sj.bjp.0705130 -
Anesthesiology Nov 1974
Review
Topics: Adenosine Triphosphate; Adenylyl Cyclases; Adrenergic beta-Antagonists; Anesthetics; Cell Membrane; Cyclic AMP; Cyclic GMP; Nucleotides, Cyclic; Phosphoric Diester Hydrolases; Protein Kinases; Synaptic Transmission
PubMed: 4154714
DOI: 10.1097/00000542-197411000-00016 -
British Medical Journal Oct 1971
Topics: Cyclic AMP; History, 20th Century; Nobel Prize; Tennessee
PubMed: 4329929
DOI: No ID Found -
Biochimica Et Biophysica Acta Dec 2014Understanding of cAMP signaling has greatly improved over the past decade. The advent of live cell imaging techniques and more specific pharmacologic modulators has led... (Review)
Review
Understanding of cAMP signaling has greatly improved over the past decade. The advent of live cell imaging techniques and more specific pharmacologic modulators has led to an improved understanding of the intricacies by which cAMP is able to modulate such a wide variety of cellular pathways. It is now appreciated that cAMP is able to activate multiple effector proteins at distinct areas in the cell leading to the activation of very different downstream targets. The investigation of signaling proteins in cancer is a common route to the development of diagnostic tools, prognostic tools, and/or therapeutic targets, and in this review we highlight how investigation of cAMP signaling microdomains driven by the soluble adenylyl cyclase in different cancers has led to the development of a novel cancer biomarker. Antibodies directed against the soluble adenylyl cyclase (sAC) are highly specific markers for melanoma especially for lentigo maligna melanoma and are being described as "second generation" cancer diagnostics, which are diagnostics that determine the 'state' of a cell and not just identify the cell type. Due to the wide presence of cAMP signaling pathways in cancer, we predict that further investigation of both sAC and other cAMP microdomains will lead to additional cancer biomarkers. This article is part of a Special Issue entitled: The role of soluble adenylyl cyclase in health and disease.
Topics: Biomarkers, Tumor; Cyclic AMP; Humans; Neoplasms
PubMed: 25205620
DOI: 10.1016/j.bbadis.2014.08.016