Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The corpus luteum formed after luteinization of follicular cells secretes progesterone under the control of luteinizing hormone (LH). Binding of LH to its G-protein-coupled receptor leads to the activation of the adenylate cyclase/ cyclic AMP (cAMP)/cAMP-dependent protein kinase (PKA) signalling pathway. The identification of a new class of cAMP-binding proteins termed 'guanine nucleotide exchange factors' (cAMP-GEFs) provides a means by which changes in cAMP could yield actions that are independent of PKA. Hence, in this study, we have explored the hypothesis that steroidogenesis in luteinizing cells is mediated in both a cAMP/PKA-dependent and cAMP-dependent, but PKA-independent, manner. Human granulosa cells were isolated from follicular aspirates of women undergoing assisted conception. Luteinizing human granulosa cells were cultured for up to 3 days in the presence of human (h)LH and the adenylate cyclase activator forskolin in the added presence or absence of increasing doses of the PKA inhibitors H89 (N-[2-(4-bromocinnamylamino)ethyl] 5-isoquinoline) and PKI (myristoylated protein kinase A inhibitor amide 14-22) or the cAMP antagonist, Rp-cAMP. Agonist-stimulated progesterone secretion was inhibited in a dose-dependent manner by the PKA inhibitors and the cAMP antagonist, with decreasing sensitivity as luteinization progressed. Pretreatment of granulosa cells for 4 h with human (h)LH reduced the effectiveness of H89 in inhibiting progesterone secretion. Under basal conditions, cAMP-GEFI expression increased progressively throughout culture, and this could be further enhanced when cells were incubated with increasing doses of LH and forskolin. Furthermore, incubation of cells in the presence of increasing concentrations of the novel cAMP-GEF-specific cAMP analogue, 8 CPT-2 ME-cAMP (8-(4-chloro-phenylthio)-2'-0-methyladenosine-3',5'-cyclic monophosphate), increased progesterone secretion in a dose-dependent manner. The results show that increases in cAMP generated by LH and forskolin, in addition to activating PKA, also induce increases in cAMP-GEFI protein expression in luteinizing human granulosa cells. In addition, activation of cAMP-GEFI results in increased progesterone secretion. Hence, increases in cAMP lead to the activation of PKA-dependent, as well as PKA-independent but cAMP-dependent (via cAMP-GEFI), signalling mechanisms. Since cAMP-GEFs have the capacity to activate the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) signalling pathways, these may provide the potential mechanisms by which cAMP-dependent but PKA-independent progesterone synthesis is regulated.
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PMID:Progesterone secretion by luteinizing human granulosa cells: a possible cAMP-dependent but PKA-independent mechanism involved in its regulation. 1552 73

The effects of camptothecin-somatostatin (CPT-SS) conjugates were investigated on small cell lung cancer (SCLC) cells. CPT was coupled to a SS agonist (SSA), c(Cys-Phe-DTrp-Lys-Thr-Cys)Thr-NH2 using the built in nucleophile assisted-releasing group (L1) N-methyl-aminoethyl-Gly-Dser-Nle-Dtyr-Dser or (L2) aminoethyl-Gly-Dser-Nle-Dtyr-Dser. The resulting CPT-L1-SSA and CPT-L2-SSA inhibited the specific binding of [125I-Tyr11]SS to NCI-H69 cell membranes with IC50 values of 0.2 and 2.1 nM, respectively. [125I]CPT-L1-SSA was internalized by SCLC cells at 37 degrees C but not at 4 degrees C. CPT-L1-SSA and CPT-L2-SSA inhibited in a dose-dependent manner the increase in adenylylcyclase activity caused by 25 microM forskolin. In vitro, 0.3 microM CPT-L1-SSA half-maximally inhibited the clonal growth of SCLC cells and 1 microM CPT-L1-SSA strongly inhibited 3H-thymidine incorporation into DNA and trypan-blue exclusion. These results suggest that CPT conjugated peptides such as CPT-L1-SSA may prove useful for exploring the efficacy of receptor-directed cytotoxicity to inhibit the proliferation of SCLC cells.
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PMID:Camptothecin-somatostatin conjugates inhibit the growth of small cell lung cancer cells. 1611 93

The lateral giant (LG)-mediated escape behavior of the crayfish habituates readily on repetitive sensory stimulation. Recent studies suggested that the biogenic amines serotonin and octopamine modulate the time course of recovery and/or re-depression of the LG response after habituation. However, little is known of how serotonin and octopamine effect LG habituation and what second-messenger cascades they may activate. To investigate the effect of biogenic amines on LG habituation, serotonin and octopamine were superfused before presenting repetitive sensory stimulation. Serotonin and octopamine increased the number of stimuli needed to habituate the LG response. Their effects were mimicked by mixed application of a cAMP analogue [8-(4-chlorophenylthio)-cAMP (CPT-cAMP)] and a phosphodiesterase inhibitor [3-isobutyl-1-methylxanthine (IBMX)] but not by a cGMP analogue (8-bromoguanosine 3',5'-cyclic monophosphate). Perfusion of the adenylate cyclase inhibitor (SQ22536) abolished the effect of serotonin but not that of octopamine. To investigate the site of action of each biogenic amines in the neural circuit meditating LG escape, the effect of drugs on directly and indirectly elicited postsynaptic potentials in LG was investigated. Serotonin, octopamine, and a mixture of CPT-cAMP and IBMX increased both the direct and indirect synaptic inputs. Simultaneous application of SQ22536 abolished the effect of serotonin on both inputs but did not block the effect of octopamine. Direct injection of the cAMP analogue (Sp-isomer of adenosine-3',5'-cyclic monophosphorothioate) into LG increased both the direct and indirect inputs to LG. These results indicate that serotonin mediates an increase in cAMP levels in LG, but octopamine acts independently of cAMP and cGMP.
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PMID:Cyclic AMP mediates serotonin-induced synaptic enhancement of lateral giant interneuron of the crayfish. 1616 94

The signal transduction mechanisms defining the role of cyclic nucleotides in the regulation of potassium channel activity in pulmonary vascular smooth muscle are currently an area of great interest. Normally, signaling mechanisms that elevate cyclic AMP (cAMP) open potassium channels. Modulation of the large-conductance, calcium- and voltage-activated potassium (BKCa) channel is important in the regulation of pulmonary arterial pressure, and inhibition (closing) of the BKCa channel has been implicated in the development of pulmonary vasoconstriction. Accordingly, studies were done to determine the effect of cAMP-elevating agents on BKCa channel activity under normoxic and hypoxic conditions using patch-clamp studies in pulmonary arterial smooth muscle cells (PASMC) of the fawn-hooded rat (FHR). Forskolin (10 microM; n = 4), a stimulator of adenylate cyclase and an activator of cAMP-dependent protein kinase (PKA), and CPT-cAMP (100 microM; n = 3), a membrane-permeable derivative of cAMP, opened BKCa channels in single FHR PASMC under normoxic conditions. Exposure of FHRs to 4 weeks of 10% O2 (hypoxia) significantly attenuated the effect of both forskolin (n = 7) and CPT-cAMP (n = 14) on BKCa channel activity in PASMC. These results suggest that this phenomenon may serve as a physiological mechanism to cause hypoxic vasoconstriction in the pulmonary circulation via modulation of BKCa channels.
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PMID:Hypoxia modulates cyclic AMP activation of BkCa channels in rat pulmonary arterial smooth muscle. 1638 27

Extracellular adenosine reduced viability of RCR-1 rat astrocytoma cells in a dose (0.3-10mM)- and treatment time (24-72h)-dependent manner. In the apoptosis assay using propidium iodide (PI) and annexin V, treatment with adenosine (1mM) for 72h increased the population of PI-negative/annexin V-positive cells, that is related to early apoptosis, and that of PI-positive/annexin V-positive cells, that is related to late apoptosis/secondary necrosis. In addition, nuclei of cells treated with adenosine (1mM) for 72h were reactive to an antibody against single-stranded DNA. Adenosine activated caspase-3, -8 and -9, but mitochondrial membrane potentials were not affected. Adenosine-induced RCR-1 cell death was significantly inhibited by 8-CPT, an antagonist of A(1) adenosine receptors, and forskolin, an adenylate cyclase activator. SQ22536, an adenylate cyclase inhibitor, alternatively, exhibited an effect similar to adenosine. CHA, an agonist of A(1) adenosine receptors, activated caspase-3 and -9, but not caspase-8. Adenosine-induced cytotoxicity of RCR-1 cells was also significantly inhibited by dipyridamole, an inhibitor of adenosine transporter, and AMDA, an inhibitor of adenosine kinase. AICAR, an activator of AMP-activated protein kinase (AMPK), reduced RCR-1 cell viability, but synergistic effect was not obtained with co-treatment with adenosine and AICAR. AICAR activated caspase-3 and -9, but not caspase-8. An additive inhibition was found in the co-presence of 8-CPT and dipyridamole. Extracellular adenosine, thus, appears to activate caspase-9 followed by the effector caspase, caspase-3, at least via two independent pathways linked to A(1) adenosine receptor-mediated adenylate cyclase inhibition and adenosine uptake into cells/conversion to AMP/activation of AMPK, possibly regardless of mitochondrial damage, thereby leading to RCR-1 cell death, dominantly by apoptosis. Moreover, caspase-8 activation could again contribute to adenosine-induced cytotoxicity, although the underlying mechanism is currently unknown. Collectively, the results of the present study may represent a new pathway for caspase activation relevant to diverse adenosine signals in cell death.
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PMID:A(1) adenosine receptor signal and AMPK involving caspase-9/-3 activation are responsible for adenosine-induced RCR-1 astrocytoma cell death. 1646 85

Essential polyunsatured fatty acids have been shown to modulate enzymes, channels and transporters, to interact with lipid bilayers and to affect metabolic pathways. We have previously shown that eicosapentanoic acid (EPA, C20:5, n-3) activates epithelial sodium channels (ENaCs) in a cAMP-dependent manner involving stimulation of cAMP-dependent protein kinase (PKA). In the present study, we explored further the mechanism of EPA stimulation of ENaC in A6 cells. Fluorescence resonance energy transfer experiments confirmed activation of PKA by EPA. Consistent with our previous studies, EPA had no further stimulatory effect on amiloride-sensitive transepithelial current (INa) in the presence of CPT-cAMP. Thus, we investigated the effect of EPA on cellular pathways which produce cAMP. EPA did not stimulate adenylate cyclase activity or total cellular cAMP accumulation. However, membrane-bound phosphodiesterase activity was inhibited by EPA from 2.46 pmol/mg of protein/min to 1.3 pmol/mg of protein/min. To investigate the potential role of an A-kinase-anchoring protein (AKAP), we used HT31, an inhibitor of the binding between PKA and AKAPs as well as cerulenin, an inhibitor of myristoylation and palmitoylation. Both agents prevented the stimulatory effect of EPA and CPT-cAMP on INa and drastically decreased the amount of PKA in the apical membrane. Colocalization experiments in A6 cells cotransfected with fluorescently labeled ENaC beta subunit and PKA regulatory subunit confirmed the close proximity of the two proteins and the membrane anchorage of PKA. Last, in A6 cells transfected with a dead mutant of Sgk, an enzyme which up-regulates ENaCs, EPA did not stimulate Na+ current. Our results suggest that stimulation of ENaCs by EPA occurs via SGK in membrane-bound compartments containing an AKAP, activated PKA, and a phosphodiesterase.
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PMID:Epithelial Na+ channel stimulation by n-3 fatty acids requires proximity to a membrane-bound A-kinase-anchoring protein complexed with protein kinase A and phosphodiesterase. 1747 24

Adenylate cyclase-activating polypeptide 1 (ADCYAP1) binds both Gs- and Gq-coupled receptors and stimulates adenylate cyclase/cAMP and protein kinase C/mitogen-activated protein kinase 3/1 (MAPK3/1) signaling pathways in pituitary gonadotrophs. In this study, we investigated the cAMP and MAPK3/1 signaling pathways induced by ADCYAP1 stimulation and examined the effects of ADCYAP1 on the expression of gonadotropin subunit genes using a clonal gonadotroph cell line, LbetaT2. ADCYAP1 increased intracellular cAMP accumulation up to 19-fold in LbetaT2 cells. Common alpha-glycoprotein subunit gene (Cga) promoter activity was strongly activated by both ADCYAP1 and the cyclic-AMP analog, 8-(4-chlorophenylthio) adenosine 3',5'-cyclic monophosphate (CPT-cAMP). Both had little effect on luteinizing hormone beta (Lhb) and follicle-stimulating hormone beta (Fshb) promoter activities. Cga promoter activity was significantly increased by transfection with constitutively active cAMP-dependent protein kinase (PKA). Activities of the Lhb and Fshb promoters were only modestly increased. Both ADCYAP1 and CPT-cAMP induced MAPK3/1 activation in LbetaT2 cells. The MEK inhibitor, U0126, and the PKA inhibitors, H89 and cAMP-dependent protein kinase peptide inhibitor (PKI), completely inhibited MAPK3/1 activation by either ADCYAP1 or CPT-cAMP. Using luciferase reporter constructs containing cis-elements, the cAMP response element (Cre) promoter was stimulated about 4-fold by ADCYAP1. ADCYAP1-induced Cre promoter activity was completely inhibited by H89, but not by U0126. ADCYAP1 also increased the activity of the serum response element (Sre) promoter, a target for MAPK3/1, and treatment of the cells with U0126 completely inhibited ADCYAP1-induced Sre promoter activity. ADCYAP1-increased Cga promoter activity was inhibited partially by both H89 and U0126. Although combining the inhibitors showed an additive inhibition effect, it did not result in complete inhibition. These results suggest that in LbetaT2 cells, ADCYAP1 mainly increases Cga through activation of PKA and MAPK3/1, as well as through an additional unknown pathway.
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PMID:Cyclic adenosine 3',5'monophosphate/protein kinase A and mitogen-activated protein kinase 3/1 pathways are involved in adenylate cyclase-activating polypeptide 1-induced common alpha-glycoprotein subunit gene (Cga) expression in mouse pituitary gonadotroph LbetaT2 cells. 1759 63

In cultured rat hepatocytes, glucagon increased the phosphoenolpyruvate carboxykinase (PCK1) mRNA by increasing cellular cAMP concentrations. The proinflammatory cytokines rhIL1beta and rhTNF alpha impaired the increase both in cAMP and PCK1 mRNA. Glucose formation from glycogen stimulated by glucagon was also attenuated by the cytokines, very likely due to the attenuation of the cAMP increase. Treatment of hepatocytes with the phosphodiesterase inhibitor IBMX or the inhibitory G-protein (G i) inactivating compound pertussis toxin did not abolish the inhibition of the glucagon-stimulated increase in cAMP by the cytokines indicating that phosphodiesterase and G i were not involved. The activation of adenylate cyclase by forskolin enhanced cAMP and PCK1 mRNA. Again, rhIL1beta and rhTNF alpha attenuated the increase in PCK1 mRNA, however, not that in cAMP. The stimulation of PCK1 mRNA increase with the nonhydrolyzable cAMP analogue CPT-cAMP was inhibited by rhIL1beta and rhTNF alpha indicating interference independent of changes in cAMP levels. It is concluded that rhIL1beta and rhTNF alpha inhibited glucagon-stimulated signal transduction at the site of cAMP formation. In addition, glucagon-stimulated PCK1 mRNA was attenuated independent of cAMP formation very likely on the transcriptional and/or post-transcriptional level.
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PMID:Inhibition of glucagon-signaling and downstream actions by interleukin 1beta and tumor necrosis factor alpha in cultured primary rat hepatocytes. 1833 79

cAMP plays a critical role in the control of oocyte maturation, as a high level of cAMP maintains oocyte arrest at the first meiotic prophase. Yet this study shows that pulsing meiotically arrested denuded oocytes (DO) with cAMP induces oocyte maturation through the activation of AMP-activated protein kinase (PRKA). Short-term (3 h) pulsing of meiotically arrested oocytes with forskolin, an adenyl cyclase (AC) activator, increased oocyte cAMP, led to elevated AMP, and induced oocyte meiotic resumption compared to oocytes continuously cultured in the control medium with or without forskolin. Western analysis showed that germinal vesicle (GV)-stage oocytes after forskolin pulsing contained increased levels of phospho-acetyl CoA carboxylase (pACACA), a primary substrate of PRKA. Pulsing oocytes with the phosphodiesterase (PDE)-sensitive cAMP analog, 8-bromo-cAMP (8-Br-cAMP), also increased pACACA and pPRKA levels in GV-stage oocytes and induced oocyte meiotic resumption. Moreover, the PRKA inhibitors, compound C and araA, prevented 8-Br-cAMP pulsing-induced maturation. The lack of effect on meiotic induction and PRKA activation when oocytes were pulsed with the PDE-resistant activators of cAMP-dependent protein kinase, Sp-cAMP-AM and Sp-5,6-DCI-cBIMPS, suggests that cAMP degradation is required for pulsing-induced maturation. Pulsing oocytes with the exchange protein directly activated by cAMP (Epac)-specific activator, 8-CPT-2'-O-Me-cAMP, had no stimulatory effect on oocyte maturation, suggesting Epac is not involved in the pulsing-induced maturation. Taken together, these data support the idea that a transient increase in oocyte cAMP can induce meiotic resumption via activation of PRKA.
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PMID:cAMP pulsing of denuded mouse oocytes increases meiotic resumption via activation of AMP-activated protein kinase. 1970 May 29

Extracellular adenosine-induced apoptosis of CW2 human colonic cancer cells by activating caspase-3, -8 and -9, and the effect was enhanced by adding EHNA, an adenosine deaminase inhibitor. Adenosine-induced CW2 cell death was inhibited by 8-CPT, an A(1) adenosine receptor inhibitor, but otherwise 2-chloroadenosine, an A(1) adenosine receptor agonist, and MDL-12330A, an inhibitor of adenylate cyclase, mimicked the adenosine effect. For mice inoculated with CW2 cells, intraperitoneal injection with adenosine reduced tumor growth and more prominent reduction was obtained with co-injection with EHNA. Adenosine, thus, suppresses CW2 human colonic cancer growth by inducing apoptosis as mediated via A(1) adenosine receptors.
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PMID:Adenosine suppresses CW2 human colonic cancer growth by inducing apoptosis via A(1) adenosine receptors. 1982 92


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