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 action of forskolin on bovine and rat fasciculata cells was examined in freshly prepared cells. Bovine cells show a close parallelism between production of steroids and production of cAMP as a function of the concentration of ACTH up to 10(-8) M. By contrast, forskolin (10(-7)-10(-5) M) causes a similar increase in steroid synthesis but relatively little effect on the production of cAMP. cAMP-dependent protein kinase shows a similar response to ACTH but no response to forskolin in the same range of concentrations. ACTH and forskolin, at submaximal concentrations, cause greater steroid production when added together than when added separately, but the two agents at high concentrations produce the same response whether added together or separately. The inhibitors of voltage-dependent Ca2+ channels inhibit the steroidogenic response to forskolin (IC50 for nifedipine is 0.1 microM and for Py108-068 is 0.4 microM). A Ca2+ channel agonist (BAY K8644) increases the steroidogenic response of bovine adrenal cells to forskolin, but not that of ACTH. Finally, forskolin causes a concentration-dependent uptake of Ca2+ by these cells; in the concentration range of 0.1-10 microM, forskolin caused an increase in [Ca2+] from 185 nM to 345 nM. By contrast, forskolin caused some stimulation of the production of cAMP, but not that of steroids in rat fasciculata cells. It is concluded that in bovine fasciculata cells forskolin activates voltage-dependent Ca2+ channels with a consequent increase in steroid synthesis. This effect is independent of the well known action of forskolin on adenylate cyclase. Rat fasciculata cells, on the other hand, do not possess such Ca2+ channels and do not show a steroidogenic response to forskolin.
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PMID:Forskolin activates voltage-dependent Ca2+ channels in bovine but not in rat fasciculata cells. 253 78

In Saccharomyces cerevisiae, lack of nutrients triggers a pleiotropic response characterized by accumulation of storage carbohydrates, early G1 arrest, and sporulation of a/alpha diploids. This response is thought to be mediated by RAS proteins, adenylate cyclase, and cyclic AMP (cAMP)-dependent protein kinases. This study shows that expression of the S. cerevisiae gene coding for a cytoplasmic catalase T (CTT1) is controlled by this pathway: it is regulated by the availability of nutrients. Lack of a nitrogen, sulfur, or phosphorus source causes a high-level expression of the gene. Studies with strains with mutations in the RAS-cAMP pathway and supplementation of a rca1 mutant with cAMP show that CTT1 expression is under negative control by a cAMP-dependent protein kinase and that nutrient control of CTT1 gene expression is mediated by this pathway. Strains containing a CTT1-Escherichia coli lacZ fusion gene have been used to isolate mutants with mutations in the pathway. Mutants characterized in this investigation fall into five complementation groups. Both cdc25 and ras2 alleles were identified among these mutants.
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PMID:Control of Saccharomyces cerevisiae catalase T gene (CTT1) expression by nutrient supply via the RAS-cyclic AMP pathway. 254 66

Current evidence indicates that signal transduction after receptor binding of PTH involves the stimulation of adenylate cyclase as well as stimulation of phosphoinositide metabolism. Recent studies, showing that PTH alters phosphate transport in opossum kidney cells at concentrations which do not increase cAMP production and that activators of protein kinase-C also alter phosphate transport, have led to the suggestion that there is a dual mechanism for the regulation of phosphate transport by PTH, namely, protein kinase-C at physiological levels of PTH and cAMP at higher levels of PTH. The present studies were designed to evaluate the relationship between cAMP-dependent protein kinase (PK-A), a more sensitive indicator of alterations in cAMP metabolism than measurements of total cellular cAMP, and phosphate transport in opossum kidney cells, in response to bovine (b)PTH 1-34 and [Nle8,Nle18,Tyr34]bPTH 3-34 amide. While bPTH 1-34 markedly stimulated cAMP accumulation (half-maximal stimulation between 1 and 10 nM), PTH 3-34 analog did not. Phosphate transport was inhibited in a dose-dependent manner by bPTH 1-34, with half-maximal effect occurring between 0.1 and 1 nM. [Nle8,Nle18,Tyr34]bPTH 3-34 amide also altered phosphate transport, although this peptide was 3 orders of magnitude less potent than bPTH 1-34. PK-A activity increased in response to bPTH 1-34 and correlated closely with the effects of PTH on phosphate transport. [Nle8,Nle18,Tyr34]bPTH 3-34 amide, which did not appear to increase cAMP, also resulted in a significant increase in the activity of PK-A. Studies of inhibition of cAMP accumulation using 2',5'-dideoxyadenosine demonstrated that while this agent markedly inhibited the accumulation of cAMP in response to PTH, the effects of PTH on phosphate transport were not altered. However, in spite of the reduction in cAMP the activation of PK-A was similar to control. These data indicate that the effects of PTH peptides on phosphate transport are more closely related to changes in the activity of PK-A than to levels of total cAMP. Activation of PK-A in response to PTH is demonstrable at the lowest doses of PTH that alter phosphate transport.
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PMID:Protein kinase-A and the effects of parathyroid hormone on phosphate uptake in opossum kidney cells. 254 5

Tick salivary glands are controlled by nerves, dopamine being a neurotransmitter at the neuroeffector junction. Dopamine and cyclic AMP (cAMP) stimulate fluid secretion by isolated salivary glands. Dopamine activates an adenylate cyclase to increase intracellular cAMP within the female salivary glands. Phosphoproteins whose levels of phosphate are affected by cAMP-dependent protein kinase have been identified in subcellular fractions. Protein(s) phosphorylated by cAMP appears to activate protein phosphatase in the salivary glands. Another phosphorylation pathway appears to act through protein kinase C because of an ability of phorbol esters (known activators of protein kinase C) to stimulate the phosphorylation of proteins, and an ability of a peptide factor in tick brain to metabolize salivary-gland phosphoinositides, an event that often precedes activation of protein kinase C. Because cAMP modulates brain-factor-stimulated formation of inositol phosphates (products of phosphoinositide breakdown) an interrelationship between the two pathways seems likely. Evidence of regulatory processes, including protein phosphorylation/dephosphorylation reactions, will provide a basis for helping assess the physiological significance of secretory products and the role of the salivary glands in disease transmission.
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PMID:Protein phosphorylation and control of tick salivary gland function. 254 51

Agonist-promoted down-regulation of beta-adrenergic receptor mRNA was investigated in S49 mouse lymphoma variants with mutations in elements of hormone-sensitive adenylate cyclase. In wild-type cells steady-state levels of beta-adrenergic receptor mRNA were established by DNA-excess solution hybridization to be 1.72 +/- 0.08 (n = 8) amol/microgram total cellular RNA. Receptor mRNA levels declined 35-45% in response to stimulation by the beta-adrenergic agonist (-)isoproterenol or forskolin as described previously in DDT1 MF-2 cells (Hadcock, J. R., and Malbon, C. C. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 5021-5025). Agonist-promoted cAMP accumulation and down-regulation of receptor mRNA were analyzed in three variants with mutations in Gs alpha (H21a, unc, cyc-) and a single variant lacking cAMP-dependent protein kinase activity (kin-). H21a (Gs alpha coupled to receptor, but not to adenylate cyclase), unc (Gs alpha uncoupled from receptor), and cyc- (lacking Gs alpha) variants accumulated cAMP and down-regulated beta AR mRNA in response to forskolin. In unc and cyc- cells isoproterenol failed to stimulate cAMP; accumulation and down-regulation of receptor mRNA was not observed. H21a cells, in contrast, displayed agonist-promoted regulation of beta-adrenergic receptor mRNA but only basal levels of cAMP accumulation in response to isoproterenol. The kin- cells displayed cAMP accumulation in response to forskolin as well as to isoproterenol but no down-regulation of receptor mRNA or receptor expression. Taken together these data demonstrate several features of agonist-promoted down-regulation of mRNA: (i) cAMP-dependent protein kinase activity is required for down-regulation of mRNA (kin-), although elevated cAMP accumulation is not (H21a); (ii) functional receptor-Gs coupling is required (H21a), and clones lacking Gs alpha (cyc-) or receptor Gs coupling (unc) lack the capacity to down-regulate mRNA in response to agonist; and (iii) in the presence of basal levels of cAMP and cAMP-dependent protein kinase activity, functional receptor-Gs coupling (H21a) to some other effector other than adenylate cyclase may be propagating the signal.
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PMID:Agonist regulation of beta-adrenergic receptor mRNA. Analysis in S49 mouse lymphoma mutants. 254 76

A mouse beta 2-adrenergic receptor (beta 2AR) DNA clone was transfected and expressed in a mouse adrenocortical tumor cell line (Kin8) that lacks both beta 2AR and cAMP-dependent protein kinase (PKA). The receptor displayed a characteristic beta 2AR agonist binding profile that was similar to that observed in beta 2AR-transfected PKA+ mouse adrenocortical tumor cells (Y1). Isoproterenol treatment of beta 2AR-transfected Kin8 and Y1 cells resulted in a rapid loss of surface beta 2AR, as determined by the binding of the hydrophilic beta 2AR radioligand [3H]CGP 12177 [( 3H]CGP), followed by a decrease in adenylate cyclase activity. Sequestration of beta 2AR in Kin8 cells was beta 2AR agonist specific, temperature dependent, and rapidly reversible. Repeated treatment and recovery from isoproterenol incubation resulted in a cycling of surface [3H]CGP binding. The reappearance of [3H]CGP binding following short isoproterenol treatment was not affected by cycloheximide treatment of the cells. Prolonged incubation of beta 2AR-transfected Kin8 cells with isoproterenol resulted in the down-regulation of beta 2AR protein without a change in beta 2AR mRNA levels. Polysome profiles of control and down-regulated cells revealed that translation of beta 2AR mRNA is inefficient and does not change upon prolonged agonist treatment. Protein synthesis was required to reverse the down-regulation of beta 2AR. These results indicate that neither sequestration nor down-regulation of beta 2AR depends on PKA.
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PMID:Beta 2-adrenergic receptor regulation after transfection into a cell line deficient in the cAMP-dependent protein kinase. 254 82

Epinephrine at concentrations approximating circulating levels in resting subjects produced significant desensitization in wild type S49 lymphoma cells after long term treatment. Desensitization by such low levels of catecholamines was measured by examining subsequent responses of the cells to higher agonist concentrations and was quantified by comparing the integral cAMP accumulations with time in naive and epinephrine-treated cells challenged with the higher epinephrine concentrations. The cells were significantly desensitized after 8 hr of treatment with 3 nM epinephrine or 3 nM terbutaline and were essentially maximally refractory after 24 hr. The 3 nM epinephrine treatment resulted in a small right shift of the EC50. Responses to epinephrine were partially restored by incubating desensitized cells for 8 hr or longer in growth medium that was free of epinephrine. The attenuation of cAMP responses was largely specific, in that the decrease in the response to prostaglandin was small and the response to forskolin was unchanged. This, together with small increases in cAMP destruction in cell-free preparations from treated cells, suggested that higher phosphodiesterase activity contributed in a minor way to the desensitization. However, the response of the adenylate cyclase system to epinephrine was dramatically attenuated, and very significant changes in the properties of the beta-adrenergic receptors were also obvious. That is, the number of binding sites for epinephrine was reduced by about 65% while the number of sites for [125I]iodocyanopindolol was unchanged. The affinity for the radioactive ligand was significantly reduced. Wild type S49 cells remained viable after several days of continuous treatment with 3 nM epinephrine or terbutaline but responded to subsequent increases in cellular cAMP levels with the expected growth arrest and cytolysis. Involvement of cAMP-dependent protein kinase in this type of desensitization was suggested by the observation that S49 kincells were not desensitized by long term incubation with 3 nM epinephrine. Further, low concentrations of dibutyryl cAMP mimicked the effect of low level epinephrine treatment. We conclude that circulating levels of epinephrine in intact animals are sufficiently high to cause desensitization in cells with sensitivities to the catecholamines in the same range as that of the S49 lymphoma cell in vitro. We would predict that cells with those characteristics would always be at least partially desensitized in vivo.
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PMID:Growth of S49 cells in low concentrations of beta-adrenergic agonists causes desensitization. 255 Jul 79

Glucocorticoid increases and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] decreases PTH activation of adenylate cyclase and cAMP-dependent protein kinase in rat osteosarcoma cells (ROS 17/2.8). Since selective cAMP-dependent protein kinase isoenzyme activation may account for specific physiological hormonal responses, we investigated steroid effects on activation of isoenzymes I and II in response to PTH using a new ion exchange separation procedure. Pretreatment of cells for 2 days with the glucocorticoid triamcinolone acetonide (TRM) or 1,25-(OH)2D3 altered the degree of cAMP-dependent protein kinase isoenzyme activation by PTH in accordance with their modulation of intracellular cAMP accumulation, but did not alter the amount of each isoenzyme present or the order in which isoenzymes I and II were activated. In all treatment groups isoenzyme I was preferentially activated by low doses of PTH, while high concentrations activated both isoenzymes, as predicted by the relative affinities of each isoenzyme for cAMP. Glucocorticoid reduced the concentration of bovine PTH-(1-34) required for maximal activation of isoenzyme I from 1 to 0.05 ng/ml and that required for activation of isoenzyme II from 10 to 1 ng/ml. This effect was abolished by simultaneous treatment of cells with 1,25-(OH)2D3. At doses of PTH that caused partial activation (0.05-0.1 ng/ml for isoenzyme I; 1 ng/ml for isoenzyme II), 1,25-(OH)2D3 treatment attenuated this activation. In all groups both isoenzymes were fully activated by 100 ng/ml PTH. Control experiments demonstrated that isoenzyme activation is not a result of cell disruption over the range of PTH doses that regulation by steroid hormone was observed. These results extend our studies on modulation of the cAMP pathway by steroid hormones and make it feasible to correlate selective isoenzyme activation with specific responses to PTH.
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PMID:Glucocorticoid and 1,25-dihydroxyvitamin D modulate the degree of adenosine 3',5'-monophosphate-dependent protein kinase isoenzyme I and II activation by parathyroid hormone in rat osteosarcoma cells. 255 28

Thyroid abnormalities may develop during chronic lithium therapy for affective disorders. Lithium, like iodide, inhibits TSH stimulation of adenylate cyclase and thyroid hormone release. The present study examined the effect of lithium on stimulation of intrathyroidal intermediary metabolism by several agonists. LiCl (5 mmol/l) did not inhibit basal cAMP, glucose oxidation or 32P incorporation into phospholipids in dog thyroid slices. Although LiCl inhibited TSH stimulation of cAMP, it did not abolish the hormone's effect on cAMP-dependent protein kinase. The stimulation of iodide organification, glucose oxidation or 32P incorporation into phospholipids by TSH, carbachol and phorbol esters was not inhibited by lithium. This is in contrast to the effects of iodide, which inhibited stimulation of glucose oxidation and 32P incorporation into phospholipids by various agonists. Thus, although both lithium and iodide inhibited TSH-stimulated cAMP formation, they act differently on intrathyroidal intermediary metabolism.
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PMID:Effects of lithium on stimulated metabolic parameters in dog thyroid slices. 255 92

In a previous paper, a model was presented showing how the group of Ca2+/calmodulin-dependent protein kinase II molecules contained within a postsynaptic density could stably store a graded synaptic weight. This paper completes the model by showing how bidirectional control of synaptic weight could be achieved. It is proposed that the quantitative level of the activity-dependent rise in postsynaptic Ca2+ determines whether the synaptic weight will increase or decrease. It is further proposed that reduction of synaptic weight is governed by protein phosphatase 1, an enzyme indirectly controlled by Ca2+ through reactions involving phosphatase inhibitor 1, cAMP-dependent protein kinase, calcineurin, and adenylate cyclase. Modeling of this biochemical system shows that it can function as an analog computer that can store a synaptic weight and modify it in accord with the Hebb and anti-Hebb learning rules.
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PMID:A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. 255 18


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