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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The papillary collecting duct (PCD) is considered to be of major importance in the final elaboration of the urine, but the metabolism of cyclic adenosine 3',5'-monophosphate (cAMP) has not yet been directly studied in the PCD. Therefore, in the present study we examined the basic properties of the cAMP system in isolated PCD microdissected from rat kidney. Vasopressin (VP) caused a marked (5- to 10-fold) stimulation of adenylate cyclase (AdC) but parathyroid hormone, calcitonin, isoproterenol, and bradykinin were without effect. A gradual increase in osmolality from 200 mosM had a biphasic effect on AdC, first enhancing (at 800 mosM) then inhibiting AdC activity at 2,000 mosM. cAMP-phosphodiesterase activity was inhibited as osmolality was increased from 200 to 800 mosM and the inhibition remained constant to 2,000 mosM. Incubation of intact PCD with VP resulted in a threefold increase in cAMP levels. As the osmolality of the incubation medium ws increased from 300 to 2,000 mosM, both basal and VP-stimulated cAMP levels continued to increase. Prostaglandin E2 (PGE2) (10(-5) M) alone (in the absence of vP) caused an increase in AdC activity, but the same dose of PGE2 had no effect on AdC activity stimulated by submaximal or maximal doses of VP. PGE2 (10(-5) M) caused a small increase in cAMP levels in intact PCD. On the other hand, PGE2 inhibited VP-stimulated cAMP levels by 50%. Incubation of PCD with PGE2 had no effect on cAMP-phosphodiesterase activity. The results demonstrate that osmolality in the physiologic range has a major influence on cAMP metabolism in the PCD and document an antagonism between PGE2 and VP at the level of cAMP accumulation in the PCD.
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PMID:ADH-sensitive cAMP system in papillary collecting duct: effect of osmolality and PGE2. 626 88

We investigated the presence and several of the properties of calmodulin in human parathyroid cells. Boiled extracts of such cell preparations contained a heat-stable factor causing a 2- to 3-fold calcium-dependent stimulation of calmodulin-deficient phosphodiesterase activity, which was parallel to that due to pure porcine calmodulin. This activation could be totally blocked by 10(-4) M trifluoperazine, with half-maximal inhibition at 3 X 10(-5) M, similar to the effects of this phenothiazine on porcine calmodulin. These results suggested the presence of calmodulin in human parathyroid cells. By comparison with known quantities of porcine calmodulin, human parathyroid cells contained 9-208 ng calmodulin/10(6) cells. The content of calmodulin in 3 normal parathyroid glands [65 +/- 8 (+/- SEM) ng/10(6) cells] did not differ significantly from that of 12 adenomas (61 +/- 16 ng/10(6) cells). Cells from 7 glands showing secondary hyperplasia, however, had significantly greater levels of calmodulin (164 +/- 11 ng/10(6) cells) than either normal cells or adenomas (P less than 0.001 and P less than 0.005, respectively). Extracts of human parathyroid cells caused half-maximal stimulation of phosphodiesterase activity at 1.1-4.8 microM free calcium. The concentrations of calcium half-maximally activating phosphodiesterase (Ka) did not differ significantly for normal or abnormal cells (3.3 +/- 0.03 vs. 2.6 +/- 0.33; P greater than 0.3). Moreover, in 2 cases in which normal parathyroid tissue was obtained from patients with adenomas, the Ka values for calcium for the normal and abnormal cells were similar (3.3 vs. 2.5 and 3.4 vs. 2.5 microM, respectively). Finally, there was no significant correlation between either the content of calmodulin or the Ka for calcium and the set-point for calcium [the calcium concentration causing half-maximal inhibition of parathyroid hormone (PTH) release] or the maximal rate of PTH secretion for dispersed parathyroid cells. These results suggest that human parathyroid cells contain calmodulin, but provide no evidence for a role of this protein in the abnormal calcium-regulated PTH release in hyperparathyroidism.
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PMID:Calmodulin in dispersed human parathyroid cells. 627 Jan 80

The effects of parathyroid hormone (PTH) and cyclic nucleotides on renal phosphoinositide metabolism were studied using cortical tubules isolated from dog kidneys. PTH stimulated the initial rates of 32Pi incorporation into phosphatidylinositol 4'5'-diphosphate, phosphatidylinositol 4'-monophosphate, phosphatidylinositol and phosphatidic acid. PTH also caused a 45-55% increase in the actual tissue levels of these phospholipids by 5 min of incubation. By 30 min of incubation, the levels of 32Pi incorporated were similar in PTH and control flasks, but the actual levels of the phosphoinositides remained elevated, indicating stimulation of their turnover. Additional evidence of increased turnover of phosphatidylinositol was obtained from tubules pre-incubated with myo-[2-3H]inositol. PTH stimulated a rapid short-lived decrement in [3H]phosphatidylinositol while total phosphatidylinositol levels increased, indicating increased turnover rates of phosphatidylinositol. In tubules pre-incubated with [14C]arachidonic acid, indicating utilization of diacylglycerol produced during turnover for resynthesis of phosphatidic acid and phosphoinositides. Cyclic nucleotides and phosphodiesterase inhibition failed to reproduce the effect of PTH on phosphoinositide metabolism. These studies indicate that PTH stimulates renal phosphoinositide metabolism through a mechanism independent of cAMP which results in a net synthesis of the phosphoinositides.
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PMID:Parathyroid hormone stimulation of renal phosphoinositide metabolism is a cyclic nucleotide-independent effect. 628 7

A significant percent of parathyroid adenomas demonstrate decreased sensitivity to the suppressive effects of calcium on parathyroid hormone secretion. The recognition that calmodulin mediates a large number of calcium-dependent cellular events suggests that calmodulin may play a key role in the normal regulation by calcium of parathyroid activity. We therefore undertook to determine if parathyroid adenomas contained calmodulin and if so, if the calmodulin content of adenomas could be correlated with the serum concentrations of calcium and immunoreactive parathyroid hormone (IPTH) in hyperparathyroid patients prior to surgery. Calmodulin was assayed by activation of a calmodulin-stimulatable phosphodiesterase (PDE) obtained from rat brain. We found PDE-stimulating activity in each of six adenoma extracts examined. The stimulation had the following properties, which are characteristic of calmodulin-mediated processes: (1) it required the presence of calcium; (2) the dose response to adenoma extract and human red blood cell calmodulin were parallel, and (3) the stimulation was phenothiazine-inhibitable. The amount of calmodulin present in the adenoma extracts ranged from 0.4 to 1.25 units/micrograms protein. No correlation was found between the calmodulin content of the adenomas and the presurgical levels of either serum calcium or serum IPTH.
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PMID:Presence of calmodulin in parathyroid adenomas. 630 60

The effects of ethanol on parathyroid hormone (PTH)-induced increases in adenosine 3':5'-phosphate (cAMP) concentrations were studied in renal cortical tubules of hamsters in vitro. Ethanol concentrations between 0.1 and 3% were found to augment the PTH response in a dose-related way while, concentrations greater than 3% produced a dose-related inhibition of the PTH response. In the absence of PTH, ethanol did not significantly elevate cAMP accumulations at any concentrations tested. In contrast to its effect on intact tubule cells, ethanol did not alter either adenylate cyclase or phosphodiesterase in renal cortical homogenates. Indomethacin, however, produced a concentration-related inhibition of the ethanol-potentiated response without altering the effects of PTH alone. The results suggest a possible involvement of prostaglandins in the potentiating effect of ethanol on the PTH-dependent accumulation of cAMP in renal tubules.
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PMID:Enhancement by ethanol of parathyroid-hormone-stimulated cyclic AMP accumulation in isolated renal tubules. 630 64

Kidney function is regulated by several hormones which act through adenylate cyclase-cyclic AMP system. The present study was undertaken to investigate cyclic AMP- and cyclic GMP-phosphodiesterase (cAMP-PDE and cGMP-PDE respectively) activities in the rat kidney, and also the effect of several hormones affecting the kidney function on these enzyme activities in vitro. Rat kidneys were separated into cortex and medulla. These were homogenized in 50 mM Tris-HCl buffer, pH 7.5, containing 0.32 M sucrose and fractionated by centrifugation. PDE activity was measured in all fractions, using the two-step assay system. A low substrate concentration (0.5 microM) was used, unless otherwise stated. Substantial activity was present in all of the fractions and most of the activity existed in the soluble fraction (105000 X g supernatant). Cyclic GMP-PDE activity was dominant in both cortex and medulla. The rat kidney contained two forms of cAMP-PDE, one of which had a Km of 2.0 X 10(-4) M and another which had a low Km of 2.5 X 10(-5) M, and one form of cGMP-PDE with a Km of 2.5 X 10(-5) M. These cAMP-PDE and cGMP-PDE were purified by Sepharose-6B column chromatography. Cyclic AMP-PDE activity was found in a broad area associated with two peaks and cGMP-PDE activity had one peak corresponding to the same peak as the high molecular weight cAMP-PDE. Calmodulin was eluted after the peak of cGMP-PDE activity. Both cAMP-PDE and cGMP-PDE activities were inhibited by calcium ion at a concentration of more than 5.0 X 10(-4) M. Cyclic GMP-PDE activity was not activated by calmodulin in the presence of enough calcium ion. The effect of 1 alpha, 25(OH)2 Vit D3, parathyroid hormone (PTH), antidiuretic hormone (ADH), calcitonin (CT), angiotensin II, and trichlormethiazide on the partially purified cAMP-PDE and cGMP-PDE activities were examined. 1 alpha, 25(OH)2 Vit D3 activated cAMP-PDE activity and did not affect cGMP-PDE activity. The concentrations of 1 alpha, 25(OH)2 Vit D3 producing 50% activation of cAMP-PDE activity were 5.0 X 10(-11) M (cortex) and 6.7 X 10(-10) M (medulla). CT and ADH inhibited both cAMP-PDE activities. The concentrations of CT producing 50% inhibition of cAMP-PDE activity were 4.0 X 10(-5) M (cortex) and 3.3 X 10(-7) M (medulla), and those of cGMP-PDE activity were 1.0 X 10(-5) M (cortex) and 1.0 X 10(-4) M (medulla). Concerning ADH, the concentrations required for 50% inhibition of cAMP-PDE activity were 5.3 X 10(-6) M (cortex) and about 1.0 X 10(-3) M (medulla), and those of cGMP-PDE activity were 5.3 X 10(-3) M (cortex) and 5.3 X 10(-8) M (medulla).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Effect of several hormones on cyclic 3',5'-nucleotide phosphodiesterase in rat kidneys]. 631 6

We studied the effects of the positive-inotropic and hypotensive agent forskolin on parathyroid hormone (PTH) release, cAMP accumulation, and adenylate cyclase activity in dispersed bovine parathyroid cells. Forskolin stimulated PTH release 1.7 to 3.7-fold at 10(-5) mol/L and increased cAMP content maximally 37.6-fold at 10(-4) mol/L. Forskolin induced a maximal increase in cAMP accumulation by 5 minutes of incubation. The rate of PTH release in forskolin-treated cells also reached maximal levels at five to ten minutes of incubation. There was a dose-dependent increase in PTH release and cAMP content over the range of 10(-7) to 10(-4) M forskolin with half-maximal stimulation at 10(-7) to 10(-6) mol/L for PTH release and between 10(-5) and 10(-4) mol/L for cAMP content. PTH release and cAMP accumulation were inhibited by increasing extracellular calcium concentrations in both control cells and those incubated with 10(-5) mol/L forskolin. Forskolin stimulated adenylate cyclase activity in lysates from parathyroid cells 15.7-fold with half-maximal activation between 10(-6) and 10(-5) mol/L forskolin. Forskolin-stimulated (10(-5) mol/L) and basal adenylate cyclase activities declined in parallel with increasing calcium concentrations. In contrast, phosphodiesterase activity was unaffected by forskolin at 10(-6) to 10(-4) mol/L. Forskolin, therefore, by directly activating adenylate cyclase, enhances cAMP accumulation and PTH release in dispersed bovine parathyroid cells. As with other agents activating cAMP accumulation in this system, these effects are inhibited by elevated calcium concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Forskolin increases cellular cyclic adenosine monophosphate content and parathyroid hormone release in dispersed bovine parathyroid cells. 632 73

Purinergic P2 receptors are present on proximal renal tubules, but their function is unknown. Because P2 agonists antagonize vasopressin-stimulated water transport in the distal tubule by inhibiting activation of adenylyl cyclase, we postulated that P2 receptor activation blocks parathyroid hormone (PTH) inhibition of phosphate uptake in proximal tubule by preventing PTH-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) generation. PTH inhibition of sodium-dependent phosphate uptake was attenuated by alpha,beta-methylene-ATP (AMP-CPP), a P2x receptor agonist, but not by 2-methyl-thio-ATP, a P2y receptor agonist, in a dose-dependent manner. AMP-CPP did not attenuate inhibition of phosphate uptake produced by direct activation of adenylyl cyclase with forskolin, by addition of the cAMP analogue 8-bromo-cAMP, or by inhibition of cAMP phosphodiesterase with RO-20-1724. Additionally, AMP-CPP had no effect on basal or PTH-stimulated cAMP production. As PTH also stimulates protein kinase C activation, the effect of AMP-CPP on inhibition of phosphate uptake stimulated by phorbol 12-myristate 13-acetate (PMA) was tested. AMP-CPP had no effect on PMA-induced inhibition of phosphate uptake. Pretreatment with pertussis toxin abolished the attenuating effect of AMP-CPP on PTH inhibition of sodium-dependent phosphate uptake. We conclude that activation of purinergic P2 receptors attenuates the inhibitory effect of PTH on sodium-dependent phosphate uptake by a G protein-dependent mechanism that is independent of cAMP generation protein kinase A activation, or protein kinase C activation.
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PMID:P2 purinoceptor stimulation attenuates PTH inhibition of phosphate uptake by a G protein-dependent mechanism. 757 78

Adult ventricular cardiomyocytes have been identified as target cells for parathyroid hormone (PTH) but little is known about its signal transduction in these cells. In the present study the influence of PTH on cyclic AMP accumulation and the activity of protein kinase C (PKC) in cardiomyocytes was evaluated. A mid-regional synthetic fragment of PTH, PTH-(28-48), which exerts a hypertrophic effect on cardiomyocytes, increased the activity of membrane-associated PKC in a dose-dependent manner (1-100 nM). Activated membranous PKC was dependent on Ca2+ and sensitive to an inhibitor of Ca(2+)-dependent isoforms of PKC. When adenylate cyclase was stimulated by the addition of isoprenaline, a beta-adrenoceptor agonist, PTH-(28-48) antagonized cyclic AMP accumulation. This antagonistic effect of PTH-(28-48) could be mimicked by activation of PKC with a phorbol ester and inhibited by isobutylmethylxanthine, a phosphodiesterase inhibitor. An N-terminal synthetic fragment, PTH-(1-34), which includes an adenylate cyclase-activating domain, did not stimulate the accumulation of cyclic AMP in cardiomyocytes. The results demonstrate that in adult cardiomyocytes PTH (1) is able to stimulate PKC, (2) is not able to cause accumulation of cyclic AMP and (3) functionally antagonizes the effect of beta-adrenoceptor stimulation to increase cellular cyclic AMP concentrations via PKC-dependent phosphodiesterase activity.
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PMID:Parathyroid hormone induces protein kinase C but not adenylate cyclase in adult cardiomyocytes and regulates cyclic AMP levels via protein kinase C-dependent phosphodiesterase activity. 765 80

The effects of insulin-like growth factor-I (IGF-I) and IGF-II on the human osteoblast cell-line OHS-4 were investigated. Both IGF-I and IGF-II stimulated cell proliferation at nanomolar concentrations and alkaline phosphatase activity was decreased in a dose-dependent manner with either IGF-I or IGF-II. The production of the bone-specific protein osteocalcin was not influenced by either IGF-I or IGF-II. However, they acted synergistically with 1,25-dihydroxy-vitamin D3 at concentrations ranging from 10 to 100 nmol/l. Neither IGF-I nor IGF-II had an effect on either the basal or the parathyroid hormone-stimulated level of adenylate cyclase activity, and likewise they had no effect on phosphodiesterase activity. Binding and cross-linking experiments confirmed the presence of both type-I and type-II IGF receptors on the OHS-4 cells. The present study shows that IGF-I and IGF-II have similar effects on the parameters studied in these osteoblastic cells. They influenced both proliferation and differentiation markers.
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PMID:Comparison of the effects of insulin-like growth factors-I and -II on the human osteosarcoma cell line OHS-4. 842 72


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