scholarly journals Parathyroid hormone and prostaglandin E2 stimulate both inositol phosphates and cyclic AMP accumulation in mouse osteoblast cultures

1988 ◽  
Vol 252 (1) ◽  
pp. 263-268 ◽  
Author(s):  
R W Farndale ◽  
J R Sandy ◽  
S J Atkinson ◽  
S R Pennington ◽  
S Meghji ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Prostaglandin E2 ◽  
Intracellular Calcium ◽  
Bone Cells ◽  
Inositol Phosphates ◽  
Bone Matrix ◽  
Bone Cell ◽  
Cyclic Amp Accumulation

Parathyroid hormone (PTH) and prostaglandin E2 (PGE2) are physiological agonists which stimulate bone cells to resorb bone, a process by which the mineralized extracellular bone matrix is dissolved. Bone resorption has a key role in the maintenance of plasma calcium levels. It has been established that both PTH and PGE2 activate adenylate cyclase in osteoblasts, but it is apparent that (1) the two agents have qualitatively different effects on osteoblasts, and (2) the generation of cyclic AMP cannot account for all the effects of PTH on bone cell metabolism. Others have demonstrated that PTH and PGE2 may also elevate intracellular calcium levels, but the mechanism by which this is achieved has not been fully defined. Here we have investigated the effects of PTH on neonatal mouse osteoblasts in culture and shown that physiological concentrations of the hormone (50 nM) caused a small increase (22%) in total inositol phosphates accumulation, with a larger increase (40%) in inositol trisphosphate. We found that this activation occurred at lower concentration than was necessary to activate adenylate cyclase. PGE2 was a more effective activator of inositol phosphates accumulation than PTH, causing up to 300% increase in the total inositol phosphates after 30 min. Both PTH and PGE2 stimulated cyclic AMP accumulation, but the activation of adenylate cyclase by forskolin did not enhance inositol phosphates production. We conclude that both PTH and PGE2 stimulate phosphoinositide turnover in mouse osteoblasts and suggest that this mechanism may contribute to their elevation of intracellular calcium in bone cells.

scholarly journals Stimulation of creatine kinase BB activity by parathyroid hormone and by prostaglandin E2 in cultured bone cells

1985 ◽  
Vol 225 (3) ◽  
pp. 591-596 ◽  
Author(s):  
D Sömjen ◽  
A M Kaye ◽  
I Binderman
Keyword(s):  
Creatine Kinase ◽  
Parathyroid Hormone ◽  
Prostaglandin E2 ◽  
Bone Cells ◽  
Combined Treatment ◽  
Fold Increase ◽  
Bone Cell ◽  
Growth Promoters ◽  
Bone Cell Cultures ◽  
Stimulation Of

Bone cells in culture responded to parathyroid hormone (PTH) and prostaglandin E2 (PGE2) by a 2-fold increase in creatine kinase (CK) activity. Combined treatment resulted in a higher response than with PTH alone. Calcitonin (CT) failed to stimulate CK activity, did not affect the response of CK to PTH, but inhibited slightly the increase in CK activity by PGE2. Bone-cell cultures grown in low [Ca2+] (0.125 mM), enriched in PTH-responsive osteoblast-like cells, responded to PTH, but not to PGE2 or CT, by increased CK activity. In both normal and low-[Ca2+] cultures, 8-bromo cyclic AMP did not affect CK activity, nor did it change the response of the cells to PTH, PGE2 or CT. The increase in CK activity was time- and dose-dependent and inhibited both by cycloheximide and by actinomycin D. The isoenzyme of CK stimulated was the CKBB form, the isoenzyme induced by other hormones. This appears to be the first report of the stimulation of CK activity by a polypeptide hormone or a prostaglandin. We suggest that stimulation of CKBB can serve as a marker for the action of a variety of hormones and growth promoters.

scholarly journals 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

1995 ◽  
Vol 310 (2) ◽  
pp. 439-444 ◽  
Author(s):  
K D Schlüter ◽  
M Weber ◽  
H M Piper
Keyword(s):  
Protein Kinase C ◽  
Parathyroid Hormone ◽  
Protein Kinase ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Phosphodiesterase Activity ◽  
Beta Adrenoceptor ◽  
Kinase C ◽  
Adult Cardiomyocytes ◽  
Cyclic Amp Accumulation

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.

scholarly journals Prostaglandins and muscarinic agonists induce cyclic AMP attenuation by two distinct mechanisms in the pregnant-rat myometrium. Interaction between cyclic AMP and Ca2+ signals

1990 ◽  
Vol 271 (3) ◽  
pp. 667-673 ◽  
Author(s):  
O Goureau ◽  
Z Tanfin ◽  
S Harbon
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Pertussis Toxin ◽  
Inositol Phosphates ◽  
Indirect Evidence ◽  
Maximal Response ◽  
Muscarinic Agonist ◽  
Phosphodiesterase Activity ◽  
Pregnant Rat ◽  
Cyclic Amp Accumulation

In pregnant-rat myometrium (day 21 of gestation), isoprenaline-induced cyclic AMP accumulation, resulting from receptor-mediated activation of adenylate cyclase, was negatively regulated by prostaglandins [PGE2, PGF2 alpha; EC50 (concn. giving 50% of maximal response) = 2 nM] and by the muscarinic agonist carbachol (EC50 = 2 microM). PG-induced inhibition was prevented by pertussis-toxin treatment, supporting the idea that it was mediated by the inhibitory G-protein Gi through the inhibitory pathway of the adenylate cyclase. Both isoprenaline-induced stimulation and PG-evoked inhibition of cyclic AMP were insensitive to Ca2+ depletion. By contrast, carbachol-evoked attenuation of cyclic AMP accumulation was dependent on Ca2+ and was insensitive to pertussis toxin. The inhibitory effect of carbachol was mimicked by ionomycin. Indirect evidence was thus provided for the enhancement of cyclic AMP degradation by a Ca2(+)-dependent phosphodiesterase activity in the muscarinic-mediated effect. The attenuation of cyclic AMP elicited by carbachol coincided with carbachol-stimulated inositol phosphate (InsP3, InsP2 and InsP) generation, which displayed an almost identical EC50 (3 microM) and was similarly unaffected by pertussis toxin. Both carbachol effects were reproduced by oxotremorine, whereas pilocarpine (a partial muscarinic agonist) failed to induce any decrease in cyclic AMP accumulation and concurrently was unable to stimulate the generation of inositol phosphates. These data support our proposal for a carbachol-mediated enhancement of a Ca2(+)-dependent phosphodiesterase activity, compatible with the rises in Ca2+ associated with muscarinic-induced increased generation of inositol phosphates. They further illustrate that a cross-talk between the two major transmembrane signalling systems contributed to an ultimate decrease in cyclic AMP in the pregnant-rat myometrium near term.

Protein kinase C activating phorbolesters enhance the cyclic AMP response to parathyroid hormone, forskolin and choleratoxin in mouse calvarial bones and rat osteosarcoma cells

1991 ◽  
Vol 11 (4) ◽  
pp. 203-211 ◽  
Author(s):  
Maria Ransjö
Keyword(s):  
Protein Kinase C ◽  
Parathyroid Hormone ◽  
Protein Kinase ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Phorbol Esters ◽  
Osteosarcoma Cells ◽  
Kinase C ◽  
Cyclic Amp Accumulation ◽  
Umr 106

The protein kinase C-(PKC) activating phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nmol/l) and phorbol 12, 13-dibutyrate (PDBU; 100 nmol/l) enhanced basal cyclin AMP accumulation in cultured neonatal mouse calvaria. The cyclic AMP response to parathyroid hormone (PTH; 10 nmol/l) and the adenylate cyclase activators forskolin (1–3 μmol/l) and choleratoxin (0.1 μmg/ml) was potentiated in a more than additive manner by TPA and PDBU. In contrast, phorbol 13-monoacetate (phorb-13; 100 nmol/l), a related compound but inactive on PKC, had no effect on basal or stimulated cyclic AMP accumulation. In the presence of indomethacin (1μmol/l), TPA and PDBU had no effect on cyclic AMP accumulation in calvarial bones per se, but were still able to cause a significant enhancement of the response to PTH, forskolin and choleratoxin. PTH-, forskolin- and choleratoxin-stimulated cyclic AMP accumulation in rat osteosarcoma cells UMR 106-01 was synergistically potentiated by TPA and PDBU, but not by phorb.-13. These data indicate that PKC enhances cyclic AMP formation and that the level of interaction may be at, or distal to, adenylate cyclase.

Effect of Diphosphonates on Adenosine 3′:5′-Cyclic Monophosphate in Mouse Calvaria after Stimulation by Parathyroid Hormone in vitro

1976 ◽  
Vol 50 (6) ◽  
pp. 473-478
Author(s):  
U. Gebauer ◽  
R. G. G. Russell ◽  
M. Touabi ◽  
H. Fleisch
Keyword(s):  
Parathyroid Hormone ◽  
Bone Resorption ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Bone Cells ◽  
Essential Feature ◽  
Cyclic Monophosphate ◽  
Inhibit Bone Resorption ◽  
Mouse Calvaria

1. The diphosphonates, disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) and disodium dichloromethylene diphosphonate (Cl2MDP), inhibit bone resorption in animals and in explanted bone in tissue culture. The possibility that these effects might be due to inhibition of skeletal adenylate cyclase has been studied. 2. EHDP and Cl2MDP, added for 30 mm to the incubation medium at concentrations known to inhibit bone resorption, had no effect on basal content of adenosine 3′:5′-cyclic monophosphate (cyclic AMP) of mouse calvaria incubated in vitro, nor did they inhibit the rise in cyclic AMP induced by bovine parathyroid hormone. 3. Pretreatment of mice for 3 days with Cl2MDP also had no effect on cyclic AMP under basal conditions or after incubation of explanted calvaria with parathyroid hormone in vitro. EHDP under similar conditions slightly inhibited the increase induced by parathyroid hormone but had no effect on basal concentrations of cyclic AMP. 4. It is suggested that the inhibition of adenylate cyclase is not an essential feature of the reduction of bone resorption by diphosphonates, which may act by direct inhibitory effects on the dissolution of hydroxyapatite and perhaps by other unidentified effects on bone cells.

Interaction between parathyroid hormone and prostaglandin E1 on cyclic AMP metabolism in rat kidney

1980 ◽  
Vol 93 (3) ◽  
pp. 339-345 ◽  
Author(s):  
Naokazu Nagata ◽  
Yuriko Ono ◽  
Narimichi Kimura
Keyword(s):  
Parathyroid Hormone ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Rat Kidney ◽  
Prostaglandin E ◽  
Cortical Tissue ◽  
Newborn Rat ◽  
Simultaneous Addition ◽  
Renal Cortical Tissue ◽  
Subsequent Addition

Abstract. The interaction between parathyroid hormone (PTH) and prostaglandin E1 (PGE1) in influencing cyclic AMP metabolism in rat renal cortical tissue was examined. PTH and PGE1 stimulated additively the adenylate cyclase activity in the homogenate of the tissue. Both PTH and PGE1 enhanced the level of cyclic AMP in the incubated renal cortical tissue, but the effect of their simultaneous addition did not exceed the effect induced by PTH alone. Cyclic AMP accumulated in the incubation medium by stimulation by PTH was decreased by the simultaneous addition of PGE1. When the tissue was pre-incubated for 30 min with 2 to 10 μg/ml of PGE1, the magnitude of the increase of cyclic AMP caused by PTH subsequently added was lessened. However, the response to PTH of adenylate cyclase preparation obtained from the homogenate of PGE1-pre-treated tissue was not decreased. When first PTH was added to the incubating renal cortical tissue, the subsequent addition of PGE1 accelerated the decrease of cyclic AMP content in the tissue and decreased the amount of cyclic AMP released from the tissue. The interaction of PTH and PGE1 on cyclic AMP metabolism in the renal cortical tissue was in contrast to that seen in newborn rat calvaria where PGE1 and PTH acted additively in enhancing the level of cyclic AMP.

Induction And Potentiation Of Platelet Aggregation By Clonidine And 7ρ-Aminoclonidine, Partial Agonists Of The α2-Receptor Which Regulates Platelet Adenylate Cyclase

1981 ◽  
Author(s):  
David C Stump ◽  
Donald E Macfarlane
Keyword(s):  
Platelet Aggregation ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Specific Binding ◽  
Phase 1 ◽  
Intrinsic Activity ◽  
Second Phase ◽  
Adrenergic Agents ◽  
Cyclic Amp Accumulation ◽  
Induced Aggregation

Epinephrine induces platelet aggregation, potentiates aggregation by other agents, and blocks the stimulation of the adenylate cyclase by prostaglandins. Synthetic α-adrenergic agents have not been shown to induce aggregation. The effects of clonidine, an α2-agonist, and ρ-aminoclonidine on platelets were examined. Clonidine potentiated aggregation induced by 0.5μM ADP by 1.4-fold (1/2 max 0.5μM). It did not induce significant aggregation itself, and it inhibited aggregation induced by 5μM epinephrine (1/2 max lμM). It inhibited cyclic AMP accumulation induced by PGE1 by a maximum of 25% (1/2 max O.lμM) and it blocked inhibition by epinephrine. No significant specific binding of [3H] clonidine was observed to intact platelets. ρ-Aminoclonidine induced aggregation with delayed second phase (1/2 max 0.2μM), and potentiated ADP aggregation by 2-fold (1/2 max 0.2μM). Aggregation induced by epinephrine was more rapid, and was partially inhibited by ρ-aminoclonidine. It inhibited cyclic AMP accumulation by 50% max (1/2 max O.lμM) and attenuated epinephrine’s effect to the same level. The direct effects of ρ-aminoclonidine were blocked by lμM yohimbine, a selective α2-antagonist. Both clonidine and ρ—aminoclonidine blocked the specific binding of [3H]yohimbine (1/2 max 0.5μM). These results suggest that the platelet bears an α2-receptor with affinity for epinephrine, ρ-aminoclonidine and clonidine as agonists but that these agents display differing intrinsic activity and/or receptor reserve.

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