Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid hormone and other bone resorptive agents function, at least in part, by inducing osteoblasts to secrete cytokines that stimulate both differentiation and resorptive activity of osteoclasts. We previously identified two potentially important cytokines by demonstrating that parathyroid hormone induces expression by osteoblasts of IL-6 and leukemia inhibitory factor without affecting levels of 14 other cytokines. Although parathyroid hormone activates multiple signal transduction pathways, induction of IL-6 and leukemia inhibitory factor is dependent on activation of adenyl cyclase. This study demonstrates that adenyl cyclase is also required for stimulation of osteoclast activity in cultures containing osteoclasts from rat long bones and UMR106-01 rat osteoblast-like osteosarcoma cells. Since the stimulation by parathyroid hormone of both cytokine production and bone resorption depends on the same signal transduction pathway, we hypothesized that IL-6 might be a downstream effector of parathyroid hormone. We found that addition of exogenous IL-6 mimics the ability of parathyroid hormone to stimulate bone resorption. More importantly, an antibody directed against the IL-6 receptor blocks moderate stimulation of osteoclast activity induced by the hormone. Interestingly, strong stimulation of resorption overcomes this dependence on IL-6. Thus, parathyroid hormone likely induces multiple, redundant cytokines that can overcome the IL-6 requirement associated with moderate stimulation. Taken together with studies showing that many other bone resorptive agents also stimulate IL-6 production, our results suggest that IL-6 may be a downstream effector of these agents as well as of parathyroid hormone.
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PMID:Adenyl cyclase and interleukin 6 are downstream effectors of parathyroid hormone resulting in stimulation of bone resorption. 765 97

1. It has been demonstrated that parathyroid hormone can increase adenylate cyclase activity in the rat papilla, produce a small antidiuretic effect and in vitro can interfere with the action of arginine vasopressin on water transport. Clearance studies were performed in the anaesthetized water diuretic thyroparathyroidectomized rat to evaluate further the effect of parathyroid hormone on urine concentration in the presence and absence of arginine vasopressin. 2. A maximal phosphaturic concentration of rat parathyroid hormone (2 micrograms/kg) reduced urine flow from 125 +/- 7 to 81 +/- 9 microliters/min within 10 min (P < 0.01). Addition of a maximal antidiuretic concentration of arginine vasopressin (100 ng/kg) produced a delayed and diminished antidiuretic response when compared with a group of rats not pretreated with parathyroid hormone (47 +/- 5 compared with 27 +/- 5 microliters/min; P < 0.01). However, a supramaximal arginine vasopressin concentration (1000 ng/kg) produced a maximal antidiuretic effect in the presence of parathyroid hormone. 3. To evaluate further the inhibitory effect of parathyroid hormone on arginine vasopressin-induced antidiuresis, parathyroid hormone (2 micrograms/kg) was administered to one group of rats and a minimally effective arginine vasopressin concentration (7.5 ng/kg) to another group, which produced a similar antidiuretic effect. However, the subsequent effect of a maximal antidiuretic arginine vasopressin concentration (100 ng/kg) was again significantly blunted in the group pretreated with parathyroid hormone. 4. Parathyroid hormone produced only a small increase in mean plasma calcium concentration, and glomerular filtration rate was not altered by either hormone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute effect of parathyroid hormone on urine concentration in the rat. 772 Mar 45

Urinary calcium excretion is regulated homeostatically. Regulation is achieved, in part, by the action of parathyroid hormone on Ca2+ absorption in the distal nephron. Parathyroid hormone increases Ca2+ absorption in the cortical portion of the thick ascending limb of Henle's loop in all species studied, in the murine distal convoluted tubule, and in the rabbit connecting tubule. All of these sites contain parathyroid hormone-stimulated adenylate cyclase. Both cellular and paracellular pathways of Ca2+ absorption are regulated by parathyroid hormone in the cortical portion of the thick ascending limb of Henle's loop. In both distal convoluted and connecting tubule cells, parathyroid hormone regulates transcellular Ca2+ absorption by controlling the insertion and open probability of luminal plasmalemmal Ca2+ ion channels. These channels are stimulated and inhibited by L-type calcium channel agonists and antagonists, respectively, but differ from similar channels in excitable cells in that membrane depolarization does not activate them. Parathyroid hormone also increases the driving force for diffusional Ca2+ ion entry from the luminal fluid into the cytosol by increasing the intracellular negative electrical potential (at least in murine distal convoluted tubule cells) by increasing the chloride ion conductance of the basolateral cell membrane. The effects of parathyroid hormone on the other components of cellular Ca2+ transport, via both protein kinases A and C and their interactions, remain to be examined.
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PMID:Parathyroid hormone action in calcium transport in the distal nephron. 774 58

Parathyroid hormone and parathyroid hormone-related protein lower blood pressure and relax contracted arteries. Parathyroid hormone also attenuates angiotensin II-induced vasoconstriction. To determine the cellular mechanism or mechanisms by which parathyroid hormone analogues antagonize pressor effects, we examined the effect of these peptides on angiotensin II-induced calcium mobilization in fura 2-AM-loaded cultured rat vascular smooth muscle cells. Either 100 nmol/L parathyroid hormone or parathyroid hormone-related protein significantly reduced the amount of calcium mobilized by 100 nmol/L angiotensin II. The attenuating effect of these peptides was mimicked by 10 mmol/L forskolin and 10 mmol/L isobutylmethylxanthine and was not dependent on the presence of extracellular calcium. This effect of the parathyroid hormone analogues was reduced when cells were pretreated with 100 mmol/L 2',5'-dideoxyadenosine, an adenylate cyclase inhibitor. Combined inhibition of cyclic nucleotide-dependent protein kinases eliminated the inhibitory effect of parathyroid hormone, whereas protein kinase C inhibition had no effect. Parathyroid hormone analogues decreased the amount of calcium released by inositol 1,4,5-trisphosphate in digitonin-permeabilized vascular smooth muscle cells. This effect was inhibited by treatment with 2',5'-dideoxyadenosine. These results suggest that these peptides attenuate inositol 1,4,5-trisphosphate-sensitive calcium mobilized by angiotensin II via an adenylate cyclase-dependent mechanism. This may be a mechanism by which acute administration of parathyroid hormone or parathyroid hormone-related peptide antagonizes vasoconstriction.
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PMID:Parathyroid hormone analogues inhibit calcium mobilization in cultured vascular cells. 812 68

Parathyroid hormone (PTH) has been shown to have actions within the brain, suggesting the presence of central PTH receptors. This possibility was examined by determining the binding of 125I-labeled [Nle8,18,Tyr34]bovine PTH to the plasma membranes of rat and rabbit brains. Specific binding of the tracer to membranes of the whole brain was time and tissue dependent, and was greater with membranes from the hypothalamus than with membranes from the cerebellum, cerebrum, or brain stem. The binding of the tracer to rat hypothalamic membranes was saturable and competitively displaced by unlabeled PTH(1-34), PTH(3-34), [Nle8,18,Tyr34]PTH(1-34), and by PTH-related protein, indicating the presence of a single class of high-affinity (dissociation constant = 2-5 nM), low-capacity (maximum binding capacity, Bmax = 110-250 fmol/mg protein) binding site. The binding of radiolabeled PTH to these sites was not displaced by unrelated peptides of comparable molecular size (calcitonin, calcitonin-gene related peptide, adrenocorticotropin). The binding of PTH to these sites did not, however, appear to stimulate adenylate cyclase activity, as in peripheral PTH target sites. Thus, although these results indicate the presence of PTH receptors in the brain, these binding sites have a lower affinity than those in peripheral tissues and may utilize a different signal transduction system.
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PMID:Parathyroid hormone binding sites in the brain. 813

Parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor expressed in rat cultured cortical type I astrocytes was identified and characterized. Northern blot analysis demonstrated that the PTH/PTHrP receptor mRNA is expressed in astrocytes. A human PTH fragment, PTH [1-34], stimulated adenylate cyclase with the EC50 value of 3 nM, but not phospholipase C. PTH [1-34] changed the morphology of protoplasmic type astrocytes into process-bearing ones. Thus, type I astrocytes possess PTH/PTHrP receptor that is coupled to an adenylate cyclase-activating system but not to phospholipase C.
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PMID:Identification and characterization of parathyroid hormone/parathyroid hormone-related peptide receptor in cultured astrocytes. 817 80

Parathyroid hormone related peptide (PTHrP), first identified in tumors from patients with the syndrome of "Humoral Hypercalcemia of Malignancy," can replace parathyroid hormone (PTH) in activating the PTH-receptor in responsive cells. Although PTHrP expression is widespread in various adult and fetal tissues, its normal biological function is as yet unknown. We have examined the possible role of PTHrP and the PTH/PTHrP-receptor in early mouse embryo development. Using F9 embryonal carcinoma (EC) cells and ES-5 embryonic stem (ES) cells as in vitro models, we demonstrate that during the differentiation of these cells towards primitive and parietal endoderm-like phenotypes, PTH/PTHrP-receptor mRNA is induced. This phenomenon is correlated with the appearance of functional adenylate cyclase coupled PTH/PTHrP-receptors. These receptors are the mouse homologues of the recently cloned rat bone and opossum kidney PTH/PTHrP-receptors. Addition of exogenous PTH or PTHrP to RA-treated EC or ES cells is an efficient replacement for dBcAMP in inducing full parietal endoderm differentiation. Endogenous PTHrP is detectable at very low levels in undifferentiated EC and ES cells, and is upregulated in their primitive and parietal endoderm-like derivatives as assessed by immunofluorescence. Using confocal laser scanning microscopy on preimplantation mouse embryos, PTHrP is detected from the late morula stage onwards in developing trophectoderm cells, but not in inner cell mass cells. In blastocyst stages PTHrP is in addition found in the first endoderm derivatives of the inner cell mass. Together these results indicate that the PTH/PTHrP-receptor signalling system serves as a para- or autocrine mechanism for parietal endoderm differentiation in the early mouse embryo, thus constituting the earliest hormone receptor system involved in embryogenesis defined to date.
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PMID:Parathyroid hormone-related peptide as an endogenous inducer of parietal endoderm differentiation. 838 Jan 75

The vascular actions of the hormones that participate in the regulation of whole animal calcium (Ca2+) homeostasis and related factors are discussed. Parathyroid hormone (PTH) has vasodilator activity that is mediated by a specific cell membrane receptor coupled to adenylate cyclase and thus increases intracellular cAMP and lowers intracellular Ca2+. The peptide may also block voltage-sensitive Ca2+ channels. However, the general consensus is that PTH does not achieve sufficient levels in the serum to modulate vascular reactivity. Parathyroid hormone does, however, share a common receptor and N-terminal amino acid sequence homology with parathyroid hormone-related peptide (PTHrp), which has many of the properties of a locally acting vascular regulator. Exciting actions of the steroid hormone, 1,25(OH)2 vitamin D3, have recently been described which suggest that the hormone is a vascular smooth muscle-differentiating agent and promises to set the stage for learning about the long-term modulatory actions of other steroid hormones. Calcitonin has minimal vascular actions, and although CGRP is not classifiable as a Ca(2+)-regulating hormone, it is a potent vasodilator neurotransmitter. Finally, within the past 2 years there has been a ground swell of activity surrounding the existence of the extracellular Ca2+ receptor that senses changes in interstitial Ca2+. The response of the smooth muscle cell to extracellular Ca2+ is discussed in the context of this receptor.
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PMID:Vascular actions of the calcium-regulating hormones. 858 14

Parathyroid hormone (PTH) activates both adenylate cyclase and phospholipase C in target cells, and cloned PTH/PTH-related protein (PTHrP) receptor can mediate both responses when expressed in host cells such as LLC-PK1 renal epithelial cells. Because calcitonin (CT) is known to augment 70-kDa heat shock protein (HSP70) mRNA by an adenosine 3',5'-cyclic monophosphate (cAMP)-independent mechanism in LLC-PK1 cells, we examined regulation of HSP70 transcription by PTH in these cells. Like CT, human PTH-(1-34) [hPTH-(1-34); 10(-10) to 10(-7) M)] increased porcine HSP70 mRNA and human HSP70 promoter-chloramphenicol acetyltransferase (CAT) expression within 4 h in LLC-PK1 cells that stably express > or = 100,000 PTH/PTHrP receptors per cell. The effect of PTH on HSP70 mRNA was not mimicked by cAMP analogues, forskolin, phorbol esters, Ca2+ ionophores, or alpha-thrombin; was insensitive to pertussis toxin; and was not due to increased mRNA stability. The upregulation of HSP70 gene transcription by hPTH (and CT) was clearly observed even after deletion of the functional heat shock consensus element in the promoter region of the human HSP70/CAT reporter. Upregulation of HSP70 transcription via endogenous PTH receptors also was observed in the osteoblastic cell lines SaOS-2 and ROS 17/2.8. Regulation of HSP70 gene transcription by PTH may be a common cellular response to the hormone, which, in some cells, may not be mediated by activation of adenylate cyclase or protein kinase C.
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PMID:Regulation of HSP70 by PTH: a model of gene regulation not mediated by changes in cAMP levels. 876 37

Parathyroid hormone (PTH) functions in part by regulating osteoblast cytokine expression. We recently demonstrated that PTH induced a rapid and transient increase in interleukin-6 (IL-6) mRNA expression in rat bones in vivo. To determine the molecular basis of this effect, we analyzed the human IL-6 promoter fused (-1,179 to +9) with the chloramphenicol acetyltransferase (CAT) reporter gene in stable transfections into human osteoblast-like osteosarcoma SaOS-2 cells. We compared the effects of PTH on IL-6 expression with adenylate cyclase activator forskolin, PKC activator phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187, interleukin-1 alpha (IL-1 alpha), prostaglandin E-2 (PGE-2), RS-66271 (a parathyroid hormone-related peptide analog), and platelet-derived growth factor-BB (PDGF-BB). Analyses of cell clones showed that IL-6 promoter expression was extremely low in the unstimulated state. Exposure to PTH (0.001-100 nM) for 12 h stimulated CAT expression in a dose-dependent manner (200-500% of control). Treatment with IL-1 alpha was more potent than PTH in inducing transcription of the IL-6 promoter (900-1,000%). Activation of the cAMP-PKA pathway by treatment with forskolin induced a comparable level of induction with PTH. Together, the effects of PTH and forskolin were additive. RS-66271, previously shown to have PTH-like effects, induced a comparable level of IL-6 promoter expression. When examined together, PTH+RS-66271 effects were comparable to PTH effects alone. Exposure to PGE-2, PMA, PDGF-BB, or A23187 for 12 h did not significantly alter IL-6 promoter expression. These results demonstrate PTH, forskolin, the PTHrP analog RS-66271, and IL-1 alpha stimulate IL-6 expression by stimulating gene transcription. The response to forskolin suggests that the messenger system mediated by PKA is sufficient to induce IL-6 expression.
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PMID:Parathyroid hormone (1-34)-mediated interleukin-6 induction. 932 32


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