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)

Parathyroid hormone acts on the osteoblast to induce osteoclastic bone resorption. Parathyroid hormone utilises cyclic AMP as a second messenger in osteoblasts, but may also cause an increase in cytoplasmatic free calcium ions ([Ca2+]i) in the same cell. To investigate the role of osteoblastic [Ca2+]i in the induction of bone resorption, we have compared the effects of parathyroid hormone and the Ca2+-ionophore, A23187, as well as the adenylate cyclase stimulating agent, forskolin, and the phorbol ester, phorbole 12,13 dibutyrate (PDB), on bone resorption in neonatal mouse calvarial bones. Parathyroid hormone (0.1 and 1 nM) dose dependently stimulated the release of prelabelled 45Ca2+ in 72 h culture. Parathyroid hormone-induced bone resorption was not affected by the addition of 1 microM indomethacin to the incubation media, and was therefore, not mediated by local prostaglandin formation. A23187 stimulated the release of 45Ca2+ at 1-10 nM. Above 100 nM, A23187 inhibited bone resorption. The A23187 (3 and 10 nM)-induced bone resorption was abolished by the cyclooxygenase inhibitor, indomethacin (1 microM), indicating that the stimulatory effect was mediated via prostaglandin formation. The adenylate cyclase stimulating agent, forskolin, dose dependently stimulated bone resorption at and above 1 microM. There was no additive or synergistic effect of forskolin and A23187 on 45Ca2+ release. Forskolin-induced bone resorption was, as with parathyroid hormone but in contrast to ionophore-induced bone resorption, not abolished by indomethacin (1 microM). The protein kinase C activator, PDB, at 10 and 1000 nM stimulated the release of prelabelled 45Ca2+. The stimulatory effect of the protein kinase C stimulating phorbol ester, PDB, on bone resorption was abolished by the addition of indomethacin. In summary, bone resorption induced by a Ca2+-ionophore is abolished by indomethacin. This indicates that bone resorbing agents known to increase [Ca2+]i subsequently enhance local prostaglandin formation. Bone resorption induced by the protein kinase C activator, PDB, was also abolished by indomethacin, whereas, forskolin and parathyroid hormone-induced bone resorption was unaffected. These data indicate that cyclic AMP, but not [Ca2+]i, is involved as a second messenger in parathyroid-induced bone resorption.
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PMID:Bone resorption induced by A23187 is abolished by indomethacin: implications for second messenger utilised by parathyroid hormone. 959 34

Parathyroid hormone (PTH) leads to the inhibition of Na-Pi cotransport activity and to the downregulation of the number of type II Na-Pi cotransporters in proximal tubules, as well as in opossum kidney (OK) cells. PTH is known also to lead to an activation of adenylate cyclase and phospholipase C in proximal tubular preparations, as well as in OK cells. In the present study, we investigated the involvement of these two regulatory pathways in OK cells in the PTH-dependent downregulation of the number of type II Na-Pi cotransporters. We have addressed this issue by using pharmacological activators of protein kinase A (PKA) and protein kinase C (PKC), i.e., 8-bromo-cAMP (8-BrcAMP) and beta-12-O-tetradecanoylphorbol 13-acetate (beta-TPA), respectively, as well as by the use of synthetic peptide fragments of PTH that activate adenylate cyclase and/or phospholipase C, i.e., PTH-(1-34) and PTH-(3-34), respectively. Our results show that PTH signal transduction via cAMP-dependent, as well as cAMP-independent, pathways leads to a membrane retrieval and degradation of type II Na-Pi cotransporters and, thereby, to the inhibition of Na-Pi cotransport activity. Thereby, the cAMP-independent regulatory pathway leads only to partial effects (approximately 50%).
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PMID:cAMP-dependent and -independent downregulation of type II Na-Pi cotransporters by PTH. 1033 54

Parathyroid hormone (PTH)-related protein (PTHrP) is present in the pancreatic islet. Recent data in transgenic mice suggest that PTHrP might modulate islet mass and insulin secretion. In the present study, we assessed the effect of the N-terminal PTH-like region of PTHrP on DNA synthesis in isolated rat islets. PTHrP (1-34), between 1 pM and 10 nM, for 48 h stimulated []thymidine incorporation into rat islets. This effect was maximally induced, about 2.5-fold over control, by 10 pM of this peptide, decreasing thereafter. In contrast, PTHrP (38-64) amide or PTHrP (107-139) were ineffective in increasing DNA synthesis in islets. Using reverse transcription followed by PCR, we confirmed that rat islets express PTHrP and the type I PTH/PTHrP receptor. Addition of a neutralizing anti-PTHrP antibody to the incubation medium of proliferating islets decreased islet DNA synthesis by 30%. The effect of a submaximal dose (30 pM) of PTHrP (1-34) on DNA synthesis in rat islets was abolished by 25 nM bisindolylmaleimide I, a protein kinase C (PKC) inhibitor, but not by 25 microM adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer, a protein kinase A inhibitor. Moreover, 100 nM phorbol-12-myristate-13-acetate for 48 h also increased DNA synthesis 2-fold over controls in islets. PTHrP (1-34), at 100 nM, in contrast to 50 microM forskolin or 10 mM NaF, failed to affect adenylate cyclase activity in islet membranes. PTHrP, at 30 pM, was also found to increase 2-fold insulin released into the islet-conditioned medium within 24-48 h. Our results suggest that PTHrP is a modulator of pancreatic islet growth and/or function by a PKC-mediated mechanism.
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PMID:Parathyroid hormone-related peptide stimulates DNA synthesis and insulin secretion in pancreatic islets. 1058 13

This paper documents for the first time a volume-sensitive Ca(2+) influx pathway in osteocytes, which transmits loading-induced signals into bone formation. Stretch loading by swelling rat and chicken osteocytes in hypo-osmotic solution induced a rapid and progressive increase of cytosolic calcium concentration, [Ca(2+)](i). The influx of extracellular Ca(2+) explains the increased [Ca(2+)](i) that paralleled the increase in the mean cell volume. Gadolinium chloride (Gd(3+)), an inhibitor of stretch- activated cation channels, blocked the [Ca(2+)](i) increase caused by hypotonic solutions. Also, the expression of alpha1C subunit of voltage-operated L-type Ca(2+) channels (alpha1C) is required for the hypotonicity-induced [Ca(2+)](i) increase judging from the effect of alpha1C antisense oligodeoxynucleotides. Parathyroid hormone (PTH) specifically potentiated the hypotonicity-induced [Ca(2+)](i) increase in a dose-dependent manner through the activation of adenyl cyclase. The increases induced by both PTH and hypotonicity were observed primarily in the processes of the osteocytes. In cyclically stretched osteocytes on flexible-bottomed plates, PTH also synergistically elevated the insulin-like growth factor-1 mRNA level. Furthermore, Gd(3+) and alpha1C antisense significantly inhibited the stretch-induced insulin-like growth factor-1 mRNA elevation. The volume-sensitive calcium influx pathways of osteocytes represent a mechanism by which PTH potentiates mechanical responsiveness, an important aspect of bone formation.
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PMID:Parathyroid hormone-activated volume-sensitive calcium influx pathways in mechanically loaded osteocytes. 1065 22

Parathyroid hormone (PTH)-related protein (PTHrP) is the main factor responsible for humoral hypercalcemia of malignancy. Both PTH and PTHrP bind to the common type I PTH/PTHrP receptor (PTHR), thereby activating phospholipase C and adenylate cyclase through various G proteins, in bone and renal cells. However, various normal and transformed cell types, including hypercalcemic Walker 256 (W256) tumor cells, do not produce cAMP after PTHrP stimulation. We characterized the PTHrP receptor and the signaling mechanism upon its activation in the latter cells. Scatchard analysis of PTHrP-binding data in W256 tumor cells revealed the presence of high affinity binding sites with an apparent K(d) of 17 nM, and a density of 90 000 sites/cell. In addition, W256 tumor cells immunostained with an anti-PTHR antibody, recognizing its extracellular domain. Furthermore, reverse transcription followed by PCR, using primers amplifying two different regions in the PTHR cDNA corresponding to the N- and C-terminal domains, yielded products from W256 tumor cell RNA which were identical to the corresponding products obtained from rat kidney RNA. Consistent with our previous findings on cAMP production, 1 microM PTHrP(1-34), in contrast to 10 microg/ml cholera toxin or 1 microM isoproterenol, failed to affect protein kinase A activity in W256 tumor cells. However, in these cells we found a functional PTHR coupling to G(alpha)(q/11), whose presence was demonstrated in these tumor cell membranes by Western blot analysis. Our findings indicate that W256 tumor cells express the PTHR, which seems to be coupled to G(alpha)(q/11). Taken together with previous data, these results support the hypothesis that a switch from the cAMP pathway to the phospholipase C-intracellular calcium pathway, associated with PTHR activation, occurs in malignant cells.
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PMID:Characterization of parathyroid hormone/parathyroid hormone-related protein receptor and signaling in hypercalcemic Walker 256 tumor cells. 1085 78

Parathyroid hormone (PTH) is known to have both catabolic and anabolic effects on bone. The dual functionality of PTH may stem from its ability to activate two signal transduction mechanisms: adenylate cyclase and phospholipase C. Here, we demonstrate that continuous treatment of UMR 106-01 and primary osteoblasts with PTH peptides, which selectively activate protein kinase C, results in significant increases in DNA synthesis. Given that ERKs are involved in cellular proliferation, we examined the regulation of ERKs in UMR 106-01 and primary rat osteoblasts following PTH treatment. We demonstrate that treatment of osteoblastic cells with very low concentrations of PTH (10(-12) to 10(-11) m) is sufficient for substantial increases in ERK activity. Treatment with PTH-(1-34) (10(-8) m), PTH-(1-31), or 8-bromo-cAMP failed to stimulate ERKs, whereas treatment with phorbol 12-myristate 13-acetate, serum, or PTH peptides lacking the N-terminal amino acids stimulated activity. Furthermore, the activation of ERKs was prevented by pretreatment of osteoblastic cells with inhibitors of protein kinase C (GF 109203X) and MEK (PD 98059). Treatment of UMR cells with epidermal growth factor (EGF), but not PTH, promoted tyrosine phosphorylation of the EGF receptor. Transient transfection of UMR cells with p21(N17Ras) did not block activation of ERKs following treatment with low concentrations of PTH. Thus, activation of ERKs and proliferation by PTH is protein kinase C-dependent, but stimulation occurs independently of the EGF receptor and Ras activation.
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PMID:Stimulation of extracellular signal-regulated kinases and proliferation in rat osteoblastic cells by parathyroid hormone is protein kinase C-dependent. 1110 12

Parathyroid hormone (PTH) and PTH-related peptide (PTH-RP) are two hypercalcemic hormones that share a common receptor subtype, the PTH/PTH-RP receptor. PTH and PTH-RP concentration dependently enhanced basal aldosterone and cortisol secretion from dispersed human adrenocortical cells, with a maximal effective concentration (approximately 2-fold increase) of 10(-8) M. The secretagogue effect of 10(-8) M PTH or PTH-RP was abolished by the PTH/PTH-RP receptor antagonist [Leu11,D-Trp12]-PTH-RP-(7-34)-amide (10(-6) M). PTH and PTH-RP (10(-8) M) raised cAMP and inositol-triphosphate release by dispersed adrenocortical cells, and these effects were blocked by the adenylate cyclase inhibitor SQ-22536 (10(-4) M) and the phospholipase C (PLC) inhibitor U-73122 (10(-5) M), respectively. SQ-22536 (10(-4) M) and U-73122 (10(-5) M) partially inhibited aldosterone and cortisol response to 10(-8) M PTH and PTH-RP; when added together, they abolished it. Similar results were obtained by using the protein kinase (PK)A and PKC inhibitors H-89 and calphostin C (10(-5) M). It is concluded that PTH and PTH-RP exert a sizeable secretagogue action on the human adrenal cortex, probably acting through the PTH/PTH-RP receptor coupled with both adenylate cyclase/PKA- and PLC/PKC-dependent signaling cascades.
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PMID:PTH and PTH-related peptide enhance steroid secretion from human adrenocortical cells. 1115 22

Parathyroid hormone (PTH)-related peptide (PTHrP) can modulate the proliferation and differentiation of a number of cell types including osteoblasts. PTHrP can activate a G protein-coupled PTH/PTHrP receptor, which can interface with several second-messenger systems. In the current study, we have examined the signaling pathways involved in stimulated type I collagen and alkaline phosphatase expression in the human osteoblast-derived osteosarcoma cells, MG-63. By use of Northern blotting and histochemical analysis, maximum induction of these two markers of osteoblast differentiation occurred after 8 h of treatment with 100 nM PTHrP-(1-34). Chemical inhibitors of adenylate cyclase (H-89) or of protein kinase C (chelerythrine chloride) each diminished PTHrP-mediated type I collagen and alkaline phosphatase stimulation in a dose-dependent manner. These effects of PTHrP could also be blocked by inhibiting the Ras-mitogen-activated protein kinase (MAPK) pathway with a Ras farnesylation inhibitor, B1086, or with a MAPK inhibitor, PD-98059. Transient transfection of MG-63 cells with a mutant form of Galpha, which can sequester betagamma-subunits, showed significant downregulation of PTHrP-stimulated type I collagen expression, as did inhibition of phosphatidylinositol 3-kinase (PI 3-kinase) by wortmannin. Consequently, the betagamma-PI 3-kinase pathway may be involved in PTHrP stimulation of Ras. Collectively, these results demonstrate that, acting via its G protein-coupled receptor, PTHrP can induce indexes of osteoblast differentiation by utilizing multiple, perhaps parallel, signaling pathways.
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PMID:Induction of osteoblast differentiation indexes by PTHrP in MG-63 cells involves multiple signaling pathways. 1150 Mar 4

Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) binding to their common receptor stimulates second messenger accumulation, receptor phosphorylation, and internalization. LLC-PK(1) cells expressing a green fluorescent protein-tagged PTH/PTHrP receptor show time- and dose-dependent receptor internalization. The internalized receptors colocalize with clathrin-coated pits. Internalization is stimulated by PTH analogs that bind to and activate the PTH/PTHrP receptor. Cell lines expressing a mutant protein kinase A regulatory subunit that is resistant to cAMP and/or a mutant receptor (DSEL mutant) that does not activate phospholipase C internalize their receptors normally. In addition, internalization of the wild-type receptor and the DSEL mutant is stimulated by the PTH analog [Gly(1),Arg(19)]hPTH-(1-28), which does not stimulate phospholipase C. Forskolin, IBMX, and the active phorbol ester, phorbol-12-myristate-13-acetate, did not promote receptor internalization or increase PTH-induced internalization. These data indicate that ligand-induced internalization of the PTH/PTHrP receptor requires both ligand binding and receptor activation but does not involve stimulation of adenylate cyclase/protein kinase A or phospholipase C/protein kinase C.
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PMID:Parathyroid hormone receptor internalization is independent of protein kinase A and phospholipase C activation. 1150 Mar 10

Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through at least three different transduction routes: Galpha s-mediated stimulation of adenylylcyclase (AC), Galpha q-mediated activation of phospholipase Cbeta (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative role of different pathways in human skin fibroblast proliferation. Using chemical inhibitors and activators of signal transduction, we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously activated following PTHrP binding to its receptors; (ii) the mitogenic response to PTHrP derives from a balance between two counteracting pathways--an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein kinase A (PKA); (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulated by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time, their point of divergence in mediating PTHrP dual and opposite mitogenic effects.
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PMID:ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts. 1256 42


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