Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was designed to characterize the cross-talk of parathyroid hormone (PTH)-responsive dual signal transduction systems (cAMP-dependent protein kinase (PKA) and calcium/protein kinase C [PKC]) and its participation in PTH-induced homologous desensitization of intracellular calcium ([Ca2+]i) in osteoblastic UMR-106 cells. Although our recent study revealed that prolonged (more than 2 h) pretreatment with PKC-activating phorbol ester, phorbol 12-myristate 13-acetate (PMA) significantly decreased the PTH-stimulated cAMP production, pretreatment with PMA (10(-7) and 10(-6) M) but not 10(-6) M 4 alpha-phorbol 12,13-didecanoate (PDD), incapable of activating PKC for 30 min significantly augmented 10(-7) M hPTH-(1-34)-stimulated cAMP production. H-7 (50 microM), a PKC inhibitor, significantly antagonized this PMA-induced effect. Pretreatment with 10(-6) M PMA for 30 min did not affect PTH receptor binding but significantly augmented a cAMP responsiveness to 10(-5) M forskolin and 1 microgram/ml cholera toxin. Pertussis toxin (0.5 microgram/ml) did not affect the PMA-induced augmentation of the PTH-stimulated cAMP production. PTH caused a complete homologous desensitization of [Ca2+]i response within 30 min. Pretreatment with 10(-4) M dibutyryl cAMP for 30 min and 6 h significantly reduced and completely blocked the PTH-induced increase in [Ca2+]i, respectively. Pretreatment with 10(-4) M Sp-cAMPs, a direct PKA activator, for 30 min completely blocked the PTH-induced increase in [Ca2+]i. Rp-cAMPS (10(-4) M), an antagonist of PKA, slightly but significantly antagonized the PTH-induced homologous desensitization of [Ca2+]i response. The present study indicates that the time of exposure to PKC activation is a critical determinant in modulating the cAMP system, while PKA activation counterregulatorily acts on the [Ca2+]i system, and that PKA activation is linked to the PTH-induced homologous desensitization of [Ca2+]i response.
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PMID:Cross-talk of parathyroid hormone-responsive dual signal transduction systems in osteoblastic osteosarcoma cells: its role in PTH-induced homologous desensitization of intracellular calcium response. 810 73

We have previously shown that parathyroid hormone (PTH)-(1-34) or its analogue PTH-(3-34) inhibits proximal tubule (PT) Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity independently of adenosine 3',5'-cyclic monophosphate generation. The present study used PT suspensions to investigate the signaling pathway responsible for this hormonal action. PTH-(1-34) and PTH-(3-34) significantly increased the release of arachidonic acid (AA) compared with control tubules, suggesting activation of phospholipase A2 (PLA2). AA, 10(-6) M, mimicked the inhibition of the pump by 10(-8) M PTH-(3-34), and together were not additive. Eicosatetraynoic acid, 3 microM, a general inhibitor of AA metabolism, blocked the PTH action. Indomethacin, 10 microM, an inhibitor of AA-dependent cyclooxygenase, did not prevent the PTH action, but 2 microM 7-ethoxyresorufin, a cytochrome P-450 inhibitor, prevented the PTH effect. 20-Hydroxyeicosatetraenoic acid (20-HETE), the main product of P-450 metabolism in PT, inhibited Na(+)-K(+)-ATPase activity to the same extent as 10(-8) M PTH-(3-34), was not additive with PTH, and was maximally inhibitory at 10(-7) M. To further investigate the signaling pathway responsible for PTH-activated PLA2, we tested the effect of PTH on cytoplasmic free Ca2+ ([Ca2+]i). PTH-(1-34), 10(-7) M, did not affect [Ca2+]i, although 10(-8) M angiotensin II promoted a Ca2+ transient. Treatment of PT with pertussis toxin (PTX) did not prevent the PTH action.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Parathyroid hormone inhibits Na(+)-K(+)-ATPase through a cytochrome P-450 pathway. 816 Aug

Neuronal effects of parathyroid hormone (PTH) have been reported in vertebrates. The effect of PTH on invertebrate central neurons within the buccal ganglion of Helisoma trivolvis snails was examined in the present study. By using a vibrating probe, PTH was found to induce a transient calcium-dependent inward current in intact buccal ganglia. Intracellular microelectrode recording revealed that PTH broadened the spontaneous action potential in buccal B5 neurons in situ. By using the whole-cell configuration of the patch-clamp technique, PTH was demonstrated to increase the N-like calcium channel currents in isolated B5 neurons in a concentration-dependent manner. This effect of PTH on the N-like calcium channel currents depended on the activation of a G protein insensitive to pertussis toxin, but was unlikely to be mediated by the cyclic AMP dependent protein kinase. Furthermore, the release of gamma-glutamyl conjugate of dopamine from buccal ganglia was selectively increased in the presence of PTH. These results represent the first demonstration that a vertebrate peptide hormone, PTH, selectively modulates the N-like voltage-dependent calcium channel currents in identified invertebrate neurons. Therefore, a novel role of PTH in the regulation of invertebrate central neural functions is indicated.
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PMID:Neural effects of parathyroid hormone: modulation of the calcium channel current and metabolism of monoamines in identified Helisoma snail neurons. 830 96

The heart is a target organ for parathyroid hormone (PTH), and the action of this hormone on the myocardium may be mediated through the ability of PTH to increase cytosolic calcium ([Ca2+]i) in the myocardial cells. However, direct evidence for such an effect of PTH is lacking, and the mechanism(s) through which the hormone can potentially exert such an effect have not been elucidated. In the present study these questions were examined using cardiac myocytes isolated from adult rats. Both PTH-(1-34) and PTH-(1-84) produced a dose-dependent increase in [Ca2+]i of myocytes, but the effect of the latter was significantly (P < 0.01) greater than the former. This action of PTH was abolished by the inactivation of the hormone, the use of a PTH antagonist, or by verapamil. The G protein activator, guanosine 5'-O-(3-thiothriphosphate) (GTP gamma S), mimicked the effect of PTH, whereas pertussis toxin, the G protein inhibitor, guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), or ryanodine significantly reduced the PTH-induced rise in [Ca2+]i. Dibutyryl- and 8-bromoadenosine-3',5'-cyclic monophosphate, forskolin, 12-O-tetradecanoylphorbol 13-acetate, and staurosporine did not increase [Ca2+]i in myocytes, and staurosporine did not alter the PTH-induced rise in [Ca2+]i. BAY K 8644 augmented the effect of PTH on [Ca2+]i. These data demonstrate that 1) PTH increases [Ca2+]i of cardiac myocytes, 2) this action is receptor mediated and is produced by activation of the L-type calcium channels following stimulation of G protein(s), and 3) the rise in [Ca2+]i is due to both augmented entry of calcium into the myocytes and mobilization of calcium from sarcoplasmic reticulum by a calcium-induced calcium release mechanism.
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PMID:Parathyroid hormone increases cytosolic calcium concentration in adult rat cardiac myocytes. 832 30

We examined the role of angiotensin II (AII) receptor subtypes in the regulation of hormone-stimulated cyclic AMP (cAMP) accumulation in isolated rat glomeruli. All inhibited cAMP formation induced by histamine, serotonin and parathyroid hormone, but not by prostaglandin E2 or calcitonin gene-related peptide. Angiotensin III but not the angiotensin fragments (1-7) and (3-8) also showed inhibitory activity. The inhibition of histamine-induced cAMP accumulation by AII was concentration-dependent and was absent in glomeruli isolated from pertussis toxin-treated rats. The effect of AII on histamine-induced cAMP levels was not mimicked by the protein kinase C activator, phorbol-12-myristate-13-acetate, nor was the effect of AII inhibited by the protein kinase C inhibitors, staurosporine and H-7. The angiotensin II receptor subtype 1 (AT1) antagonists, SK&F 108566 and losartan, attenuated the inhibitory effect of AII on histamine-stimulated cAMP accumulation, whereas the AT2 selective antagonists, CGP 42112A, WL-19 and PD 123319, had no effect. Displacement of [125I]AII from glomerular membrane using the subtype-selective antagonists confirmed that the glomerular AII receptor has characteristics of an AT1 subtype. The results suggest that AII, through activation of the AT1 receptor, may act to maintain the contractile state of glomerular mesangial cells by attenuating the increase in cAMP levels induced by some hormones.
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PMID:Angiotensin II inhibits glomerular adenylate cyclase via the angiotensin II receptor subtype 1 (AT1). 839 7

The involvement of dopamine (DA) receptor subtypes in regulation of renal phosphate transport by DA, either exogenous or locally synthesized from L-dihydroxyphenylalanine (L-dopa) was evaluated in opossum kidney (OK) cells with proximal tubular phenotype. DA synthesis from L-dopa by OK cells was abolished by carbidopa and benserazide, two dissimilar inhibitors of aromatic L-amino acid decarboxylase. L-Dopa stimulated cyclic AMP generation and inhibited Na-dependent Pi uptake, and these effects were abolished by carbidopa and benserazide. The effects of L-dopa or DA on cyclic AMP generation and on Na-Pi co-transport were mimicked by SKF 38393, a DA1 receptor agonist, and were potentiated by S-sulpiride, a DA2 receptor antagonist. Bromocriptine, a DA2 receptor agonist, blunted in a pertussis toxin-dependent manner parathyroid hormone (PTH)-induced cyclic AMP generation and inhibition of Pi uptake. In contrast with PTH, neither L-dopa nor DA affected significantly the cytosolic calcium concentration. These results support the involvement of DA1 and DA2 receptors, positively and negatively coupled into adenylate cyclase respectively, in modulation of renal phosphate transport.
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PMID:Locally formed dopamine modulates renal Na-Pi co-transport through DA1 and DA2 receptors. 852 52

The effects of alpha 2-adrenergic receptors are usually attributed to inhibition of adenylyl cyclase through pertussis toxin-sensitive Gi coupling. In kidney distal convoluted tubule (DCT) cells, stimulation of Na+/K(+)-ATPase by alpha 2 receptors involves activation of protein kinase C (PKC). To identify the signal pathways coupled to alpha 2 receptors, we measured cAMP production and show that the alpha 2 agonist B-HT 933 had no effect on basal or stimulated (forskolin, parathyroid hormone) cAMP accumulation in DCT cells but inhibited parathyroid hormone-stimulated cAMP accumulation in proximal tubule cells. I tested whether alpha 2 receptors on DCT cells stimulate PKC through second messengers generated from phospholipase C (PLC) activation. In DCT cells, B-HT 933 increased inositol-1,4,5-trisphosphate formation by 4-6-fold over control and increased diacylglycerol formation by 46%. Basal intracellular calcium concentration in single DCT cells averaged 114 nM and increased within 2 min to 196 nM with B-HT 933. Treatment with the PLC inhibitor U-73122 but not pertussis toxin blocked B-HT 933-induced rises in inositol-1,4,5-trisphosphate and intracellular calcium concentration. B-HT 933 increased PKC activity by 45% over control in DCT cells. These findings provide evidence that alpha 2-adrenergic receptors activate PLC in DCT cells through a pertussis toxin-insensitive mechanism.
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PMID:Alpha 2-adrenergic receptors activate phospholipase C in renal epithelial cells. 870 Jan 50

Extracellular cations have paradoxical trophic and toxic effects on osteoblast function. In an effort to explain these divergent actions, we investigated in MC3T3-E1 osteoblasts if polyvalent cations differentially modulate the agonist-stimulated cyclic adenosine monophosphate (cAMP) pathway, an important regulator of osteoblastic function. We found that a panel of cations, including gadolinium, aluminum, calcium, and neomycin, inhibited prostaglandin E1 (PGE)-stimulated cAMP accumulation but paradoxically potentiated parathyroid hormone (PTH)-stimulated cAMP production. In contrast, these cations had no effect on forskolin- or cholera toxin-induced increases in cAMP, suggesting actions proximal to adenylate cyclase and possible modulation of receptor interactions with G proteins. Phorbol 12-myristate 13-acetated (PMA) mimicked the effects of cations on PGE1- and PTH-stimulated cAMP accumulation in MC3T3-E1 cells, respectively, diminishing and augmenting the responses. Moreover, down-regulation of protein kinase C (PKC) by overnight treatment with PMA prevented gadolinium (Gd3+) from attenuating PGE1- and enhancing PTH-stimulated cAMP production, indicating involvement of PKC-dependent pathways. Cations, however, activated signal transduction pathways not coupled to phosphatidylinositol-specific phospholipase C (PI-PLC), since there was no corresponding increase in inositol phosphate formation or intracellular calcium concentrations. In addition, pertussis toxin treatment failed to prevent Gd(3+)-mediated suppression of PGE1-stimulated cAMP, suggesting actions independent of Gm. Thus, polyvalent cations may either stimulate or inhibit hormone-mediated cAMP accumulation in osteoblasts. These differential actions provide a potential explanation for the paradoxical trophic and toxic effects of cations on osteoblast function that occur in vivo under different hormonal conditions.
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PMID:Differential regulation of receptor-stimulated cyclic adenosine monophosphate production by polyvalent cations in MC3T3-E1 osteoblasts. 872 76

We previously reported the preparation and partial characterization of a series of human embryonic kidney cell lines (HEK-293) stably expressing various numbers of the recombinant human (h) parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (Rc). Using this expression system we examined ligand (PTH or PTHrP) binding characteristics and cyclic AMP responsiveness. We have now extended these studies to investigate the calcium signal transduction pathways activated by the hPTH/PTHrP Rc. In parental HEK-293 cells, which lack endogenous PTH/PTHrP Rc, incubation with hPTH(1-34) had no effect on cytosolic free Ca2+ concentration [Ca2+]i. In HEK-293 clone C-21, stably expressing approximately 400,000 Rc/cell, PTH stimulated an increase in [Ca2+]i by Ca2+ release from intracellular stores; PTH released Ca2+ exclusively from the IP3 sensitive Ca2+ pool. Unlike previous studies, the ability of PTH to elicit both cAMP responses and [Ca2+]i transients occurred over a wide range of Rc numbers (between 400,000 and 3000 Rc/cell); both responses were always observed at PTH concentrations in the same dose range although the magnitude of the responses decrease with Rc number. Pretreatment of C-21 cells with pertussis toxin for 24 h, which significantly enhanced PTH-stimulated cAMP accumulation, did not modulate PTH-stimulated [Ca2+]i transients. At each PTH concentration tested which resulted in increased cAMP levels, there was also an increase in [Ca2+]i transients. Treatment of C-21 cells with a battery of midregion and C-terminal PTH or PTHrP peptides showed no effect on either [Ca2+]i transients or cAMP accumulation, indicating a lack of functional interactions between these peptides and the form of the hPTH/PTHrP Rc stably expressed in these cells. Immunological analysis of G-protein expression demonstrated the presence of Gs, Gi, and Gq in all parental and transfected cells lines examined. Taken together, these data demonstrate that the hPTH/PTHrP Rc, stably expressed in HEK-293 cells, elicits responses in both the cAMP and IP3-dependent [Ca2+]i pathways and is responsive only to N-terminal PTH/PTHrP peptides.
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PMID:Inositol 1-,4-,5-trisphosphate-dependent Ca2+ signaling by the recombinant human PTH/PTHrP receptor stably expressed in a human kidney cell line. 872 98

The involvement of multiple G-proteins in parathyroid hormone regulation of acid production was demonstrated in a highly enriched osteoclast population. Osteoclasts were isolated from the endosteum of 2.5 to 3-week-old chicken tibia using sequential enzymatic digestion. Single cell analysis of acid production was accomplished using microscope photometry and vital staining with acridine orange, a hydrogen ion concentration sensitive fluorescent dye. Lithium chloride, an uncoupler of G-proteins from their respective receptors, blocked parathyroid hormone stimulated production of acid. Cholera toxin, which permanently activates Gs-proteins, mimicked PTH stimulation. Pertussis toxin, which prevents receptor interaction with Gi- and Go-proteins, blocked both 10(-8) M and 10(-11) M PTH stimulated acid production, suggesting that the pertussis toxin-sensitive G-protein is utilized at both PTH concentrations. Immunoblots of osteoclast plasma membrane proteins, using a panel of antibodies generated against specific G-protein alpha subunits, revealed a 48 kDa Gs alpha, a 41 kDa Go alpha, a 34 kDa Gi alpha-3, and a unique 68 kDa G alpha subunit, with the 41 kDa and 34 kDa bands being the most intense. Immunoblots of osteoblast plasma membrane proteins had a substantially different profile with the most intense bands being a Gs alpha (48 kDa) and a Go alpha (36 and 38 kDa). The studies suggest the utilization of at least two different G-proteins in the parathyroid hormone regulation of acid formation by osteoclasts, a Gs and a pertussis toxin-sensitive G-protein (Go and/or Gi alpha-3).
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PMID:Multiple G-protein involvement in parathyroid hormone regulation of acid production by osteoclasts. 901 64


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