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 effects of the monokines tumor necrosis factor alpha (TNF) and interleukin 1 (IL 1) on parathyroid hormone (PTH)-responsive adenylate cyclase were examined in clonal rat osteosarcoma cells (UMR-106) with the osteoblast phenotype. Recombinant TNF and IL 1 incubated with UMR-106 cells for 48 hr each produced concentration-dependent inhibition of PTH-sensitive adenylate cyclase, with maximal inhibition of PTH response (40% for TNF, 24% for IL 1) occurring at 10(-8) M of either monokine. Both monokines also decreased adenylate cyclase stimulation by the tumor-derived PTH-related protein (PTHrP). In contrast, TNF and IL 1 had little or no inhibitory effect on receptor-mediated stimulation of adenylate cyclase by isoproterenol and nonreceptor-mediated enzyme activation by cholera toxin and forskolin; both monokines increased prostaglandin E2 stimulation of adenylate cyclase. Binding of the radioiodinated agonist mono-[125I]-[Nle8,18, Tyr34]bPTH-(1-34)NH2 to UMR-106 cells in the presence of increasing concentrations of unlabeled [Nle8,18, Tyr34]bPTH-(1-34)NH2 revealed a decline in PTH receptor density (Bmax) without change in receptor binding affinity (dissociation constant, Kd) after treatment with TNF or IL 1. Pertussis toxin increased PTH-sensitive adenylate cyclase activity but did not attenuate monokine-induced inhibition of PTH response. In time course studies, brief (1 hr) exposure of cells to TNF or IL 1 during early culture was sufficient to decrease PTH response but only after exposed cells were subsequently allowed to grow for prolonged periods. Inhibition of PTH response by monokines was blocked by cycloheximide. The results indicate that TNF and IL 1 impair responsiveness to PTH (and PTHrP) by a time- and protein synthesis-dependent down-regulation of PTH receptors linked to adenylate cyclase.
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PMID:Tumor necrosis factor and interleukin 1 inhibit parathyroid hormone-responsive adenylate cyclase in clonal osteoblast-like cells by down-regulating parathyroid hormone receptors. 132 78

Because the presence of the angiotensin II (ANG II)-dependent phosphoinositide hydrolysis has been questioned from studies in proximal cells in culture, we looked for this transduction pathway in suspension of freshly isolated rat proximal tubule fragments. ANG II-receptor activation induced a prompt (within 15 s) and sustained increase in [3H]inositol phosphates (IPs; inositol trisphosphate, inositol bisphosphate, and inositol monophosphate). In fura-2-loaded tubules, it elicited a rapid and biphasic rise in cytosolic free calcium ([Ca2+]i) with an early peak (within 15 s) followed by a plateau. The peak was maintained in the absence of extracellular calcium. ANG II-induced inositol trisphosphate and [Ca2+]i rises showed a similar dose dependency, with a 50% effective concentration (EC50) of 2.9 and 5.5 nM, respectively. We checked that ANG II inhibited basal (EC50 4.4 nM) and parathyroid hormone- and forskolin-stimulated cAMP production, the latter effect being inhibited by pertussis toxin pretreatment. The effects of ANG II on IPs and [Ca2+]i were inhibited by the ANG II receptor subtype 1 (AT1) antagonist losartan and not by the ANG II receptor subtype 2 (AT2) antagonists PD 123177 and PD 123319. The effect of ANG II on forskolin-stimulated cAMP was inhibited by losartan and not by PD 123319. In agreement with these results, specific binding of 125I-[Sar1,Ile8]ANG II was markedly inhibited by losartan, whereas PD 123319 had no effect. These results demonstrate that AT1 receptor subtypes are present in intact rat proximal tubule cells and are coupled to both IPs-Ca2+ and cAMP signaling pathways. No evidence for AT2 receptor subtype is found.
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PMID:Effects of angiotensin II and nonpeptide receptor antagonists on transduction pathways in rat proximal tubule. 132 42

Angiotensin II (ANG II) was shown to modulate transport in the renal proximal tubule through both inhibition of adenylate cyclase and protein kinase C (PKC) activation. We evaluated the effects of ANG II on adenosine 3',5'-cyclic monophosphate (cAMP) content and Na-H exchange activity (amiloride-sensitive Na influx) in two strains of opossum kidney (OK) cells originating from different sources, OK-VD and OK-RR cells. In OK-VD cells, ANG II inhibited basal and parathyroid hormone (PTH)-induced cAMP generation in a pertussis toxin-sensitive manner and reversed PTH inhibition of Na-H exchange. These effects of ANG II were prevented by PD 123319, a selective nonpeptide antagonist of AT2 receptors. In contrast, DuP 753, which antagonizes selectively AT1 receptors, had no effect. In OK-RR cells, ANG II had no effect on cAMP content and decreased Na-H exchange activity. The effect of ANG II persisted in the presence of PTH but was abolished by PKC downregulation and by DuP 753, but not by PD 123319. In conclusion, two types of ANG II receptors, coupled to distinct signaling pathways, were expressed independently in OK cells originating from two different sources and mediated opposite effects of ANG II on Na-H exchange activity. Those models provide a powerful tool for studying the intracellular steps involved in the tubular effects of ANG II and to evaluate the effect of pharmacological inhibitors of ANG II binding to its receptors.
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PMID:Modulation of Na-H exchange activity by angiotensin II in opossum kidney cells. 133 86

Regulation of phosphate uptake by the blood-brain barrier was studied in isolated bovine capillaries. Dibutyryl cAMP, in the presence of 3-isobutylmethylxanthine, resulted in a dose-dependent inhibition of phosphate uptake. Phosphate influx, with or without 3-isobutylmethylxanthine, was not different. Inhibition of phosphate uptake was also observed when capillaries were preincubated with isoproterenol, parathyroid hormone, insulin and acidic or basic fibroblast growth factors. Treatment of capillaries with vasoactive intestinal peptide, prostaglandin E1, angiotensin II, epidermal growth factor and phorbol esters did not affect phosphate transport. Endothelin I increased phosphate uptake by 15%. Preincubation with cholera toxin also resulted in a dose-dependent decrease in phosphate uptake. In addition, pertussis toxin inhibited phosphate transport by 29%, but only in the presence of 3-isobutylmethylxanthine. These results demonstrate that generation of second messengers, following receptor stimulation, can induce physiological effects on capillary phosphate influx and suggest that G proteins may modulate this transport.
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PMID:Regulation of phosphate transport by second messengers in capillaries of the blood-brain barrier. 138 98

The effects on ionic permeability of toxins and hormones that activate or deactivate the guanine nucleotide regulatory (G) proteins that govern adenylate cyclase activity were examined in rat renal proximal tubule cell brush-border membranes. These studies demonstrate that activation of stimulatory G (Gs) proteins by cholera toxin or parathyroid hormone and deactivation of inhibitory (G (Gi) proteins by pertussis toxin result in a selective increase in Cl- permeability relative to that of K+ as determined with the potential-sensitive fluorescent probe 3,3'-dipropylthiadicarbocyanine iodide [diS-C3-(5)]. In contrast, activation of Gi by angiotensin II significantly decreases relative Cl- permeability. The selective increase in relative Cl- permeability induced by parathyroid hormone results in an inside-negative potential in membrane vesicles exposed to an inward NaCl gradient that is of sufficient magnitude to stimulate electrogenic, Na(+)-dependent glucose transport. These data suggest that the relative ionic permeabilities of brush-border membranes are tonically regulated by the opposing effects of hormones that act via Gs or Gi proteins. Changes in membrane potential resulting from this regulation may play an important role in modifying transport in the proximal tubule.
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PMID:Hormonal regulation of rat renal proximal tubule brush-border membrane ionic permeability. 163 38

The effect of prostaglandin F2 alpha (PGF2 alpha) was investigated in MC3T3E1 cells on the succeeding cAMP response to parathyroid hormone (PTH). PGF2 alpha increased the membrane-associated protein kinase C (PKC) activity, indicating the activation of this enzyme. The effect of PTH to increase cAMP production was enhanced by pretreatment with PGF2 alpha. Phorbol 12-myristate 13-acetate also enhanced cAMP production stimulated by PTH, and PKC inhibitor H7 attenuated the enhancement of PGF2 alpha. A23187 did not reproduce the PGF2 alpha effect, and this effect was not antagonized by the calmodulin antagonist W7. PGF2 alpha did not change the ED50 nor the maximally responsive dose of PTH in stimulating cAMP production. The effect of PGF2 alpha was not affected by pertussis toxin, and PGF2 alpha also enhanced cholera toxin- or forskolin-stimulated cAMP production. In accordance with the response of cAMP to PTH, the resorption of mouse limb bones stimulated submaximally by PTH was enhanced by the concomitant presence of PGF2 alpha. These results indicate that PGF2 alpha modulates cAMP response through the activation of PKC, the target of which might be the catalytic unit of adenylate cyclase. Such interaction between signal transduction systems may have significance in modulating the effect of PTH on bone, i.e., bone resorption.
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PMID:The effect of PGF2 alpha on parathyroid hormone-stimulated cyclic AMP production in mouse osteoblastic cell, MC3T3E1. 164 32

In the renal proximal tubule, external Ca2+ ([Ca2+]o) is required for parathyroid hormone to elevate cytosolic Ca2+ ([Ca2+]i). However, other hormones increase [Ca2+]i in the absence of [Ca2+]o. These differences may arise from a diversity of signal transduction pathways acting on external and internal Ca2+ pools. However, Ca2+ influx may be necessary to expedite and maintain the rise of [Ca2+]i for a period after the initial surge. In this study, F- was used to probe the roles of intracellular Ca2+ mobilization, Ca2+ influx, and phosphoinositide (PI) hydrolysis on the surge of [Ca2+]i in rat proximal tubules. In the presence of external Ca2+; 1-20 mM F- evoked incremental rises of [Ca2+]i in tubules loaded with aequorin. Whereas 10 mM F- increased [Ca2+]i in the absence of [Ca2+]o, the time constant for the [Ca2+]i surge was increased. These findings are consistent with a role of Ca2+ influx on the effect of F- on [Ca2+]i. Indeed, 10 mM F- also enhanced the uptake of 45Ca2+, and promoted Ca2+ influx in aequorin- and fura-2-loaded, Ca(2+)-deprived tubules. In tubules, F- also activated PI hydrolysis with a time course that paralleled Ca2+ mobilization. The effect of F- on [Ca2+]i was not altered when the 39-kDa pertussis toxin substrate was inactivated with the toxin. This G protein was most likely Gi, because prostaglandin E2, an activator of Gi in tubules, dissociated the pertussis toxin-sensitive protein. The results support the notion that activation of a signal-transduction complex, the F- substrate, causes Ca2+ influx, mobilizes internal Ca2+, and activates PI hydrolysis in rat proximal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fluoride mobilizes intracellular calcium and promotes Ca2+ influx in rat proximal tubules. 165 6

The cellular basis for hormonal control of bone resorption is poorly understood. As the identifiable receptors for bone resorbing agents such as parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are located on osteoblasts rather than osteoclasts, the nature of cellular signaling is obscure. Here it is reported that exposure of fetal rat limb bones to pertussis toxin, a bacterial protein that inhibits certain GTP binding proteins (G-proteins) involved in signal transduction, markedly inhibits bone resorption elicited by PTH, 1,25(OH)2D3 and prostaglandin E2. Pertussis toxin does not block the inhibition of alkaline phosphatase activity by PTH or 1,25(OH)2D3, and it potentiates the cyclic AMP response to PTH. These data support the existence of a pertussis toxin-sensitive G-protein that participates in regulation of bone resorption. The putative G-protein is apparently not involved in the initial transduction of hormonal signals, but it may be part of a final common pathway through which the osteoclast is activated by agents with widely divergent initial actions.
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PMID:Pertussis toxin inhibits hormonal stimulation of bone resorption in fetal rat limb bones. 165 45

Calcitonin (CT) is a well-known inhibitor of osteoclastic bone resorption both in vivo and in vitro. The effect is mediated by activation of adenylate cyclase and subsequent increased levels of cyclic AMP (cAMP). We report here that CT-induced (30 nmol/liter) accumulation of cAMP in cultured neonatal mouse calvaria is enhanced two-fold by 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nmol/liter) and phorbol 12,13-dibutyrate (PDBU; 100 nmol/liter), two protein kinase C (PKC)-activating phorbol esters, whereas phorbol 13-monoacetate (phorb-13; 100 nmol/liter), a related compound that does not activate PKC, has no effect. The ability of TPA and PDBU to enhance CT-stimulated cAMP accumulation was obtained also in the presence of indomethacin (1 mumol/liter). Kinetic studies revealed that TPA enhanced the cAMP response to CT at all the time points at which CT had a significant effect per se and that TPA did not alter the time-course of the cAMP response to CT. Treatment with pertussis toxin (100 ng/ml) enhanced cAMP response to parathyroid hormone (10 nmol/liter) and prostaglandin E2, but not to CT. From these data it is concluded that PKC, but not pertussis toxin-sensitive guanyl nucleotide-binding proteins (G-proteins), can interact with and modify the signal transducing system for CT in osteoclasts.
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PMID:Effects of phorbol esters and pertussis toxin on calcitonin-stimulated accumulation of cyclic AMP in neonatal mouse calvarial bones. 166 13

The cellular distribution (apical vs. basolateral) of parathyroid hormone (PTH) signal transduction systems in opossum kidney (OK) cells was evaluated by measuring the action of PTH on apically located transport processes (Na/Pi cotransport and Na/H exchange) and on the generation of intracellular messengers (cAMP and IP3). PTH application led to immediate inhibition of Na/H-exchange without a difference in dose/response relationships between apical and basolateral cell-surface hormone addition (half-maximal inhibition at approximately 5 x 10(-12) M). PTH required 2-3 hr for maximal inhibition of Na/Pi cotransport with a half-maximal inhibition occurring at approximately 5 x 10(-10) M PTH for basolateral application and approximately 5 x 10(-12) M for apical application. PTH addition to either side of the monolayer produced a dose-dependent production of both cAMP and IP3. Half-maximal activation of IP3 was at about 7 x 10(-12) M PTH and displayed no differences between apical and basolateral hormone addition, while cAMP was produced with a half maximal concentration of 7 x 10(-9) M for apical PTH application and 10(-9) M for basolateral administration. The PTH analog [nle8.18,tyr34]PTH(3-34), (nlePTH), produced partial inhibition of Na/Pi cotransport (agonism) with no difference between apical and basolateral application. When applied as a PTH antagonist, nlePTH displayed dose-dependent antagonism of PTH inhibition of Na/Pi cotransport on the apical surface, failing to have an effect on the basolateral surface. Independent of addition to the apical or basolateral cell surface, nlePTH had only weak stimulatory effect on production of cAMP, whereas high levels of IP3 could be measured after addition of this PTH analog to either cell surface. Also an antagonistic action of nlePTH on PTH-dependent generation of the internal messengers, cAMP and IP3, was observed; at the apical and basolateral cell surface nelPTH reduced PTH-dependent generation of cAMP, while PTH-dependent generation of IP3 was only reduced by nlePTH at the apical surface. Pertussis toxin (PT) preincubation produced an attenuation of both PTH-dependent inhibition of Na/Pi cotransport and 1P3 generation while producing an enhancement of PTH-dependent cAMP generation; these effects displayed no cell surface polarity, suggesting that PTH action through either adenylate cyclase or phospholipase C was transduced through similar sets of G-proteins at each cell surface.
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PMID:Apical and basolateral effects of PTH in OK cells: transport inhibition, messenger production, effects of pertussis toxin, and interaction with a PTH analog. 166 60


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