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)

Leukotriene C4 is an arachidonic acid metabolite and an important mediator of inflammation and anaphylaxis that is known to induce production of prostacyclin in endothelial cells. The goal of this study was to examine the signal transduction mechanisms activated by leukotriene C4 stimulation. Formation of inositol phosphates was measured to determine the activation of phospholipase C and pertussis toxin was used to explore the role of G-proteins. Additionally, we evaluated the role of protein kinase C in these events, especially whether there was an interaction between pertussis toxin mediated effects and the activity of protein kinase C. Leukotriene C4 induced a dose- and time-dependent formation of inositol phosphates and prostacyclin. The response to leukotriene C4 was greater than the response to leukotriene D4 even after treatment with L-serine borate complex, suggesting the presence of a specific leukotriene C4 receptor. Exposure to pertussis toxin potentiated, time-dependently, the leukotriene C4 induced formation of inositol phosphates and prostacyclin through a mechanism which was altered by manipulation of protein kinase C activity. The exact mechanism is not clear but our results are consistent with a postulated dual mechanism of phospholipase C control, in which leukotriene C4 induced stimulation is attenuated by a pertussis toxin sensitive G-protein.
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PMID:Potentiating effects of pertussis toxin on leukotriene C4 induced formation of inositol phosphate and prostacyclin in human umbilical vein endothelial cells. 973 50

It is widely held that only one prostacyclin (IP) receptor exists that can couple to guanine stimulatory nucleotide binding proteins (Gs) leading to activation of adenyl cyclase. Although IP receptor mRNA is expressed in vascular arterial smooth muscle cells and platelets, with lower level expression in mature thymocytes, splenic lymphocytes, and megakaryocytes, there is no molecular evidence for IP receptor expression in renal epithelial cells. The purpose of the present study was to obtain molecular evidence for the expression and localization of the IP receptor and to study the signaling pathways of IP receptor in rat medullary thick ascending limb (MTAL). Biochemical studies showed that IP prostanoids do not increase cAMP in rat MTAL. However, in the presence of vasopressin, inhibition of cAMP formation by prostacyclin (PGI2) analogs is pertussis toxin sensitive and does not activate protein kinase C. In situ hybridization studies localized IP receptor mRNA expression to MTAL in the rat kidney outer medulla. The results of RT-PCR of freshly isolated RNA from MTAL, with primers specific for the mouse IP receptor cDNA, produced an amplification product of the correct predicted size that contained an expected Nco I endonuclease restriction site. We conclude that rat renal epithelial cells express the IP receptor, coupled to inhibition of cAMP production.
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PMID:Prostanoid signaling, localization, and expression of IP receptors in rat thick ascending limb cells. 984 7

Mechanical loading of bone stimulates resident bone cells to produce prostacyclin (PGI(2)) and prostaglandin (PG)E(2) by a mechanism that can be differentially regulated by ion channel blockers. We have investigated differences in the loading-related PG production mechanisms in rat ulnae explants loaded ex vivo. Loading and aluminium fluoride (AlF(3), a nonselective activator of G-proteins) both increased PGI(2) and PGE(2) release into culture medium. Pertussis toxin (PTX) blocked loading-related release of PGE(2), but not PGI(2), while isotetrandrine, an inhibitor of G-protein-mediated activation of phospholipase (PL)A(2), abolished the loading-related release of both PGs. This suggests both PTX-sensitive and -insensitive G-protein-dependent, PLA(2)-mediated mechanisms for loading-related PG production. Blockade of secretory (s)PLA(2) activity prevented loading-related release of PGE(2) and PGI(2), whereas inhibition of cytosolic (c)PLA(2) activity blocked loading-related release of PGE(2) alone. cPLA(2) was localized immuno-cytochemically to osteoblasts, but not to osteocytes. sPLA(2) was localized to osteocytes and osteoblasts. Exogenous type-IA sPLA(2) and type-IB sPLA(2) stimulated significant increases in PGE(2) and PGI(2) release. PTX reduced the release of both PGs stimulated by type IA PLA(2), but not type IB. Furthermore, inhibition of protein kinase C (PKC) activity blocked loading-related release of PGE(2), but not that of PGI(2). These data suggest that loading-related release of PGI(2) and PGE(2) utilizes arachidonic acid derived from the activity of different PLA(2)s. In osteocytes and osteoblasts, arachidonic acid for PGI(2) synthesis is liberated by PTX-insensitive G-protein-dependent sPLA(2) alone. In osteoblasts, arachidonic acid for PGE(2) synthesis is released by PTX-sensitive, G-protein-dependent, cPLA(2)-mediated activity, which also requires upstream sPLA(2) and PKC activities.
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PMID:Arachidonic acid for loading induced prostacyclin and prostaglandin E(2) release from osteoblasts and osteocytes is derived from the activities of different forms of phospholipase A(2). 1091 17

Prostaglandin (PG) F(2alpha) may act on its G protein-coupled receptor (FP) or be imported intracellularly via a transporter, which has high affinity for PGF(2alpha) and PGE(2), but not prostacyclin (PGI(2)). In cells overexpressing the epitope-tagged FP together with the human prostaglandin transporter (hPGT), stimulation of the FP with PGF(2alpha) (1 nM-1 microM), or the less potent FP agonist, the isoprostane 8,12-iso-iPF(2alpha)-III, inhibited prostaglandin uptake via the hPGT. This effect was abolished by pretreatment of the cells with cholera toxin, but not with pertussis toxin. Furthermore, two dominant negative constructs directed against Galpha(s) partially blocked FP-mediated regulation of hPGT function, also suggesting Galpha(s) involvement in this phenomenon. Surprisingly, neither an activator (dibutyryl cyclic AMP) nor an inhibitor (H89) of cyclic AMP-dependent protein kinase had any effect on FP-mediated inhibition of hPGT activity. Furthermore, although PGF(2alpha) increases intracellular cyclic AMP via Galpha(s) activation, it does not induce phosphorylation of the transporter, excluding a role of cyclic AMP-dependent protein kinase in hPGT regulation. Activation of the PGI(2) receptor, which is also coupled to Galpha(s), does not regulate hPGT activity, despite markedly augmenting adenylate cyclase activation. In conclusion, activation of the FP reduces intracellular import of prostaglandins for metabolic inactivation, increasing prostanoid availability for membrane receptor activation. This effect seems to be mediated via Galpha(s), independent of adenylate cyclase and cyclic AMP-dependent protein kinase activation.
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PMID:Prostaglandin F(2alpha) receptor-dependent regulation of prostaglandin transport. 1135 12

Cytosolic Phospholipase A(2) (cPLA(2)) has been implicated in receptor-mediated release of arachidonic acid from membrane phospholipids, the limiting step in prostacyclin and other eicosanoid production. Its activity is controlled by Ca(++) levels and enzymatically regulated phosphorylation. The purpose of this study was to assess the importance of phosphorylation of cPLA(2) in human umbilical vein endothelial cells and to identify the kinases involved. Inhibitors were used to study the pathways leading to phosphorylation and activation of mitogen activated protein kinases (MAP-kinases) and cPLA(2), as well as release of arachidonic acid and prostacyclin production after stimulation with different agonists. We have found that agonists that release arachidonic acid, including histamine, thrombin, AlF(4)(-), and pervanadate, all activate the MAP kinases ERK, p38 and JNK and cause phosphorylation of cPLA(2). Agonist specific differences in the signal transduction pathways included variable contribution of tyrosine phosphorylation, protein kinase C and ERK activity, and different effects of pertussis toxin. Treatment with PD98059 (inhibitor of ERK-activation) or SB203580 (inhibitor of p38) caused partial decrease in arachidonic acid release and cPLA(2) activity. In contrast the nonspecific protein kinase inhibitor staurosporin completely inhibited cPLA(2) activity. We conclude that in endothelial cells arachidonic acid release is largely mediated by cPLA(2) through agonist-specific pathways. The MAP kinases ERK and p38 both have demonstrable but not major effect on agonist stimulated arachidonic acid release and the data suggest that an additional unidentified kinase also has a role.
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PMID:Involvement of MAP kinases in the control of cPLA(2) and arachidonic acid release in endothelial cells. 1136

Octimibate and related nonprostanoid prostacyclin mimetics are partial agonists displaying highly tissue-specific responses. Octimibate demonstrated considerably greater efficacy for stimulation of adenylyl cyclase activity in Chinese hamster ovary cells transiently expressing mouse prostacyclin receptors (mIP-CHO cells) when compared to human SK-N-SH neuroblastoma cells, which endogenously express prostacyclin (IP) receptors. Pretreatment of both cell types with pertussis toxin (PTx) failed to influence IP agonist efficacy or potency, indicating a lack of involvement of an agonist-stimulated inhibitory G(i)-coupled pathway. Although stimulation of mIP-CHO cells with the full agonist cicaprost increased both [3H]cyclic AMP and [3H]inositol phosphate ([3H]IP) accumulation (pEC(50) values of 8.35 and 6.82, respectively), IP receptor signalling through G(q) in SK-N-SH cells was absent. Inhibition of protein kinase C (PKC) in mIP-CHO cells increased [3H]IP accumulation but had no effect on [3H]cyclic AMP accumulation. Therefore, the poor coupling of the IP receptor in SK-N-SH cells to G(q) is unlikely to explain the relatively low efficacy of octimibate for stimulating adenylyl cyclase in these cells. Furthermore, protein kinase A (PKA) inhibition appears to enhance IP receptor signalling through both G(s) and G(q) in mIP-CHO cells.
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PMID:Factors affecting prostacyclin receptor agonist efficacy in different cell types. 1158 20

Extracellular regulated kinases (ERKs)-1 and -2 are members of the MAPK family of protein kinases involved in the proliferation, differentiation, and apoptosis of bone cells. We have shown previously that ROS 17/2.8 cells show increased activation of ERK-1 or -2, which is sustained for 24 h, when the strips onto which they are seeded are subjected to a 10 min period of cyclic four point bending that produces physiological levels of mechanical strain along with associated fluid movement of the medium. Movement of the strips through the medium without bending causes fluid movement without strain. This also increases ERK-1/2 activation, but in a biphasic manner over the same time period. Our present study investigates the role of components of signaling pathways in the activation of ERK-1/2 in ROS 17/2.8 cells in response to these stimuli. Using a range of inhibitors we show specific differences by which ERK-1 and ERK-2 are activated in response to fluid movement alone, compared with those induced in response to strain plus its associated fluid movement. ERK-1 activation induced by fluid movement was markedly reduced by nifedipine, and therefore appears to involve L-type calcium channels, but was unaffected by either L-NAME or indomethacin. This suggests independence from prostacyclin (PGI(2)) and nitric oxide (NO) production. In contrast, ERK-1 activation induced by application of strain (and its associated fluid disturbance) was abrogated by TMB-8 hydrochloride, L-NAME, and indomethacin. This suggests that strain-induced ERK-1 activation is dependent upon calcium mobilization from intracellular stores and production of NO and PGI(2). ERK-2 activation appears to be mediated by a separate mechanism in these cells. Its activation by fluid movement alone involved both PGI(2) and NO production, but its activation by strain was not affected by any of the inhibitors used. The G protein inhibitor, pertussis toxin, did not cause a reduction in the activation of ERK-1 or -2 in response to either stimulus. These results are consistent with earlier observations of ERK activation in bone cells in response to both strain (with fluid movement) and fluid movement alone, and further demonstrate that these phenomena stimulate distinct signaling pathways.
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PMID:Mechanical strain and fluid movement both activate extracellular regulated kinase (ERK) in osteoblast-like cells but via different signaling pathways. 1211 Apr 33

To clarify the role of the PGI(2)/PGI(2) receptor (IP) system in rabbit cortical collecting duct (RCCD), we characterized the expression of IP receptors in the rabbit kidney. We show by Northern and Western blotting that IP mRNA and protein was detectable in all three regions of the kidney. To determine how PGI(2) signals, we compared the effects of different PGI(2) analogs [iloprost (ILP), carba-prostacyclin (c-PGI(2)), and cicaprost (CCP)] in the isolated perfused RCCD. PGI(2) analogs did not increase water flow (L(p)). Although PGI(2) analogs did not reduce an established L(p) response to 8-chlorophenylthio-cAMP, they equipotently inhibited AVP-stimulated L(p) by 45%. The inhibitory effect of ILP and c-PGI(2) on AVP-stimulated L(p) is partially reversed by the protein kinase C inhibitor staurosporine and abolished by pertussis toxin; no effect was obtained with CCP. In fura 2-loaded RCCD, CCP did not alter cytosolic Ca(2+) concentration ([Ca(2+)](i)), but, in the presence of CCP, individual infusion of ILP and PGE(2) increased [Ca(2+)](i), suggesting that CCP did not cause desensitization to either ILP or PGE(2). We concluded that ILP and c-PGI(2) activate PKC and the liberation of [Ca(2+)](i) but not CCP. This suggested an important role for phosphatidylinositol hydrolysis in mediating ILP and c-PGI(2) effects but not CCP in RCCD.
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PMID:Localization of IP in rabbit kidney and functional role of the PGI(2)/IP system in cortical collecting duct. 1221 60

Endothelial cells in most vascular beds release a factor that hyperpolarizes the underlying smooth muscle, produces vasodilatation, and plays a fundamental role in the regulation of local blood flow and systemic blood pressure. The identity of this endothelium-derived hyperpolarizing factor (EDHF), which is neither NO nor prostacyclin, remains obscure. Herein, we demonstrate that in mesenteric resistance arteries, release of C-type natriuretic peptide (CNP) accounts for the biological activity of EDHF. Both produce identical smooth muscle hyperpolarizations that are attenuated in the presence of high [K(+)], the G(i) G protein (G(i)) inhibitor pertussis toxin, the G protein-gated inwardly rectifying K(+) channel inhibitor tertiapin, and a combination of Ba(2+) (inwardly rectifying K(+) channel blocker) plus ouabain (Na(+)K(+)-ATPase inhibitor). Responses to EDHF and CNP are unaffected by the natriuretic peptide receptor (NPR)-AB antagonist HS-142-1, but mimicked by the selective NPR-C agonist, cANF(4-23). EDHF-dependent relaxation is concomitant with liberation of endothelial CNP; in the presence of the myoendothelial gap-junction inhibitor 18alpha-glycyrrhetinic acid or after endothelial denudation, CNP release and EDHF responses are profoundly suppressed. These data demonstrate that acetylcholine-evoked release of endothelial CNP activates NPR-C on vascular smooth muscle that via a G(i) coupling promotes Ba(2+)ouabain-sensitive hyperpolarization. Thus, we have revealed the identity of EDHF and established a pivotal role for endothelial-derived CNP in the regulation of vascular tone and blood flow.
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PMID:Release of C-type natriuretic peptide accounts for the biological activity of endothelium-derived hyperpolarizing factor. 1255 27

This study sought to assess the role of several signaling pathways in the fluid flow shear stress-induced proliferation and differentiation of normal human osteoblasts. We evaluated the effects of an effective dose of selective inhibitors of the extracellular signal-regulated kinases (ERK) pathway (PD98059 and U0126), the nitric oxide synthase pathway (N(omega)-nitro-L-arginine methyl ester), the cyclo-oxygenase pathway (indomethacin), or the Gi/o pathway (pertussis toxin [PTX]) on the flow-mediated effects. A 30-min steady flow shear stress at 20 dynes/cm(2) increased significantly [(3)H]thymidine incorporation (an indicator of proliferation), alkaline phosphatase activity (an index of osteoblast differentiation), phosphorylation of ERK, and expression of integrin beta1. PD98059, U0126, and N(omega)-nitro-L-arginine methyl ester completely blocked the shear stress-induced increases in ERK phosphorylation, [(3)H]thymidine incorporation, and alkaline phosphatase, but without an effect on integrin beta1 expression, indicating that the ERK and nitric oxide synthase pathways are essential for the shear stress-induced proliferation and differentiation of normal human osteoblasts and that each involves ERK activation but not integrin beta1 upregulation. Indomethacin blocked the shear stress-induced osteoblast proliferation and differentiation and integrin beta1 upregulation but not ERK activation, suggesting that the cyclo-oxygenase pathway (i.e., prostacyclin and/or prostaglandin E(2)) mediates the shear stress-induced osteoblast proliferation in an ERK-independent manner. In contrast, PTX completely blocked the flow-induced increase in integrin beta1 expression but had no effect on the increase in the ERK phosphorylation or [(3)H]thymidine incorporation. PTX not only did not inhibit but also significantly enhanced the stimulatory effect of shear stress on alkaline phosphatase activity, suggesting that a PTX-sensitive signaling pathway may have an inhibitory role in osteoblast differentiation. In summary, this study shows, for the first time, that the signal transduction mechanism of shear stress in osteoblasts is complex and involves multiple ERK-dependent and independent pathways, and provides circumstantial evidence that there may be a PTX-sensitive pathway that has completing effects with an unknown pathway on the differentiation of normal human osteoblasts.
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PMID:Fluid flow shear stress stimulates human osteoblast proliferation and differentiation through multiple interacting and competing signal transduction pathways. 1266 51


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