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

We have earlier demonstrated that dopamine stimulates the liberation of the prostaglandin E(2) (PGE(2)) precursor, arachidonic acid, in Chinese hamster ovary cells transfected with the rat dopamine D(2) receptor (long isoform), also without concomitant administration of a Ca(2+)-releasing agent [Nilsson et al., Br J Pharmacol 1998;124:1651-8]. In the present report, we show that dopamine, under the same conditions, also induces a concentration-dependent increase in the production of PGE(2), with a maximal effect of 235% at approximately 100 microM, and with an EC(50) of 794 nM. The effect was counteracted by the D(2) antagonist eticlopride, pertussis toxin, the inhibitor of intracellular Ca(2+) release TMB-8, incubation in Ca(2+)-free experimental medium, and PKC desensitization obtained by chronic pretreatment with the phorbol ester TPA. It was also antagonized by the non-specific cyclooxygenase (COX) inhibitor, indomethacin, and by the selective COX-2 inhibitor, NS-398, but not by the specific COX-1 inhibitor, valeryl salicylate. Both the non-specific phospholipase A(2) inhibitor, quinacrine, and an inhibitor of cPLA(2) and iPLA(2), AACOF3, counteracted the effect; in contrast, a selective iPLA(2) inhibitor, BEL, and a selective sPLA(2) inhibitor, TAPC, were ineffective. No effects of dopamine were obtained in control cells mock-transfected with the p3C vector only. The results reinforce previous assumptions that dopamine may interact with eicosanoid metabolism by means of D(2) receptor activation, and implicate an involvement of cPLA(2) and COX-2 in this effect. It is suggested that measurement of dopamine-induced PGE(2) production may serve as a convenient way to study D(2) receptor function in vitro.
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PMID:Dopamine D(2) receptor-induced COX-2-mediated production of prostaglandin E(2) in D(2)-transfected Chinese hamster ovary cells without simultaneous administration of a Ca(2+)-mobilizing agent. 1211 Mar 74

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

We studied the effects of ANG II on extracellular signal-regulated kinase (ERK)1/2 phosphorylation in rat pituitary cells. ANG II increased ERK phosphorylation in a time- and concentration-dependent way. Maximum effect was obtained at 5 min at a concentration of 10-100 nM. The effect of 100 nM ANG II was blocked by the AT1 antagonist DUP-753, by the phospholipase C (PLC) inhibitor U-73122, and by the MAPK kinase (MEK) antagonist PD-98059. The ANG II-induced increase in phosphorylated (p)ERK was insensitive to pertussis toxin blockade and PKC depletion or inhibition. The effect was also abrogated by chelating intracellular calcium with BAPTA-AM or TMB-8 by depleting intracellular calcium stores with a 30-min pretreatment with EGTA and by pretreatment with herbimycin A and PP1, two c-Src tyrosine kinase inhibitors. It was attenuated by AG-1478, an inhibitor of epidermal growth factor receptor (EGFR) activation. Therefore, in the rat pituitary, the increase of pERK is a Gq- and PLC-dependent process, which involves an increase in intracellular calcium and activation of a c-Src tyrosine kinase, transactivation of the EGFR, and the activation of MEK. Finally, the response of ERK activation by ANG II is altered in hyperplastic pituitary cells, in which calcium mobilization evoked by ANG II is also modified.
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PMID:Angiotensin II phosphorylation of extracellular signal-regulated kinases in rat anterior pituitary cells. 1275 18

Despite the recognized role of bradykinin (BK)-induced calcium and chloride conductance in regulating salt transport in the kidney, the signaling pathway involved has not been well examined. Patch clamp of murine proximal tubule (TKPTS) cells revealed that BK (10 nM) produced an increase in an outwardly rectifying current from a basal level of 2.9 +/- 0.6 to 13.8 +/- 1.1 pA/pF following addition of BK (n = 8; p < 0.001). The shift in reversal potential seen with BK on changing the intracellular solution to 152 mM chloride and significant inhibition of the current by 100 microM 4,4'-di-isothiocyanato-stilbene-2,2'-disulphonic acid (DIDS) suggested that BK activated a chloride current. BK-induced current was blocked by B2 receptor antagonist but not by B1 antagonist or pertussis toxin indicating that the current was mediated by B2 receptors possibly through Gq activation. TMB-8 completely blocked the BK-calcium rise in fura-2 studies but did not block the BK-chloride response indicating that BK-mediated chloride current is calcium-independent. BK-induced current was dependent on phospholipase C (PLC) since U73122, a PLC-beta blocker (10 microM) blocked it completely. Furthermore, chloride conductance was not modulated by bisindolylmaleimide, an inhibitor of protein kinase C (PKC), but was enhanced by dibutyryl cAMP. We conclude that BK-induced rise in chloride current is mediated by B2 receptors and dependent on PLC activation but not dependent on calcium rise. Furthermore, the current can be modulated by cAMP but not PKC.
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PMID:Bradykinin-induced chloride conductance in murine proximal tubule epithelial cells. 1700 50

Gastric acid secretion is not only stimulated via the classical known neuronal and hormonal pathways but also by the Ca(2+)-Sensing Receptor (CaSR) located at the basolateral membrane of the acid-secretory gastric parietal cell. Stimulation of CaSR with divalent cations or the potent agonist Gd(3+) leads to activation of the H(+)/K(+)-ATPase and subsequently to gastric acid secretion. Here we investigated the intracellular mechanism(s) mediating the effects of the CaSR on H(+)/K(+)-ATPase activity in freshly isolated human gastric glands. Inhibition of heterotrimeric G-proteins (G(i) and G(o)) with pertussis toxin during stimulation of the CaSR with Gd(3+) only partly reduced the observed stimulatory effect. A similar effect was observed with the PLC inhibitor U73122. The reduction of the H(+)/K(+)-ATPase activity measured after incubation of gastric glands with BAPTA-AM, a chelator of intracellular Ca(2+), showed that intracellular Ca(2+) plays an important role in the signalling cascade. TMB-8, a ER Ca(2+)store release inhibitor, prevented the stimulation of H(+)/K(+)-ATPase activity. Also verapamil, an inhibitor of L-type Ca(2+)-channels reduced stimulation suggesting that both the release of intracellular Ca(2+) from the ER as well as Ca(2+) influx into the cell are involved in CaSR-mediated H(+)/K(+)-ATPase activation. Chelerythrine, a general inhibitor of protein kinase C, and Go 6976 which selectively inhibits Ca(2+)-dependent PKC(alpha) and PKC(betaI)-isozymes completely abolished the stimulatory effect of Gd(3+). In contrast, Ro 31-8220, a selective inhibitor of the Ca(2+)-independent PKCepsilon and PKC-delta isoforms reduced the stimulatory effect of Gd(3+) only about 60 %. On the other hand, activation of PKC with DOG led to an activation of H(+)/K(+)-ATPase activity which was only about 60 % of the effect observed with Gd(3+). Incubation of the parietal cells with PD 098059 to inhibit ERK1/2 MAP-kinases showed a significant reduction of the Gd(3+) effect. Thus, in the human gastric parietal cell the CaSR is coupled to pertussis toxin sensitive heterotrimeric G-Proteins and requires calcium to enhance the activity of the proton-pump. PLC, ERK 1/2 MAP-kinases as well as Ca(2+) dependent and Ca(2+)-independent PKC isoforms are part of the down-stream signalling cascade.
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PMID:Stimulatory pathways of the Calcium-sensing receptor on acid secretion in freshly isolated human gastric glands. 1731 98

The effects of carbachol and histamine on changes in cytosolic-free calcium ([Ca2+]i) and cell proliferation have been characterized in human ovarian cancer cells (OVCAR-3) and non-tumourigenic Chinese hamster ovary cells (CHO). The muscarinic agonist carbachol increased [Ca2+]i significantly with a rapid biphasic response due to both influx of extracellular calcium and release of calcium from intracellular stores. None of these effects were however seen in CHO cells. The increase in cellular calcium by carbachol was also confirmed by calcium uptake experiments using Ca-45. Carbachol increased Ca-45 uptake by 25% in OVCAR-3 cells but had no effect in CHO cells. Histamine also stimulated calcium mobilization in OVCAR-3 cells but had no effect in CHO cells. The response to histamine was also biphasic although the calcium increase was smaller than with carbachol. Data obtained with selective histamine antagonists showed that the response to histamine was mediated by H-1 histaminergic receptors. Both carbachol and histamine also stimulated cell growth of OVCAR-3 cells but were without effect on CHO cells. The cell proliferating effect of carbachol and of histamine on OVCAR-3 cells as well as the increase in [Ca2+], was totally blocked by atropine and selective H-1 histaminergic receptor antagonist pyrilamine, respectively. Fetal calf serum (FCS) which increased [Ca2+]i in both cell lines also caused a substantial increase in cell growth in the two cell lines. Verapamil partially and TMB-8 totally blocked carbachol stimulated release of calcium from intracellular stores, whereas prenylamine had only a minor inhibitory effect on calcium influx. The effect of verapamil and TMB-8 were most likely resulted from their inhibition of cholinergic receptors rather than a direct inhibition of intracellular calcium release. The carbachol induced effects on calcium transients were also partially inhibited by pertussis toxin and the phorbol ester PMA. Our data suggest that the mitogenic action of carbachol occurs through an increase in [Ca2+]i which promote DNA synthesis and cell growth. These data also indicate the involvement of both a pertussis toxin sensitive and insensitive G-protein as well as protein kinase C in the signal transduction pathway induced by carbachol.
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PMID:Muscarinic acetylcholine and histamine-receptor mediated calcium mobilization and cell-growth in human ovarian-cancer cells. 2156 46


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