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)

Tachykinins of different classes (NK1, NK2, NK3) caused the concentration-dependent synthesis of IP3 in rat submandibular acinar cells with the potency rank order of NK1 greater than NK2 greater than NK3. Enhancement of IP3 was not affected by pertussis toxin treatment. The reverse rank order was found in the tachykinin inhibition of isoproterenol-induced cAMP synthesis and this inhibition was abolished by pertussis toxin, an inactivator of the adenylate cyclase Gi regulatory protein. It is suggested that different tachykinin receptor subtypes are preferentially coupled to phospholipase C or adenylate cyclase by separate G regulatory proteins in rat submandibular acinar cells.
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PMID:Different tachykinin receptor subtypes are coupled to the phosphoinositide or cyclic AMP signal transduction pathways in rat submandibular cells. 246 21

Variations in intracellular free calcium concentration (delta[Ca2+]i) were measured in intact and isolated human astrocytoma cells (U373 MG) loaded with fura-2 acetoxymethylester. Microperfusion of 50 nM substance P (SP), applied for 1 s, increased [Ca2+]i by 351 nM from a stable basal level of [Ca2+]i of 26 nM. The peak delta[Ca2+]i induced by SP was dose dependent with a threshold of 10(-3) nM, an ED50 of 1.3 nM and a maximal effect for concentrations of SP greater than 100 nM. The NK1 receptor agonist, [Sar9Met(O2)11]SP, mimicked the effect of SP, while the NK2 and NK3 selective receptor agonists, [N1(10)]NKA(4-10) and senktide, respectively, had no effect. The delta[Ca2+]i induced by SP was unaffected by 100 microM cadmium or by removal of extracellular calcium ions. Caffeine up to 30 mM had no effect on [Ca2+]i. In contrast, thapsigargin increased resting [Ca2+]i by 92 nM and reduced the delta[Ca2+]i induced by SP. A pertussis treatment (500 ng/ml-24 h) did not modify the delta[Ca2+]i induced by SP. We conclude that SP, acting on a NK1 receptor, mobilizes cytosolic calcium from an intracellular calcium pool which can be partially depleted by thapsigargin.
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PMID:Mobilization of intracellular calcium by substance P in a human astrocytoma cell line (U-373 MG). 752 79

As previously reported, alveolar macrophages (AMs) from ovalbumin-sensitized guinea pigs present an enhanced responsiveness to tachykinins but not to N-formylmethionyl-leucyl-phenylalanine (fMLP). We have investigated the biochemical mechanisms underlying this varied responsiveness to tachykinins. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) induced a larger superoxide anion (O2-) production in AMs from sensitized guinea pigs, as did tachykinins. Pretreatment of AMs with pertussis toxin abolished tachykinin-evoked respiratory burst, had no effect on PMA-evoked O2- production and strongly inhibited fMLP-evoked one, with no appreciable variation between control or sensitized AMs. Staurosporine and its derivative cgp 41251, significantly decreased PMA- and tachykinin-evoked O2- production in both populations, being more potent in control AMs, but exerted little effects against fMLP. Pretreatment of AMs with PMA significantly inhibited fMLP-, PMA- and tachykinin-evoked O2- production in both control and sensitized AMs. fMLP, substance P (SP), neurokinin A (NKA) and the NK2 agonist [beta-Ala8]-NKA(4-10) dose-dependently increased [3H] phorbol 12, 13 dibutyrate (PDBu) binding to control and sensitized AMs. While fMLP exerted similar effects in both populations, dose-response curves for SP1 NKA and the NK2 receptor agonist were shifted leftwards (1, 4 and 3 orders of magnitude, respectively) in sensitized AMs. These results indicate a possible PKC involvement in the enhanced responsiveness to tachykinins in actively sensitized AMs.
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PMID:Modulation by protein kinase C of the enhanced responsiveness to tachykinins in ovalbumin-sensitized guinea pig alveolar macrophages. 881 49

We studied the chemotactic effects of calcitonin gene-related peptide, vasoactive intestinal peptide, substance P (SP), and secretoneurin on PBMC and PBL using micropore filter assays. All four peptides induced migration of PBMC, whereas only calcitonin gene-related peptide, vasoactive intestinal peptide, and SP were chemotactic for PBL. Secretoneurin, known to induce monocyte chemotaxis, was unable to affect lymphocyte migration. Effects of SP on PBL were characterized by checkerboard analyses and represented true chemotaxis. Both T and B cells responded chemotactically to SP, the functional activity of SP residing in its C-terminal amino acid sequence. Involvement of neurokinin (NK) receptors was supported by inhibition of SP-induced migration of PBL with an NK1 receptor antagonist and induction of migration with [Sar9, Met(O2)11]SP and [PyrGlu6, Pro9]SP(6-11), two specific agonists for NK1 receptors, but not with [beta-Ala8]NK A(4-10), an agonist for NK2 receptors. PBL chemotaxis to SP was abolished by inhibition of tyrosin kinase but not by that of protein kinase C. Preincubation of PBL with pertussis or cholera toxin inhibited SP chemotaxis, indicating that in PBL, NK receptors for chemotaxis probably are coupled with G protein and involve a tyrosin kinase signaling pathway. We conclude that, together with calcitonin gene-related peptide and vasoactive intestinal peptide, SP is a lymphocyte chemoattractant, whereas secretoneurin, which is coreleased from sensory nerve endings, is not.
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PMID:Differential chemotactic activities of sensory neuropeptides for human peripheral blood mononuclear cells. 910 59

In [3H]myristic acid-prelabeled Chinese hamster ovary cells stably expressing the rat NK1 tachykinin receptor, the selective NK1 agonist [Pro9]substance P ([Pro9]SP) time and concentration dependently stimulated the formation of [3H]phosphatidylethanol in the presence of ethanol. This [Pro9]SP-induced activation of phospholipase D (PLD) was blocked by NK1 receptor antagonists and poorly or not mimicked by NK2 and NK3 agonists, respectively. In confirmation of previous observations, [Pro9]SP also stimulated the hydrolysis of phosphoinositides, the release of arachidonic acid, and the formation of cyclic AMP (cAMP). All these [Pro9]SP-evoked responses could be mimicked by aluminum fluoride, but they remained unaffected in cells pretreated with pertussis toxin, suggesting that a Gi/Go protein is not involved in these different signaling pathways. The activation of PLD by [Pro9]SP was sensitive to external calcium and required an active protein kinase C because the inhibition of this kinase (Ro 31-8220) or its down-regulation (long-term treatment with a phorbol ester) abolished the response. In contrast, a cAMP-dependent process was not involved in the activation of PLD because the [Pro9]SP-evoked response was neither affected by Rp-8-bromoadenosine 3',5'-cyclic monophosphorothioate nor mimicked by cAMP-generating compounds (cholera toxin or forskolin) or by 8-bromo-cyclic AMP. A functional coupling of NK1 receptors to PLD was also demonstrated in the human astrocytoma cell line U 373 MG stimulated by SP or [Pro9]SP. These results suggest that PLD activation could be an additional signaling pathway involved in the mechanism of action of SP in target cells expressing NK1 receptors.
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PMID:Functional coupling of the NK1 tachykinin receptor to phospholipase D in chinese hamster ovary cells and astrocytoma cells. 957 95

The human tachykinin NK2 receptor stably expressed in Chinese hamster ovary cells (CHO-hNK2R cells) was characterized by studying the effect of neurokinin A (NKA), the preferred natural ligand, and that of other agonists and antagonists in both binding experiments and functional assays. Competition experiments using [125I]NKA showed that CHO-hNK2R cells express binding sites which have high affinity for NKA (Ki=3.4+/-0.9 nM), GR 64349 (Ki=12+/-3 nM) and [betaAla8]NKA(4-10) (Ki=21+/-8 nM) and for the antagonists MEN 10627 (Ki=0.55+/-0.2 nM), and MEN 11420 (Ki=2.4+/-0.8 nM). In contrast, the tachykinin NK1 and NK3 receptor agonists [Sar9,Met(O2)11]SP and senktide, respectively, were recognized with low affinity (Ki>10 microM). NKA (EC50=68+/-18 nM) induced a rapid and concentration-dependent increase in the intracellular level of inositoltrisphosphate (IP3). The concentration-response curve to GR 64349 (EC50=155+/-14 nM) was close to that of NKA, whereas [betaAla8]NKA(4-10) (EC50=445+/-78 nM) and SP (EC50=3197+/-669 nM) were 7- and 50-fold less potent, respectively. In addition, NKA stimulated the release of arachidonic acid and the production of prostaglandin E2 (PGE2) in a concentration-dependent manner. Also in this assay, NKA was found to be more potent than the other agonists tested (the EC50 values were 3+/-0.3, 9+/-3, 7.8+/-0.9 and 217+/-37 nM for NKA, GR 64349, [betaAla8]NKA(4-10) and SP, respectively). MEN 10627 and MEN 11420 were potent and competitive antagonists in blocking NKA-induced IP3 formation and PGE2 release: MEN 10627 and MEN 11420 displayed comparable potencies in blocking the two functional responses initiated by occupancy of the NK2 receptor by NKA. Pretreatment of the cells with pertussis toxin (500 ng/ml for 18 h) did not significantly modify the basal or stimulated phosphatidylinositol turnover but reduced the basal and NKA-induced PGE2 release by about 35%. The phospholipase C inhibitor U-73122 (10 microM) prevented the NKA-induced formation of IP3 but did not affect PGE2 release. Conversely, the phospholipase A2 inhibitor quinacrine (100 microM) blocked the release of arachidonic acid and PGE2 without affecting the NKA-stimulated formation of IP3. Chelation of extracellular calcium with 3 mM EGTA inhibited the NKA-induced PGE2 release by 81% but was without effect on basal and NKA-stimulated IP3 production. The calcium channel blockers verapamil (10 microM) and omega-conotoxin GVIA (0.1 microM) did not modify the basal PGE2 production and had no significant effect on the response to tachykinins while the blocker of non-selective cation channels, SKF-96365 (10 microM), inhibited the response to NKA by about 74%. SKF-96365 did not affect the basal or the NKA-induced IP3 formation. In conclusion, our data demonstrate that the human tachykinin NK2 receptor expressed in CHO cells displays binding affinity and functional properties which are those of a native NK2 receptor. No pharmacological evidence for heterogeneity of the human NK2 receptor was obtained in this study. Our findings indicate that the human tachykinin NK2 receptor is independently coupled to both PLC and PLA2 signaling pathways. Activation of the PLA2 pathway may be linked to the opening of a voltage-independent cation channel which activates a Ca2+-dependent PLA2.
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PMID:Independent coupling of the human tachykinin NK2 receptor to phospholipases C and A2 in transfected Chinese hamster ovary cells. 982 60

The present study evaluated some of the mechanisms underlying prostaglandin E2 (PGE2)-induced paw edema formation in mice. Intraplantar (i.pl.) injection of PGE2 (0.10-10.0 nmol/paw) into the hindpaw elicited a dose-related edema formation, with a mean ED50 value of 0.42 nmol/paw. The coinjection of selective E-prostanoid (EP)3 [(2E)-N-[(5-bromo-2-methoxyphenyl)-sulfonyl]-3-[5-chloro-2-(2-naphthylmethyl)phenyl]acrylamide; L826266), but not EP2 or EP4 (all 10 nmol/paw), receptor antagonists significantly inhibited PGE2-induced paw edema. Like L826266, the PGE2-induced paw edema was markedly reduced by treatment with pertussis toxin and phospholipase C (PLC) inhibitor 1-[6-[[17beta-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122). Likewise, the selective neurokinin (NK)1 receptor antagonist N-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-l-prolyl]-N-methyl-N-phenyl-methyl-3-(2-aphthyl)-l-alaninamide (FK888) and the antagonist of vanilloid receptor (TRPV1) receptors 4'-chloro-3-methoxycinnamanilide (SB366791) (both 1 nmol/paw) also significantly inhibited PGE2-mediated paw edema. Conversely, the selective NK2, NK3, and calcitonin gene-related peptide (CGRP) CGRP(8-37) receptor antagonists all failed to interfere with PGE2-induced paw edema. The neonatal treatment of mice with capsaicin was also able to reduce PGE2-induced paw edema. The inhibitors of protein kinase C (PKC) 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X) and mitogen protein-activated kinases (MAPKs; 30 nmol/paw) c-Jun NH2-terminal kinase (JNK) (anthra[1,9-cd]pyrazol-6(2H)-one; SP600125), extracellular signal-regulated kinase (PD98059), and p38 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; SB203580], but not protein kinase A, markedly decreased the PGE2-mediated edema formation. The i.pl. injection of PGE2 (3 nmol/paw) induced a significant activation of MAPKs, namely, JNK and p38, an effect that was largely prevented by the selective EP3 receptor antagonist L826266 (10 nmol/paw). Collectively, these findings indicate that edematogenic responses elicited by PGE2 are mediated by EP3 receptor activation, also involving the stimulation of PLC, PKC, and MAPKs pathways and the participation of TRPV1 and NK1 receptors. These results make a considerable contribution to our comprehension of the mechanisms involved in PGE2-mediated inflammatory responses in mice.
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PMID:Pharmacological and molecular characterization of the mechanisms involved in prostaglandin E2-induced mouse paw edema. 1664 3