UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the muscarinic activation of Ca(2+)-activated Cl- currents [ICl(Ca)] in voltage-clamped equine tracheal myocytes. The threshold of cytosolic free Ca2+ concentration ([Ca2+]i) required for activation of ICl(Ca) was 202 +/- 22 nM, and full activation of the current occurred at 771 +/- 31 nM. Hexahydro-sila-difenidol (M3 antagonist) inhibited the methacholine-induced phasic [Ca2+]i increase and ICl(Ca) in a concentration-dependent manner, whereas methoctramine (M2 antagonist) only slightly attenuated the [Ca2+]i increase and ICl(Ca) (14.8 and 21.4%, respectively), consistent with incomplete selectivity. Dialysis of heparin (10 mg/ml) blocked methacholine-induced [Ca2+]i and ICl(Ca) but had no effect on the caffeine-induced Ca2+ release or ICl(Ca); inositol 1,4,5-trisphosphate (100 microM) induced ICl(Ca) and blocked the methacholine current. Conversely, ruthenium red (50 microM) prevented the caffeine-induced [Ca2+]i release and ICl(Ca) but had no effect on methacholine-induced [Ca2+]i or current. Intracellular dialysis of the calmodulin antagonist N-(6-aminohexyl)-1-naphthalenesulfonamide (W-7, 500 microM) or the Ca2+/calmodulin-dependent protein kinase inhibitor KN93 (5 microM) had no effect on the [Ca2+]i increase or ICl(Ca). Pertussis toxin (0.5 mg/ml) did not affect the increase in [Ca2+]i or ICl(Ca). Dialysis with antibodies directed against the alpha-subunit of Gq/G11 (Gq alpha/ G alpha 11) blocked the methacholine-induced ICl(Ca) in a concentration-dependent manner, whereas anti-G alpha i-1/G alpha 1-2 antibodies (1:35) and anti-G alpha i-3/G(o) alpha antibodies (1:35) were without effect. The results indicate that stimulation of phospholipase C via M3/Gq proteins is the predominant signaling pathway for the activation of ICl(Ca); at high agonist concentrations, Ca(2+)-induced Ca2+ release does not appear to play a prominent role in muscarinic signaling.
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PMID:Muscarinic signaling pathway for calcium release and calcium-activated chloride current in smooth muscle. 927 48

The corticostriatal pathway is among the largest glutamatergic pathways in the brain, and of particular interest to the study of glutamatergic transmission. The metabotropic glutamate receptors (mGluRs) couple the actions of glutamate to intracellular second messenger systems through G-proteins. The most prominent of the mGluRs present in the target of this pathway, the striatum, is mGluR5. The identity of the G-proteins mediating the actions of mGluR5 are unknown, but the receptor is linked to stimulation of phosphoinositide (PI) turnover and largely resistant to the effects of pertussis toxin, which inhibits some G-proteins. We used in situ hybridization to examine the expression and regulation of three pertussis toxin insensitive G-protein alpha sub-units: Gq, G11, and Gz. We found that these mRNAs are differentially distributed in the rat brain, but all three are expressed by striatal neurons. After glutamatergic deafferentation of the striatum by decortication, there is a modest upregulation of G11 mRNA, while expression of Gq and Gz are unchanged. Following dopaminergic deafferentation, expression of Gq, G11, and Gz are not altered, although expression of the pertussis-sensitive sub-unit Go is increased. Our data suggests that Gz, Gq, and G11 are each expressed by striatal neurons, and therefore may be involved in mediating the actions of mGluR5 in these cells. After decortication G11 is upregulated, but the magnitude of this effect is small, and alone seems insufficient to account for the marked biochemical supersensitivity of glutamate-stimulated PI turnover which is observed.
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PMID:Differential localization of the mRNAs for the pertussis toxin insensitive G-protein alpha sub-units Gq, G11, and Gz in the rat brain, and regulation of their expression after striatal deafferentation. 955 65

The tachykinin NK1 receptor is widely expressed in the mammalian central and peripheral nervous system. Powerful pharmacological tools (agonists and antagonists) are now available to elucidate the physiological role of NK1 receptors at these levels, as well as to understand their role in diseases and establish the possible therapeutic usefulness of NK1 receptor antagonists for treatment of human diseases. The structure-activity studies that have led to the development of potent peptide and non-peptide ligands for the tachykinin NK1 receptor are here reviewed. Among the peptide agonists and antagonists, linear and cyclic sequences have been developed. The non peptide antagonists belong to different chemical classes, i.e. steroids, perhydroisoindolones, quinuclidines, piperidines and tryptophane derivatives. The first non peptide antagonists for NK1 receptors have been obtained by random screening of chemical compounds large collections. The resulting leads were optimized with 'classic' structure activity approaches, aiming at identifying 'common' motifs for interaction with the receptor by ligands of different chemical classes. The results derived from the recent application of molecular biology techniques were useful to drive the design of new ligands toward a precise structural definition of ligand-receptor bi-molecular interactions. Studies on mutant receptors have established that the sites of interaction of peptide agonists and non peptide antagonists with the tachykinin NK1 receptor are largely non overlapping. Moreover, data obtained from mutagenesis of the NK1 receptor further indicate that some amino acid residues in the NK1 receptor sequence are critical for determining the binding affinity of some but not all ligands. Therefore, different antagonists discovered from random screening may not possess common points of interaction or common structural and conformational characteristics for their interaction with the tachykinin NK1 receptor. The tachykinin NK1 receptor couples with G-proteins to determine its biological effects in target cells. Several G-proteins both sensitive (Go, Gi) and insensitive (Gq, G11) to pertussis toxin can mediate the action of NK1 receptors. Moreover, several second messanger signalling systems (elevation of intracellular calcium, stimulation of phosphoinositol turnover, arachidonic acid mobilization, cAMP accumulation) have to be activated following NK1 receptor signalling. Also a direct modulation of certain ion channels at membrane level has been proposed. The NK1 receptor undergoes prompt and significant tachyphylaxis upon exposure to the agonist: this has been shown to be linked with receptor internalization which also occurs physiologically when the NK1 receptor is stimulated by endogenous tachykinins.
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PMID:The tachykinin NK1 receptor. Part I: ligands and mechanisms of cellular activation. 957 22

The diverse physiological functions exerted by the neuropeptide galanin may be regulated by multiple G protein-coupled receptor subtypes and intracellular signaling pathways. Three galanin receptor subtypes (GalRs) have been recently cloned, but the G protein coupling profiles of these receptors are not completely understood. We have generated GalR1- and GalR2-expressing Chinese hamster ovary (CHO) cell lines and systematically examined the potential for these two receptors to couple to the Gs, Gi, Go, and Gq proteins. Galanin did not stimulate an increase in cAMP levels in GalR1/CHO or GalR2/CHO cells, suggesting an inability of either receptor to couple to Gs. Galanin inhibited forskolin-stimulated cAMP production in GalR1/CHO cells by 70% and in GalR2/CHO cells by 30%, suggesting a strong coupling of GalR1 to Gi and a more modest coupling between GalR2 and Gi. GalR1 and GalR2 both mediated pertussis toxin-sensitive MAPK activity (2-3-fold). The stimulation mediated by GalR1 was inhibited by expression of the C-terminus of beta-adrenergic receptor kinase (beta ARKct), which specifically inhibits G beta gamma signaling, but was not affected by the protein kinase C (PKC) inhibitor, bis[indolylmaleimide], or cellular depletion of PKC. In contrast, GalR2-mediated MAPK activation was not affected by beta ARKct expression but was abolished by inhibition of PKC activity. The data demonstrate that GalR1 is coupled to a Gibetagamma signaling pathway to mediate MAPK activation. In contrast, GalR2 utilizes a distinct signaling pathway to mediate MAPK activation, which is consistent with Go-mediated MAPK activation in CHO cells. Galanin was unable to stimulate inositol phosphate (IP) accumulation in CHO or COS-7 cells expressing GalR1. In contrast, galanin stimulated a 7-fold increase in IP production in CHO or COS-7 cells expressing GalR2. The GalR2-mediated IP production was not affected by pertussis toxin, suggesting a linkage of GalR2 with Gq/G11. Thus, the GalR1 receptor appears to activate only the Gi pathway. By contrast, GalR2 is capable of stimulating signaling which is consistent with activation of Go, Gq/G11, and Gi. The differential signaling profiles and the tissue distribution patterns of GalR1 and GalR2 may underlie the functional spectra of galanin action mediated by these galanin receptors and regulate the diverse physiological functions of galanin.
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PMID:Differential intracellular signaling of the GalR1 and GalR2 galanin receptor subtypes. 957 54

In most tissues and cells the opioid receptor-like (ORL1) receptor regulates effectors primarily through the pertussis toxin (PTX)-sensitive guanine nucleotide-binding regulatory proteins (G proteins) Gi/Go. Many Gi-coupled receptors possess additional capability to interact with one or more PTX-insensitive G proteins. Using the betagamma-induced stimulation of type 2 adenylyl cyclase as a readout, we screened the ability of ORL1 receptor to interact with a panel of PTX-insensitive G proteins. In the presence of PTX, activation of the ORL1 receptor resulted in the stimulation of type 2 adenylyl cyclase only in HEK 293 cells coexpressing the alpha subunit of Gz, G12, G14, or G16, but not in cells coexpressing G11, G13, or Gq. Coupling to both Gz and G16 was expected because close relatives of the ORL1 receptor, the opioid receptors, are known to couple productively to these G proteins. ORL1 receptor coupling to either G12 or G14 has not been demonstrated. As predicted by the type 2 adenylyl cyclase assays, activation of the ORL1 receptor resulted in the formation of inositol phosphates in COS-7 cells transiently cotransfected with Galpha14. The ORL1 receptor-mediated stimulation of phospholipase C was found to be Galpha14 dependent, agonist dose dependent, ligand selective, and PTX insensitive. We conclude that G14 can link the ORL1 receptor to regulation of phopholipase C.
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PMID:GalphaL1 (Galpha14) couples the opioid receptor-like1 receptor to stimulation of phospholipase C. 986 75

The early signaling mechanism of sphingosine 1-phosphate (S1P) on extracellular signal-regulated kinase (ERK) activation was investigated in C6 glioma cells. S1P activated the enzyme in association with a shift in the mobility on electrophoresis reflecting phosphorylation of both ERK1/ERK2 at as low as 10 nM. The lipid-induced ERK1/2 activation was partially inhibited by treatment of the cells with either phorbol 12-myristate 13-acetate (a long-term treatment to desensitize protein kinase C) or pertussis toxin (PTX) and was completely inhibited by a simultaneous treatment with both agents. Similarly, either calphostin C, an inhibitor of protein kinase C, or U73122, an inhibitor of phospholipase C, partially inhibited the S1Pinduced ERK1/2 activation in the nontreated cells with PTX and completely in the toxin-treated cells. On the other hand, the S1P-induced ERK activation was hardly affected by ethanol, which switched the product of phospholipase D from phosphatidic acid to metabolism-resistant phosphatidylethanol. S1P was able to activate ERK1/2 without a detectable increase in the intracellular content of the lipid, but sphingosine, a substrate of sphingosine kinase, which is an enzyme for S1P generation in the cells, hardly affected the ERK1/2 activation in spite of a marked elevation of intracellular S1P accumulation. This indicates that intracellular increase in S1P is not necessary for the S1P-induced ERK activation, and hence suggests the extracellular action mechanism of S1P. Supporting this idea, mRNAs of recently identified S1P specific receptors, Edg-1 and AGR16/H218, were expressed in C6 cells. Taken together, these results suggested that S1P acts on C6 cells extracellularly possibly through S1P receptors which are linked to at least two signaling pathways, i.e., the PTX-sensitive Gi/Go protein pathway and the toxin-insensitive Gq/G11-phospholipase C-PKC pathway, resulting in the activation of ERK.
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PMID:Possible involvement of cell surface receptors in sphingosine 1-phosphate-induced activation of extracellular signal-regulated kinase in C6 glioma cells. 988 6

1. Three pharmacological types of opioid receptors, mu, delta and kappa, and their corresponding genes have been identified. Although other types of opioid receptors have been suggested, their existence has not been established unequivocally. A fourth opioid receptor, ORL1, which is genetically closely related to the others, has also been isolated. ORL1 responds to the endogenous agonist nociceptin (orphanin FQ) and displays a pharmacological profile that differs greatly from mu, delta and kappa receptors. 2. All opioid receptors mediate many of their cellular effects via activation of heterotrimeric G-proteins. The mu, delta and kappa receptors are all capable of interacting with the pertussis toxin-sensitive G-protein alpha-subunits Gi1, Gi2, Gi3, Go1, Go2 and the pertussis toxin-insensitive Gz and G16. None of the opioid receptors interacts substantially with Gs and mu receptors do not activate Gq, G11, G12, G13, or G14. 3. Differential coupling of different opioid receptors to most types of G-proteins is marginal. The mu, delta and kappa receptors appear to preferentially activate Go and Gi2 over other pertussis toxin-sensitive G-proteins, although there is evidence that mu receptors show some preference for Gi3. delta Receptors couple more efficiently to G16 than do mu or kappa receptors. 4. There is some evidence that opioid receptors, particularly mu and ORL1 receptors, can also couple to cellular effectors in a G-protein-independent manner. 5. In general, the consequences of activation of any of the opioid receptors in a given cell type depend more on the profile (stoichiometry) of the G-proteins and effectors expressed than on the type of opioid receptor present in the cell. Notions that different types of opioid receptors intrinsically couple preferentially to one type of effector rather than another should, therefore, be discarded.
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PMID:Opioid receptor signalling mechanisms. 1040 72

Previously it has been shown that persistent activation of the stimulatory adenylyl cyclase pathway with cholera toxin (CT) downregulates the Gs alpha polypeptide (80%) in a cAMP-independent manner in C6 glioma cells (Shah, 1997). This study was conducted to examine the short and long term effects of CT on the regulation of pertussis toxin-sensitive and -insensitive G proteins and their transcripts in C6 glioma cells. Treatment of C6 cells with CT (100 ng/ml) up to 16 h had no effect on either Gi or Gq/11 alpha proteins. However, prolonged exposure (24-48 h) caused increased expression of Gi (20-30%) and Gq/11 alpha proteins (40%). Urea gradient gels, which can separate Gq alpha and G11 alpha proteins, revealed that prolonged CT treatment increased the expression of both of these G proteins. The CT-mediated enhanced expression of Gq alpha and G11 alpha proteins was accompanied by increased mRNA levels of these proteins as determined by RT/PCR. Cyclic-AMP elevating agents like forskolin (10 microM) and db-cAMP (1 mM) mimicked the effect of CT on Gi but not Gq/11 alpha proteins. These studies show long term cAMP-dependent regulation of Gi and cAMP-independent expression of Gq/11 alpha proteins in C6 glioma cells.
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PMID:Cholera toxin mediated regulation of the expression of Gq alpha and G11 alpha GTP binding proteins. 1041 Mar 8

The purpose of this study was to compare the efficiency of two different Gq protein-coupled receptors (AT1 receptor for angiotensin II and B2 receptor for bradykinin) to activate phospholipase C (PLC). When the receptors were expressed at a similar level of 0.5 pmol/mg of protein, inositol trisphosphate (IP) accumulation elicited by AT1 receptor was four times higher than that elicited by B2 receptor. Genistein and pertussis toxin did not modify AT1 receptor- or B2 receptor-induced IP accumulation. These results indicate that in COS-7 cells, the two receptors activate PLC beta through G proteins of the Gq family. AT1 or B2 receptors were co-expressed with the alpha subunit of either Gq or G11. Both alpha subunits potentiated to the same extent AT1 receptor-induced IP accumulation. alpha 11 was also as efficient as alpha q to potentiate B2 receptor-induced response. Interestingly, however, the potentiating effect of alpha q and alpha 11 was more important (by 5-fold) on AT1 receptor-mediated response than on B2 receptor-mediated response. These results demonstrate that the extent of activation of PLC beta by different Gq-coupled receptors depends on the level of expression of these receptors and on their coupling efficiency. These are important parameters that determine the relative contribution of specific hormones to different biological processes.
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PMID:The bradykinin B2 receptor couples less efficiently than the angiotensin AT1 receptor to the G protein Gq in transiently transfected COS-7 cells. 1063 60

The mitogen-activated protein kinase signaling cascade is used by many G protein-coupled receptors to initiate functional events. In this study, activation of the Gq/G11-coupled thromboxane A2 (TxA2) receptor (TP) by the TxA2 mimetic IBOP in ECV304 cells was found to induce extracellular regulated kinase (ERK) phosphorylation and tyrosine phosphorylation of the epidermal growth factor receptor (EGFR), which were inhibited by the TP antagonist SQ29548, the EGFR kinase inhibitor AG1478, the Src family kinase inhibitor PP1, the Gi/o protein inhibitor pertussis toxin (PTX), or the protein kinase C (PKC) inhibitor calphostin C. TP activation also increased Src kinase activity, which was blocked by PTX, PP1, and calphostin C, but not by AG1478, indicating that Src activation occurs before phosphorylation of EGFR. Blockade of Src activity by expression of dominant negative mutant of Src inhibits mitogen-activated protein kinase (MAPK) activation induced by TxA2. ERK activation induced by the PKC activator phorbol myristate acetate was inhibited by PTX, PP1, AG1478, and calphostin C. In contrast, activation of ERK by lysophosphatidic acid, a Gi-coupled receptor activator, was inhibited by PTX, PP1, and AG1478, but not by calphostin C. Thus, TP-stimulated ERK activation requires Gi, which in turn requires PKC activation. Immunoprecipitation of Galphai showed increased association of Galphai with TPalpha following PKC activation. In conclusion, TPalpha is directly coupled to the Gi protein by a PKC-regulated mechanism; Gi coupling causes Src-dependent transactivation of the EGFR, which is the dominant pathway in TP-mediated ERK activation.
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PMID:The thromboxane A2 receptor activates mitogen-activated protein kinase via protein kinase C-dependent Gi coupling and Src-dependent phosphorylation of the epidermal growth factor receptor. 1116 Jun 27

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