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)

Both beta(2)- and beta(3)-adrenergic receptors (ARs) are able to activate the extracellular signal-regulated kinase (ERK) pathway. We previously showed that c-Src is required for ERK activation by beta(2)AR and that it is recruited to activated beta(2)AR through binding of the Src homology 3 (SH3) domain to proline-rich regions of the adapter protein beta-arrestin1. Despite the absence of sites for phosphorylation and beta-arrestin binding, ERK activation by beta(3)AR still requires c-Src. Agonist activation of beta(2)AR, but not beta(3)AR, led to redistribution of green fluorescent protein-tagged beta-arrestin to the plasma membrane. In beta-arrestin-deficient COS-7 cells, beta-agonist-dependent co-precipitation of c-Src with the beta(2)AR required exogenous beta-arrestin, but activated beta(3)AR co-precipitated c-Src in the absence or presence of beta-arrestin. ERK activation and Src co-precipitation with beta(3)AR also occurred in adipocytes in an agonist-dependent and pertussis toxin-sensitive manner. Protein interaction studies show that the beta(3)AR interacts directly with the SH3 domain of Src through proline-rich motifs (PXXP) in the third intracellular loop and the carboxyl terminus. ERK activation and Src co-precipitation were abolished in cells expressing point mutations in these PXXP motifs. Together, these data describe a novel mechanism of ERK activation by a G protein-coupled receptor in which the intracellular domains directly recruit c-Src.
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PMID:Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation. 1101 30

Estrogen causes rapid endothelial nitric oxide (NO) production because of the activation of plasma membrane-associated estrogen receptors (ER) coupled to endothelial NO synthase (eNOS). In the present study, we determined the role of G proteins in eNOS activation by estrogen. Estradiol-17beta (E(2), 10(-8) m) and acetylcholine (10(-5) m) caused comparable increases in NOS activity (15 min) in intact endothelial cells that were fully blocked by pertussis toxin (Ptox). In addition, exogenous guanosine 5'-O-(2- thiodiphosphate) inhibited E(2)-mediated eNOS stimulation in isolated endothelial plasma membranes, and Ptox prevented enzyme activation by E(2) in COS-7 cells expressing ERalpha and eNOS. Coimmunoprecipitation studies of plasma membranes from COS-7 cells transfected with ERalpha and specific Galpha proteins demonstrated E(2)-stimulated interaction between ERalpha and Galpha(i) but not between ERalpha and either Galpha(q) or Galpha(s); the observed ERalpha-Galpha(i) interaction was blocked by the ER antagonist ICI 182,780 and by Ptox. E(2)-stimulated ERalpha-Galpha(i) interaction was also demonstrable in endothelial cell plasma membranes. Cotransfection of Galpha(i) into COS-7 cells expressing ERalpha and eNOS yielded a 3-fold increase in E(2)-mediated eNOS stimulation, whereas cotransfection with a protein regulator of G protein signaling, RGS4, inhibited the E(2) response. These findings indicate that eNOS stimulation by E(2) requires plasma membrane ERalpha coupling to Galpha(i) and that activated Galpha(i) mediates the requisite downstream signaling events. Thus, novel G protein coupling enables a subpopulation of ERalpha to initiate signal transduction at the cell surface. Similar mechanisms may underly the nongenomic actions of other steroid hormones.
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PMID:Plasma membrane estrogen receptors are coupled to endothelial nitric-oxide synthase through Galpha(i). 1136 63

The neuropeptide head activator stimulates cell proliferation of neuronal precursor and neuroendocrine cells. The mitogenic signaling cascade requires Ca(2+) influx for which, as we show in this paper, the growth-factor-regulated Ca(2+)-permeable cation channel, GRC, is responsible. GRC is a member of the transient receptor potential channel family. In uninduced cells only low amounts of GRC are present on the plasma membrane but, upon stimulation with head activator, GRC translocates from an intracellular compartment to the cell surface. Head activator functions as an inducer of GRC translocation in neuronal and neuroendocrine cells, which express GRC endogenously, and also in COS-7 cells after transfection with GRC. Head activator is no direct ligand for GRC, but its action requires the presence of a receptor coupled to a pertussis-toxin inhibitable G-protein. Heterologously expressed GRC becomes activated by head activator, which results in opening of the channel and Ca(2+) influx. SK&F 96365, an inhibitor specific for TRP-like channels, blocks Ca(2+) entry and, consequently, translocation of GRC is prevented. Head activator-induced GRC activation and translocation are also inhibited by wortmannin and KN-93, blockers of the phosphatidylinositol 3-kinase and of the Ca(2+)/calmodulin-dependent kinase, respectively, which implies a role for both kinases in head-activator signaling to GRC.
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PMID:The neuropeptide head activator induces activation and translocation of the growth-factor-regulated Ca(2+)-permeable channel GRC. 1170 12

Dexras1 is a novel GTP-binding protein (G protein) that was recently discovered on the basis of rapid mRNA up-regulation by glucocorticoids in murine AtT-20 corticotroph cells and in several primary tissues. The human homologue of Dexras1, termed activator of G protein signaling-1 (AGS-1), has been reported to stimulate signaling by G(i) heterotrimeric G proteins independently of receptor activation. The effects of Dexras1/AGS-1 on receptor-initiated signaling by G(i) have not been examined. Here we report that Dexras1 inhibits ligand-dependent signaling by the G(i)-coupled N-formyl peptide receptor (FPR). Dexras1 and FPR were transiently co-expressed in both COS-7 and HEK-293 cells. Activation of FPR by ligand (N-formyl-methionine-leucine-phenylalanine (f-MLF)) caused phosphorylation of endogenous Erk-1/2 that was reduced by co-expression of Dexras1. Direct effects of Dexras1 on the activity of co-expressed, epitope-tagged Erk-2 (hemagglutinin (HA)-Erk-2) were measured by immune complex in vitro kinase assay. Expression of Dexras1 alone resulted in a 1.9- to 4.9-fold increase in HA-Erk-2 activity; expression of the unliganded FPR alone resulted in a 6.2- to 8.1-fold increase in HA-Erk-2 activity. Stimulation of FPR by f-MLF produced a further 8- to 10-fold increase in HA-Erk-2 activity over the basal (non-ligand-stimulated) state, and this ligand-dependent activity was attenuated at the time points of maximal activity by co-expression of Dexras1 (reduced 31 +/- 6.8% in COS-7 at 10 min and 86 +/- 9.2% in HEK-293 at 5 min, p < 0.01 for each). Expression of Dexras1 did not influence protein expression of FPR or Erk, suggesting that the inhibitory effects of Dexras1 reflect a functional alteration in the signaling cascade from FPR to Erk. Expression of Dexras1 had no effect on expression of G(i)alpha species, but significantly impaired pertussis toxin-catalyzed ADP-ribosylation of membrane-associated G(i)alpha. Expression of Dexras1 also significantly decreased in vitro binding of GTPgammaS in f-MLF-stimulated membranes of cells co-transfected with FPR. These data suggest that Dexras1 inhibits signal transduction from FPR to Erk-1/2 through an effect that is very proximal to receptor-G(i) coupling. While Dexras1 weakly activates Erk in the resting state, more potent effects are evident in the modulation of ligand-stimulated receptor signal transduction, where Dexras1 functions as an inhibitor rather than activator of the Erk mitogen-activated protein kinase signaling cascade.
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PMID:Dexras1/AGS-1 inhibits signal transduction from the Gi-coupled formyl peptide receptor to Erk-1/2 MAP kinases. 1175 35

The rat cytomegalovirus (RCMV) R33 gene is conserved among all betaherpesviruses and encodes a protein (pR33) that shows sequence similarity with chemokine-binding G protein-coupled receptors (GPCRs). Previously, the physiological significance of the R33 gene was demonstrated by the finding that an RCMV strain with R33 deleted is severely attenuated in vivo and is unable to either enter or replicate in the salivary glands of infected rats. Here, we report that RCMV pR33 is expressed as a functional GPCR that signals in an agonist-independent manner in both COS-7 and Rat2 cells. Transient expression of pR33 in COS-7 cells results in constitutive activation of phospholipase C (PLC) due to coupling to G proteins of the G(q) class. Interestingly, PLC activation is partially inhibited by cotransfection with G(alpha)-transducin subunits, which indicates the involvement of G(betagamma) as well as Galpha subunits in pR33-mediated signaling. Surprisingly, PLC activation is also partially inhibited by addition of pertussis toxin (PTX), suggesting that pR33 activates not only G(q) but also G(i/0) proteins. The constitutive activation of G(i/0) proteins by pR33 is further demonstrated by the PTX-sensitive decrease of CRE-mediated transcription and the PTX-sensitive increase of both NF-kappaB- and SRE-mediated transcription. In contrast to its homolog of human herpesvirus 6B (pU12), pR33 does not bind RANTES.
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PMID:The rat cytomegalovirus R33-encoded G protein-coupled receptor signals in a constitutive fashion. 1177 7

We previously demonstrated that the mouse EP3beta receptor and its C-terminal tail-truncated receptor (abbreviated T-335) expressed in Chinese hamster ovary cells showed agonist-dependent and fully constitutive Gi activity in forskolin-stimulated cAMP accumulation, respectively. Here we examined the effect of the EP3beta receptor or T-335 receptor on adenylyl cyclase activity stimulated by the Gs-coupled EP2 subtype receptor in COS-7 cells. As a result, sulprostone, a selective EP3 agonist, dose dependently augmented butaprost-stimulated adenylyl cyclase activity in EP3beta receptor- or T-335 receptor-expressing COS-7 cells. However, such adenylyl cyclase augmentation was not attenuated by either pertussis toxin treatment or expression of the PH domain of rat betaARK1, which serves as a scavenger of Gbetagamma subunits, but was partially attenuated by treatment with either 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester, an intracellular Ca(2+) chelator, or W-7, a calmodulin inhibitor. These findings suggest that the C-terminal tail of the EP3beta receptor is not essentially involved in activation of EP2 receptor-stimulated adenylyl cyclase in a Ca(2+)/calmodulin-dependent but Gbetagamma subunit-independent manner.
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PMID:Augmentation of receptor-mediated adenylyl cyclase activity by Gi-coupled prostaglandin receptor subtype EP3 in a Gbetagamma subunit-independent manner. 1177 48

Melatonin is a pineal hormone involved in neuroendocrine processes in mammals. It has been shown that melatonin inhibits the enzymatic activities of adenylyl cyclases and the transcriptional activities of CREB. In this report, we demonstrate that 2-iodomelatonin (2IMT) treatment on COS-7 cells transfected with melatonin receptors (mt1 and MT2) induces c-Jun N-terminal kinase (JNK) activation, which is pertussis toxin (PTX)-sensitive, Ras/Rac-dependent and may involve Src-family protein tyrosine kinases. Moreover, PTX-insensitive Gs, Gz and G16 are capable of linking activated melatonin receptors to the stimulation of JNK. Agonist stimulation on PTX-pretreated COS-7 cells overexpressing mt1 receptor, Galpha(s) and adenylyl cyclase VI led to increased cAMP accumulation. Stimulation of endogenous mt1 receptors in MCF-7 cells was associated with the activation of both JNK and extracellular signal-regulated kinase (ERK). This report demonstrates the stimulatory effect of melatonin receptors on JNK, and provides experimental evidence for a functional coupling between the G(i)-coupled melatonin receptor and Gs, in terms of adenylyl cyclase activation.
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PMID:Melatonin mt1 and MT2 receptors stimulate c-Jun N-terminal kinase via pertussis toxin-sensitive and -insensitive G proteins. 1181 53

Both lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are platelet-derived phospholipids that elicit diverse biological responses. In endothelial cells, S1P stimulates the EDG-1 receptor-mediated activation of the endothelial isoform of nitric oxide synthase (eNOS), but the role of LPA in eNOS regulation is less well understood. We now report that LPA treatment of bovine aortic endothelial cells (BAEC) activates eNOS enzyme activity in a pathway that involves phosphorylation of eNOS on serine 1179 by protein kinase Akt. In contrast to the cellular responses elicited by S1P in COS-7 cells, LPA can stimulate the activation of eNOS and Akt independently of EDG-1 receptor transfection. LPA-stimulated enzyme activation was significantly attenuated in an eNOS mutant lacking the site that is phosphorylated by kinase Akt (eNOS S1179A). In BAEC, activation of eNOS by LPA is completely blocked by pertussis toxin, by the intracellular calcium chelator BAPTA (1,2-bis(aminophenoxy) ethane-N,N,N',N'-tetraacetic acid), and by the phosphoinositide 3-kinase (PI3-K) inhibitor wortmannin, but is unaffected by U0126, an inhibitor of mitogen-activated protein (MAP) kinase pathways. Analysis of the LPA dose response for eNOS activation reveals an EC(50) of approximately 40 nM, a concentration well below the potency of LPA at the EDG-1 receptor. Taken together, these results indicate that LPA potently activates eNOS in BAEC in a pathway distinct from the EDG-1 receptor, but mediated by a similar receptor-mediated pathway dependent on pertussis toxin-sensitive G proteins and involving activation of the PI3-K/Akt pathway. These studies have identified a role for the phospholipid LPA in eNOS activation, and point out the complementary role of distinct platelet-derived lipids in endothelial signaling pathways.
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PMID:Lysophosphatidic acid and receptor-mediated activation of endothelial nitric-oxide synthase. 1193 94

We have examined the functional significance of the naturally occurring mutation at position 64 of human beta3-adrenergic receptor (beta3AR), which changes the amino acid from tryptophan to arginine (W64R-beta3AR). The affinities of betaAR agonists for W64R-beta3AR expressed in COS-7 cells were not significantly different from those for wild type beta3AR. When two receptors are expressed at various expression levels, and stimulated with CGP12177A, they showed essentially the same EC50 values and maximal responses. Overexpression of Gi and Go, or the treatment with pertussis toxin did not affect the agonist-induced cAMP response, suggesting that Gi and Go did not contribute to the beta3AR-induced cAMP response. However, the enhanced cAMP response was observed when W64R-beta3AR was coexpressed with the adenylyl cyclase type III isoform, and stimulated by CGP12177A and isoproterenol. These results indicate that the cAMP response of W64R-beta3AR can be enhanced under the particular condition that adenylyl cyclase type III was coexpressed.
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PMID:Enhanced cAMP response of naturally occurring mutant of human beta3-adrenergic receptor. 1194 87

Conventional mode of activation of SH2 domain-containing phosphatase 1 (SHP-1) by a single transmembrane (TM) inhibitory receptor such as killer cell inhibitory receptor, Fcgamma receptor type IIb1, and paired Ig-like receptors of inhibitory types requires tyrosine phosphorylation of immunoreceptor tyrosine-based inhibitory (ITIM) motifs in the cytoplasmic domains of the inhibitory receptors. Contrary to this paradigm, AT(2), a G protein-coupled 7TM receptor that does not undergo tyrosine phosphorylation in response to angiotensin II (Ang II) stimulation, also activates SHP-1. Here we show that SHP-1 constitutively and physically associates with AT(2) receptor in transfected COS-7 cells. On stimulation by Ang II, SHP-1 becomes activated and dissociated from AT(2) receptor, independent of pertussis toxin. Cotransfection of transducin G(betagamma) inhibits SHP-1/AT(2) association and the SHP-1 activation, whereas cotransfection of C-terminal of beta-adrenergic receptor kinase, which abrogates G(betagamma) signaling, facilitates SHP-1 activation. Surprisingly, SHP-1/AT(2) association and the SHP-1 activation requires the presence of G(alphas) as shown by differential coimmunoprecipitation, dominant negative G(alphas), constitutively active G(alphas), and G(alpha) peptides. A mutant AT(2) receptor D141A-R142L that is inactive in G(alpha) protein activation constitutively associates with SHP-1 and activates it. Together, these results indicate that G(alphas) alone, rather than exclusively in the form of G(alphabetagamma) heterotrimer may facilitate signal transduction for G protein-coupled receptors, suggesting a novel mechanism distinct from the classic paradigm of heterotrimeric G proteins. The AT(2)-mediated ITIM-independent activation of SHP-1 that is distinct from the conventional mode of activation, may represent a general paradigm for activation of SHP-1/2-class tyrosine phosphatases by G protein-coupled receptors.
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PMID:Gbeta gamma -independent constitutive association of Galpha s with SHP-1 and angiotensin II receptor AT2 is essential in AT2-mediated ITIM-independent activation of SHP-1. 1222 Dec 92


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