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)

Endothelin-1 has dual vasoactive effects, mediating vasoconstriction via ETA receptor activation of vascular smooth muscle cells and vasorelaxation via ETB receptor activation of endothelial cells. Although it is commonly accepted that endothelin-1 binding to endothelial cell ETB receptors stimulates nitric oxide (NO) synthesis and subsequent smooth muscle relaxation, the signaling pathways downstream of ETB receptor activation are unknown. Here, using a model in which we have utilized isolated primary endothelial cells, we demonstrate that ET-1 binding to sinusoidal endothelial cell ETB receptors led to increased protein kinase B/Akt phosphorylation, endothelial cell nitric-oxide synthase (eNOS) phosphorylation, and NO synthesis. Furthermore, eNOS activation was not dependent on tyrosine phosphorylation, and pretreatment of endothelial cells with pertussis toxin as well as overexpression of a dominant negative G-protein-coupled receptor kinase construct that sequesters betagamma subunits inhibited Akt phosphorylation and NO synthesis. Taken together, the data elucidate a G-protein-coupled receptor signaling pathway for ETB receptor-mediated NO production and call attention to the absolute requirement for heterotrimeric G-protein betagamma subunits in this cascade.
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PMID:Endothelin-1 activates endothelial cell nitric-oxide synthase via heterotrimeric G-protein betagamma subunit signaling to protein jinase B/Akt. 1452 27

G-protein-coupled receptor 100 (GPR100) was discovered by searching the human genome database for novel G-protein-coupled peptide receptors. Full-length GPR100 was amplified from a cDNA library of the neuroendocrine cell line BON, which is derived from a human pancreas carcinoid. The open-reading frame, present on a single exon, coded for a protein of 374 amino acids with highest sequence identity (43%) to the human orphan somatostatin- and angiotensin-like peptide receptor. The analysis of chromosomal localisation mapped the GPR100 gene to chromosome 1q21.2-q21.3. The stable expression of GPR100 in Chinese hamster ovary cells together with aequorin as calcium sensor and the promiscuous G-protein subunit alpha16 as signal transducer revealed bradykinin and kallidin as effectors to elicit a calcium response. Dose-response curves yielded EC50 values for both ligands in the low nanomolar range, while the respective analogues without arginine at the carboxy-terminus were inactive. Calcium mobilisation was inhibited by the phospholipase C blocker U73122, but not by pertussis toxin, suggesting the involvement of the G-protein subunit alphaq and not alphai or alphao in signal transduction. In line with the main function of kinins as peripheral hormones, we found that GPR100 was expressed predominantly in tissues like pancreas, heart, skeletal muscle, salivary gland, bladder, kidney, liver, placenta, stomach, jejunum, thyroid gland, ovary, and bone marrow, but smaller amounts were also detected in the brain and in cell lines derived from tumours of various origins.
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PMID:Identification and characterisation of GPR100 as a novel human G-protein-coupled bradykinin receptor. 1453 Feb 18

Human chymase is known to function as a chemoattractant for human leukocytes. To investigate the mechanism of the chymase-induced cell migration, change in intracellular calcium concentration ([Ca(2+)]i) was examined in human polymorphonuclear (PMN) cells using Fluo-3 as a fluorescent Ca(2+) indicator. Treatment of PMN cells with human chymase caused [Ca(2+)]i elevation in a concentration-dependent manner. Depletion of extracellular Ca(2+) from the medium partially attenuated the chymase-induced [Ca(2+)]i increase, showing that both Ca(2+) influx and Ca(2+) release from internal stores might be involved in the [Ca(2+)]i response. Pretreatment of the cells with pertussis toxin completely blocked the chymase-induced [Ca(2+)]i signal, suggesting an involvement of G protein in the chymase-mediated [Ca(2+)]i elevation. The data in the present study raise the possibility that the chymase-induced cell migration is mediated by the [Ca(2+)]i elevation, which might be caused by stimulation of a G-protein-coupled receptor such as protease-activated receptors (PARs).
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PMID:Human chymase stimulates Ca2+ signaling in human polymorphonuclear cells. 1455 74

PLCepsilon (phospholipase Cepsilon) is a novel PLC that has a CDC25 guanine nucleotide exchange factor domain and two RA (Ras-association) domains of which the second (RA2) is critical for Ras activation of the enzyme. In the present studies, we examined hormonal stimulation to elucidate receptor-mediated pathways that functionally regulate PLCepsilon. We demonstrate that EGF (epidermal growth factor), a receptor tyrosine kinase agonist, and LPA (lysophosphatidic acid), S1P (sphingosine 1-phosphate) and thrombin, GPCR (G-protein-coupled receptor) agonists, stimulate PLCepsilon overexpressed in COS-7 cells. EGF stimulated PLCepsilon in an RA2-dependent manner through Ras and Rap. In contrast, LPA, S1P and thrombin stimulated PLCepsilon by both RA2-independent and -dependent mechanisms. To determine the G-proteins that mediate the effects of these GPCR agonists, we co-expressed constitutively active G-proteins with PLCepsilon and found that G(alpha12), G(alpha13), Rho, Rac and Ral stimulate PLCepsilon in an RA2-independent manner; whereas TC21, Rap1A, Rap2A and Rap2B stimulate PLCepsilon in an RA2-dependent manner similar to H-Ras. Of these G-proteins, we show that G(alpha12)/G(alpha13) and Rap partly mediate the effects of LPA, S1P and thrombin to stimulate PLCepsilon. In addition, the stimulation by LPA and S1P is also partly sensitive to pertussis toxin. These studies demonstrate diverse hormonal regulation of PLCepsilon by distinct and overlapping pathways.
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PMID:Hormonal regulation of phospholipase Cepsilon through distinct and overlapping pathways involving G12 and Ras family G-proteins. 1456 55

The topology of the signalling pathway linking the G-protein-coupled receptor agonist lysophosphatidic acid (LPA) to extracellular-signal-regulated kinase activation remains undeciphered. In the present study, we report that analysis of LPA signals at the level of Ras-GTP formation and Ras nucleotide exchange discriminates true mediatory signals from permissive activities that do not participate in signal relay. Hence, whereas pertussis toxin (PTX) treatment impairs stimulation of nucleotide exchange, epidermal growth factor receptor (EGFR) inhibition does not compromise LPA-induced acceleration of nucleotide exchange, but instead attenuates basal nucleotide turnover on Ras. Our data indicate that LPA activation of Ras proceeds via PTX-sensitive G(i/o)-proteins and requires a permissive input from basal EGFR activity.
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PMID:Ras activation in response to lysophosphatidic acid requires a permissive input from the epidermal growth factor receptor. 1465 16

Ras proteins mediate the proliferative effects of G-protein-coupled receptors (GPCRs), but the role of Rap proteins in GPCR signaling is unclear. We have developed a novel cellular proliferation assay for examining signal transduction to Rap utilizing Ras-rap chimeras that respond selectively to Rap-specific exchange factors, but which stimulate cellular proliferation through Ras effectors. Both the D1 dopamine receptor (Gs-coupled) and the 5HT1E serotonin receptor (Gi-coupled) mediated cellular proliferation in a Ras/rap chimera-dependent manner. Responses to both receptors were PKA-independent. Both receptors activated Ras/rap and full-length Rap as measured by activation-specific probes. Pertussis toxin blocked Ras/rap-dependent responses to 5HT1E but not D1. Ras/rap-dependent responses to both receptors were insensitive to beta-gamma scavengers. Responses to 5HT1E, but not D1, were sensitive to inhibition by a dominant-negative C3G fragment, by the Src-like kinase inhibitors PP1 and PP2, and by a dominant-negative mutant of Src. Very similar data were obtained for two other Gi-coupled receptors, the D2 dopamine receptor and the alpha2C adrenergic receptor. A constitutively active mutant of Galphai2 also mediated Ras/rap-dependent responses. These data indicate that GPCRs coupled to pertussis-toxin-sensitive G-proteins activate Rap through a Galpha subunit, C3G, and Src-dependent pathway.
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PMID:G-protein-coupled receptor-mediated activation of rap GTPases: characterization of a novel Galphai regulated pathway. 1471 29

A Drosophila melanogaster G-protein-coupled receptor (NPFR76F) that is activated by neuropeptide F-like peptides has been expressed in Xenopus oocytes to determine its ability to regulate heterologously expressed G-protein-coupled inwardly rectifying potassium channels. The activated receptor produced inwardly rectifying potassium currents by a pertussis toxin-sensitive G-protein-mediated pathway and the effects were reduced in the presence of proteins, such as the betaARK 1 carboxy-tail fragment and alpha-transducin, which bind G-protein betagamma-subunits. Short Drosophila NPF-like peptides were more potent than long NPF-like peptides at coupling the receptor to the activation of inwardly rectifying potassium channels. The putative endogenous short Drosophila NPF-like peptides showed agonist-specific coupling depending on whether their actions were assessed as the activation of the inwardly rectifying potassium channels or as the activation of endogenous inward chloride channels through a co-expressed promiscuous G-protein, Galpha16. As inwardly rectifying potassium channels are known to be encoded in the Drosophila genome and the NPFR76F receptor is widely expressed in the Drosophila nervous system, the receptor could function to control neuronal excitability or slow wave potential generation in the Drosophila nervous system.
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PMID:The activation of G-protein gated inwardly rectifying K+ channels by a cloned Drosophila melanogaster neuropeptide F-like receptor. 1498 7

Parathyroid hormone (PTH) binds its cognate G-protein-coupled receptor (PTH1R) and signals through both adenylyl cyclase and phospholipase C (PLC). C-terminal determinants of the PTH1R interact with the Na+/H+ exchanger regulatory factor 1 (NHERF-1) by binding the first of two PDZ (psd95, discs-large, ZO-1) domains. Compared with wild-type opossum kidney (OK) cells, OKH cells, a sub-clone, do not display PTH-mediated increases of [Ca2+]i and express NHERF-1 at markedly lower levels. Stable expression of NHERF-1 in the OKH parent (OKH-N1) restores the PTH-mediated increase of [Ca2+]i that arises from an influx of extracellular calcium and is both PLC-dependent and pertussis toxin-sensitive. From a morphological perspective, NHERF-1 and the PTH1R co-localize to apical patches of OKH-N1 cells, an expression pattern that is absent in OKH cells and depends on a direct NHERF-1-PTH1R interaction in OKH-N1 cells. Actin and PLCbeta1 and -beta3 co-localize with NHERF-1 and the PTH1R in OKH-N1 cell apical patches. Actin is also an integral component of the NHERF-1-assembled complex because cytochalasin D disrupts apical localization of both NHERF-1 and the PTH1R and inhibits the PTH-mediated increase of [Ca2+]i. Expression of the first PDZ domain of NHERF-1 acts as a dominant-negative interactor by blocking apical localization of the PTH1R and inhibiting PTH-elicited increases of [Ca2+]i. Thus, NHERF-1 assembles a signaling complex in the apical domains of OK cells that contains the PTH1R, PLCbeta, and the actin cytoskeleton. Disruption of this complex blocks the PTH mediated increases of intracellular calcium.
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PMID:Stimulation by parathyroid hormone of a NHERF-1-assembled complex consisting of the parathyroid hormone I receptor, phospholipase Cbeta, and actin increases intracellular calcium in opossum kidney cells. 1503 30

Mouse fibroblast cells overexpressing phosphatidylinositol transfer protein alpha [PI-TPalpha; sense PI-TPalpha (SPIalpha) cells] show a significantly increased rate of proliferation and an extreme resistance toward ultraviolet- or tumor necrosis factor-alpha-induced apoptosis. The conditioned medium (CM) from SPIalpha cells or the neutral lipid extract from CM stimulated the proliferation of quiescent wild-type NIH3T3 cells. CM was also highly effective in increasing resistance toward induced apoptosis in both wild-type cells and the highly apoptosis-sensitive SPIbeta cells (i.e., wild-type cells overexpressing PI-TPbeta). CM from SPIalpha cells grown in the presence of NS398, a specific cyclooxygenase-2 (COX-2) inhibitor, expressed a diminished mitogenic and antiapoptotic activity. This strongly suggests that at least one of the bioactive factor(s) is an eicosanoid. In accordance, SPIalpha cells express enhanced levels of COX-1 and COX-2. The antiapoptotic activity of CM from SPIalpha cells tested on SPIbeta cells was inhibited by approximately 50% by pertussis toxin and suramin as well as by SR141716A, a specific antagonist of the cannabinoid 1 receptor. These inhibitors had virtually no effect on the COX-2-independent antiapoptotic activity of CM from SPIalpha cells. The latter results imply that PI-TPalpha mediates the production of a COX-2-dependent eicosanoid that activates a G-protein-coupled receptor, most probably a cannabinoid 1-like receptor.
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PMID:Phosphatidylinositol transfer protein alpha regulates growth and apoptosis of NIH3T3 cells: involvement of a cannabinoid 1-like receptor. 1514 75

Discovery of "regulators of G-protein signaling" (RGS) as GTPase-activating proteins for heterotrimeric G proteins has provided a highly sought "missing link," reconciling past discrepancies between the in vitro GTPase activity of purified G proteins and the kinetics of physiological responses mediated by G-protein signaling in vivo. With the number of RGS genes in the mammalian genome at more than 30, associating specific RGS proteins to specific G-protein-coupled receptor (GPCR) signaling events has become a focus of RGS investigators. The ubiquitous expression of multiple RGS proteins has complicated this effort, yet the outlook has been encouraged with the identification of RGS9 as the determinant mediating rapid recovery of the transducin-dependent photoresponse. G-protein-gated inwardly rectifying potassium (GIRK) channels that mediate inhibitory synaptic transmission via GPCR activation of pertussis toxin-sensitive G proteins are similarly accelerated by RGS proteins when reconstituted in heterologous cell expression systems and fully reproduce the gating properties of native GIRK channels in neurons and cardiomyocytes. The endogenous neuronal and cardiac RGS protein(s) that accelerate GPCR-->GIRK channel-gating kinetics are currently not known. This article describes methods used to measure the receptor-dependent GIRK channel-gating parameters reconstituted in Chinese hamster ovary (CHO-K1) cells and Xenopus oocytes, as well as rat atrial myocytes and rat cerebellar granule neurons as model cells with native GPCR-->GIRK channel signaling. Applications of these methods for structure-function-based studies of RGS proteins, G proteins, and GPCRs are discussed. We also describe single cell reverse transcriptase polymerase chain reaction methods developed to profile atrial myocyte and neuronal RGS expression to identify specific RGS proteins for targeted knockdown or knockout.
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PMID:Measuring the modulatory effects of RGS proteins on GIRK channels. 1531 64


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