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)

The role of neuropeptide Y (NPY) in the regulation of cardiac function was compared in mammalian and fish hearts. In mammalian heart, most studies have shown that neuropeptide Y inhibits coronary flow and exerts a negative inotropic effect in isolated perfused hearts and cardiac muscles. The mechanisms involved in the action of neuropeptide Y in the heart are under active investigation. Our studies have shown that [Leu31,Pro34]NPY. NPY13-36, neuropeptide Y and peptide YY induced a concentration-dependent decrease in inositol 1,4,5-trisphosphate levels in rat cardiomyocytes, which was blocked by neuropeptide Y antagonists NPY18-36 or PYX-2. There is no difference in the inhibitory effect of neuropeptide Y and peptide YY on inositol 1,4,5-trisphosphate formation. Furthermore, the effects of neuropeptide Y and its analogues were insensitive to pertussis toxin pretreatment. These observations indicate that Y1 and Y2 subtypes of neuropeptide Y receptor in rat cardiomyocytes may be associated with inositol 1,4,5-trisphosphate formation through a pertussis toxin-insensitive Gq protein. The decreased formation of inositol 1,4,5-trisphosphate may be implicated in the negative inotropic effect of neuropeptide Y in the mammalian heart. In dogfish hearts, on the other hand, neuropeptide Y increased cardiac output by increasing heart rate, whereas norepinephrine increased cardiac output by increasing stroke volume. Although neuropeptide Y or norepinephrine alone did not have significant effects on pressure development in these hearts, neuropeptide Y plus norepinephrine did increase pressure development. The inositol 1,4-5-triphosphate level was elevated by norepinephrine alone and was further increased by neuropeptide y plus norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative aspects of the role of neuropeptide Y in the regulation of the vertebrate heart. 774 79

Evidence is presented that the neuropeptide Y receptor is directly coupled to an inhibitory G protein existing in cultured bovine adrenal chromaffin cell membranes. Pertussis toxin catalyzes the [32P]ADP-ribosylation of a 41 kDa plasma membrane protein. 5'-Guanylylimidodiphosphate inhibited the [32P]ADP labelling of this protein in a dose-dependent manner whereas GTP had no effect. Preincubation of the plasma membranes with high concentrations of neuropeptide Y followed by a brief exposure to a low concentration of 5'-guanylylimidodiphosphate significantly inhibited ADP-ribosylation beyond that observed with 5'-guanylylimidodiphosphate alone. These results suggest that the neuropeptide Y receptor in bovine adrenal chromaffin cells is directly coupled to a 41 kDa PTX substrate (presumably the alpha subunit of an inhibitory G protein).
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PMID:Neuropeptide Y inhibits pertussis toxin-catalyzed ADP-ribosylation in bovine adrenal chromaffin cell membranes. 850 26

In human erythroleukemia (HEL) cells, stimulation of alpha2-adrenoceptors by adrenaline or neuropeptide Y Y1 receptors by neuropeptide Y, concomitantly inhibit cAMP accumulation and stimulate mobilization of Ca2+ from intracellular stores via pertussis toxin-sensitive G-proteins. Treatment of HEL cells in chemically-defined, serum-free medium with 1.25% dimethylsulfoxide (DMSO) for 4 days, increased alpha2-adrenoceptor number by 120%, while the neuropeptide Y receptor number was not significantly changed. In DMSO-treated HEL cells, Ca2+ elevations by adrenaline or neuropeptide Y were significantly reduced by 28% and 57%, respectively, while basal Ca2+ and elevations by thrombin or thapsigargin were not significantly altered. Adrenaline and neuropeptide Y-induced inhibition of forskolin-stimulated cAMP accumulation was not significantly altered upon DMSO treatment. While immunodetectable alpha-subunits of Gi2 were not significantly changed by DMSO treatment, those of Gi3 were reduced by 27%. Inactivation of pertussis toxin substrates by pertussis toxin treatment and inhibition of adrenaline or neuropeptide Y stimulated Ca2+ elevations were linearly correlated. These data are compatible with the idea that, in HEL cells, alpha2-adrenoceptors and neuropeptide Y receptors couple to inhibition of adenylyl cyclase via Gi2 while they couple to Ca2+ elevations via Gi3.
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PMID:Concomitant regulation of Ca2+ mobilization and G13 expression in human erythroleukemia cells. 965 Aug 40

The cardiac alpha1-adrenergic chronotropic response changes from stimulatory to inhibitory post-natally. The mature inhibitory response is mediated by the alpha1B-adrenoceptor and a pertussis toxin sensitive G protein. In vivo and in vitro studies identify sympathetic innervation as critical for the maturation of this inhibitory response. Additional experiments in a culture model indicate the effect of innervation is dependent on neurally released neuropeptide Y. The present study establishes that the individual signaling elements in the neuropeptide Y induced alpha1-adrenergic cascade are the same as those appearing during normal in vivo development. In addition, the data demonstrate that the effect of neuropeptide Y does not result from activation of the putative cardiac Y3 neuropeptide Y receptor subtype, since it is reproduced by the peptide fragment neuropeptide Y-(13-36) but not by [Leu31, Pro34]neuropeptide Y.
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PMID:Characterization of the alpha1-adrenergic chronotropic response in neuropeptide Y-treated cardiomyocytes. 967 Nov 20

Although thrombopoietin has been shown to promote megakaryocyte (MK) proliferation and maturation, the exact mechanism and site of platelet formation are not well defined. Studies have shown that MKs may transmigrate through bone marrow endothelial cells (BMEC), and release platelets within the sinusoidal space or lung capillaries. In search for chemotactic factor(s) that may mediate transmigration of MKs, we have discovered that mature polyploid MKs express the G protein-coupled chemokine receptor CXCR4 (Fusin, LESTR). Therefore, we explored the possibility that stromal cell-derived factor 1 (SDF-1), the ligand for CXCR4, may also induce transendothelial migration of mature MKs. SDF-1, but not other CXC or CC chemokines, was able to mediate MK migration (ED50 = 125 pmol/liter). The MK chemotaxis induced by SDF-1 was inhibited by the CXCR4-specific mAb (12G5) and by pertussis toxin, demonstrating that signaling via the G protein-coupled receptor CXCR4 was necessary for migration. SDF-1 also induced MKs to migrate through confluent monolayers of BMEC by increasing the affinity of MKs for BMEC. Activation of BMEC with interleukin 1beta resulted in a threefold increase in the migration of MKs in response to SDF-1. Neutralizing mAb to the endothelial-specific adhesion molecule E-selectin blocked the migration of MKs by 50%, suggesting that cellular interaction of MKs with BMEC is critical for the migration of MKs. Light microscopy and ploidy determination of transmigrated MKs demonstrated predominance of polyploid MKs. Virtually all platelets generated in the lower chamber also expressed CXCR4. Platelets formed in the lower chamber were functional and expressed P-selectin (CD62P) in response to thrombin stimulation. Electron microscopy of the cells that transmigrated through the BMEC monolayers in response to SDF-1 demonstrated the presence of intact polyploid MKs as well as MKs in the process of platelet formation. These results suggest that SDF-1 is a potent chemotactic factor for mature MKs. Expression of CXCR4 may be the critical cellular signal for transmigration of MKs and platelet formation.
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PMID:Transendothelial migration of megakaryocytes in response to stromal cell-derived factor 1 (SDF-1) enhances platelet formation. 968 31

(R)-N 2-(diphenacetyl)-N-[(4-hydroxyphenyl)methyl]-argininamide (BIBP 3226) is a selective neuropeptide Y Y1 receptor antagonist with structural similarity to the C-terminal tripeptide of neuropeptide Y. Based on this similarity we questioned whether BIBP 3226 could act as an agonist. Incubation of BIBP 3226 with bovine chromaffin cells in culture results in the inhibition of nicotinic receptor-stimulated catecholamine secretion (IC50 = 2.4 microM). The effect of BIBP 3226 is independent of neuropeptide Y action since the presence of neuropeptide Y in the culture medium does not alter the effect of BIBP 3226. BIBP 3226 decreased the efficacy of the nicotinic receptor agonist, 1,1-dimethyl-4-phenylpiperizinium (DMPP), but did not change its potency suggesting non-competitive inhibition. BIBP 3226 has a similar effect on nicotinic receptor-stimulated 45Ca2+ influx. BIBP 3226 does not inhibit [3H]norepinephrine release induced by high K+ and its effect is not pertussis toxin-sensitive. We conclude that not only can BIBP 3226 act as a neuropeptide Y receptor antagonist in bovine chromaffin cells but also act as an agonist and inhibit catecholamine secretion.
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PMID:BIBP 3226 inhibition of nicotinic receptor mediated chromaffin cell secretion. 987 61

Chemokines are chemotactic cytokines that activate and direct the migration of leukocytes. However, their role in modulating platelet function has not been shown. We studied the direct effect of chemokines on human platelets and found that of the 16 tested only stromal cell-derived factor (SDF)-1 induced platelet aggregation, accompanied by a rise in intracellular calcium. Platelets expressed the SDF-1 receptor, CXCR4, and an antibody to CXCR4 and pertussis toxin inhibited SDF-1-induced platelet aggregation, confirming that this effect is mediated through CXCR4, a Galphai-coupled receptor. SDF-1-induced platelet aggregation was also inhibited by wortmannin, LY294002, and genistein, suggesting that phosphatidylinositol 3-kinase and tyrosine kinase are likely involved in SDF-1-induced platelet aggregation. Because chemokines are produced from multiple vascular cells and atherosclerotic vessels are prone to develop platelet-rich thrombi, we examined the expression of SDF-1 in human atheroma. SDF-1 protein was highly expressed in smooth muscle cells, endothelial cells, and macrophages in human atherosclerotic plaques but not in normal vessels. Our studies demonstrate a direct effect of a chemokine in inducing platelet activation and suggest a role for SDF-1 in the pathogenesis of atherosclerosis and thrombo-occlusive diseases.
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PMID:The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. 1066 7

B-cell accumulation and formation of ectopic germinal centers are characteristic changes in the diseased joints of patients with rheumatoid arthritis (RA). Earlier studies suggested that interactions between B lymphocytes and specialized synovial "nurse-like" cells peculiar to the RA synovium may be responsible for the homing and sustained survival of B cells in the synovium. However, in this study, we found that B cells spontaneously migrate beneath ordinary fibroblast-like synoviocytes (FLSs) and then experience prolonged survival. FLSs isolated from joints of patients with osteoarthritis also supported this activity, termed B-cell pseudoemperipolesis. We found that FLSs constitutively expressed the chemokine stromal cell-derived factor-1 (SDF-1), and that pertussis toxin or antibodies to the SDF-1 receptor (CXCR4) could inhibit B-cell pseudoemperipolesis. However, expression of SDF-1 is not sufficient, as dermal fibroblasts also expressed this chemokine but were unable to support B-cell pseudoemperipolesis unless previously stimulated with IL-4 to express CD106 (VCAM-1), a ligand for the alpha(4)beta(1) integrin, very-late-antigen-4 (VLA-4 or CD49d). Furthermore, mAb's specific for CD49d and CD106, or the synthetic CS1 fibronectin peptide, could inhibit B-cell pseudoemperipolesis. We conclude that ordinary FLSs can support B-cell pseudoemperipolesis via a mechanism dependent upon fibroblast expression of SDF-1 and CD106.
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PMID:Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism. 1116 Jan 54

The dissemination of T cell hybridomas to multiple nonhematopoietic tissues is blocked by pertussis toxin, suggesting the involvement of a chemokine. To study whether this chemokine is SDF-1, we employed a strategy proposed previously for gene therapy of AIDS, whereby the SDF-1 receptor CXCR4 (also a coreceptor for HIV) is retained in the endoplasmic reticulum (ER) and fails to reach the cell surface. We transfected SDF-1, carrying an ER retention sequence, into a T cell hybridoma. This altered chemokine is retained in the ER, where it binds CXCR4 and prevents the latter protein from reaching the surface. These cells failed to migrate toward SDF-1 or to invade fibroblast monolayers, although they could still migrate toward thymus and activation-regulated chemokine (TARC) and invade TARC-treated monolayers. Furthermore, the ability of the transfected cells to disseminate to multiple organs upon intravenous injection into mice was abolished. This dissemination reflects the in vivo migration patterns of activated and memory T cells into nonhematopoietic tissues, which is thus likely to depend on CXCR4. Attempts to block CXCR4 function as a therapy for AIDS may affect this migration with consequences for T cell function. Our results also suggest a decisive role for CXCR4 in the dissemination of hematopoietic malignancies expressing this receptor.
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PMID:Retention of CXCR4 in the endoplasmic reticulum blocks dissemination of a T cell hybridoma. 1145 80

Marrow stromal cells play an important role in regulating the development and proliferation of haematopoietic stem cells (HSC) within the marrow microenvironment. However, the molecular mechanisms of stem cell-stromal cell interactions are not fully understood. We observed that mobilized peripheral blood and cord-blood-derived CD34+ progenitor cells, or CD34+ acute myeloid leukaemia (AML) cells spontaneously migrated beneath marrow stromal cells, an in vitro migration phenomenon termed pseudoemperipolesis. In contrast, the CD34+ myeloid leukaemia cell line, Kasumi-1, did not display pseudoemperipolesis. Cord blood CD34+ cells had a higher capacity than granulocyte-colony-stimulating-factor-mobilized CD34+ cells for pseudoemperipolesis (28.7 +/- 12%vs 18.1 +/- 6.1% of input cells within 24 h, mean +/- SD, n = 8), whereas 9.4 +/- 12.6% (mean +/- SD, n = 10) of input AML cells displayed this phenomenon. Pseudoemperipolesis of CD34+ progenitor and AML cells was significantly inhibited by pertussis toxin and antibodies to the CXCR4 chemokine receptor (CXCR4, CD184), but not control antibodies. Moreover, CD34+ and AML cell migration was significantly inhibited by a CS1 peptide that blocks alpha4beta1 integrin binding, but not by a control peptide, in which the fibronectin binding motif was scrambled. Pseudoemperipolesis was associated with an increased proliferation of migrated CD34+ progenitor cells but not AML cells within the stromal layer, demonstrated by cell cycle analysis and cell division tracking. We conclude that alpha4beta1 integrin binding and CXCR4 chemokine receptor activation are prerequisites for the migration of CD34+ haematopoietic progenitors and AML cells beneath marrow stromal cells. These observations suggest a central role of marrow stromal cells for HSC trafficking and homing within the marrow microenvironment.
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PMID:CXCR4 chemokine receptors (CD184) and alpha4beta1 integrins mediate spontaneous migration of human CD34+ progenitors and acute myeloid leukaemia cells beneath marrow stromal cells (pseudoemperipolesis). 1289 13


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