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)

Binding of FMLP to the neutrophil N-formyl peptide receptor (FPR) transmits signals through pertussis toxin-sensitive G proteins triggering Ca2+ flux, superoxide production, granule exocytosis, and neutrophil aggregation and adhesion involving the beta 2 (CD18) integrins. Expression of the FPR in mouse fibroblasts or human kidney cells has been shown to confer an N-formyl peptide-inducible Ca2+ flux in transfectants. Here we demonstrate that the transfected receptor can also support ligand-induced alterations in cellular adhesion. We established stable transfectants of mouse L1-2 pre-B cells with cDNA for human FPR (L1-2 FPR cells). The transfectants bind N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein with 1.4 x 10(5) sites per cell and a dissociation constant of 3.3 nM. Stimulation with FMLP induces a transient Ca2+ flux. FMLP also triggers adhesion of L1-2 FPR cells to TNF-alpha- or LPS-activated bEnd3 cells (mouse brain-derived endothelial cells) and to purified mouse VCAM-1. Binding is inhibited by Abs to VCAM-1 and to the alpha-chain of its lymphocyte receptor (the alpha 4 beta 1 integrin, VLA-4). Stimulation with FMLP does not induce a change in cell surface expression of alpha 4. Induced adhesion to VCAM-1 is rapid, detectable at the earliest times measurable (30 to 60 s after FMLP addition), and is inhibited by pertussis toxin. We conclude that FPR can mediate integrin activation not only in neutrophils but also in lymphocytes, and can trigger rapid adhesion via lymphocyte alpha 4 beta 1. The adhesion of lymphocytes is critical to their migration and targeting; our results suggest the possibility of manipulating adhesive responses through expression of chemoattractant receptors in lymphoid cells engineered for cellular therapy, allowing targeted adhesion and potentially migration in response to locally administered ligands.
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PMID:Ligand-induced adhesion to activated endothelium and to vascular cell adhesion molecule-1 in lymphocytes transfected with the N-formyl peptide receptor. 751 63

We have investigated the role of alpha 4 beta 1 and alpha 5 beta 1 integrins in adhesion and migration of T lymphocytes to extracellular matrix proteins. Fibronectin, collagen type IV, and laminin promoted haptotactic and chemotactic migration of lymphoid T cell lines and 12-O-tetradecanoylphorbol 13-acetate-stimulated blood lymphocytes, as determined using a modified Boyden chamber system. Adhesion studies of the T cell lines indicated involvement of both alpha 4 beta 1 and alpha 5 beta 1 integrins in the binding to fibronectin. In contrast, migration assays demonstrated that haptotactic and chemotactic migration to fibronectin in most cases was mediated by only one of the beta 1 integrins. FACS analysis demonstrated comparable amounts of alpha 4 beta 1 and alpha 5 beta 1 on the various cell lines, indicating that utilization of the integrins for migration is not determined by their expression on the cells. Haptotactic migration toward a 120-kDa fibronectin fragment containing the RGD sequence, confirmed the selectivity of the different beta 1 integrins in directing migration. Thus, T cells using alpha 5 beta 1 for haptotaxis against fibronectin were migrating against the 120 kDa fragment whereas T cells using alpha 4 beta 1 were not. These results indicate that the response of T cells to haptotactic and chemotactic signals usually is mediated selectively via alpha 4 beta 1 or alpha 5 beta 1 although binding of fibronectin to the cells is not restricted to only one of the integrins. Cholera toxin and 8-Br-cAMP but not pertussis toxin inhibited migration of T cell lines to fibronectin. Adhesion of these cells to fibronectin was not influenced by any of the toxins. Thus, both in their integrin utilization and in their signaling pathways, adhesion and migration show substantial differences in T cells.
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PMID:Functional specialization of fibronectin-binding beta 1-integrins in T lymphocyte migration. 802 66

The CC chemokines regulated on activation normal T expressed and secreted (RANTES) and monocyte chemotactic protein 3 (MCP-3), and the anaphylatoxin C5a, induce activation, degranulation, chemotaxis, and transendothelial migration of eosinophils. Adhesion assays on purified ligands showed differential regulation of beta 1 and beta 2 integrin avidity in eosinophils. Adhesiveness of VLA-4 (alpha 4 beta 1, CD29/CD49d) for vascular cell adhesion molecule 1 or fibronectin was rapidly increased but subsequently reduced by RANTES, MCP-3, or C5a. The deactivation of VLA-4 lead to cell detachment, whereas phorbol 12-myristate 13-acetate induced sustained activation of VLA-4. In contrast, chemoattractants stimulated a prolonged increase in the adhesiveness of Mac-1 (alpha M beta 2, CD11b/CD18) for intercellular adhesion molecule 1. Inhibition by pertussis toxin confirmed signaling via G protein-coupled receptors. Chemoattractants induced transient, while phorbol 12-myristate 13-acetate induced sustained actin polymerization. Disruption of actin filaments by cytochalasins inhibited increases in avidity of VLA-4 but not of Mac-1. Chemoattractants did not upregulate a Mn2+-inducible beta 1 neoepitope defined by the mAb 9EG7, but induced prolonged expression of a Mac-1 activation epitope recognized by the mAb CBRM1/5. This mAb inhibited chemoattractant-stimulated adhesion of eosinophils to intercellular adhesion molecule 1. Thus, regulation of VLA-4 was dependent on the actin cytoskeleton, whereas conformational changes appeared to be crucial for activation of Mac-1. To our knowledge, this is the first demonstration that physiological agonists, such as chemoattractants, can differentially regulate the avidity of a beta 1 and a beta 2 integrin expressed on the same leukocyte.
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PMID:Differential regulation of beta 1 and beta 2 integrin avidity by chemoattractants in eosinophils. 885 87

The chemokine RANTES is a potent chemoattractant and activator of T lymphocytes. Mechanisms underlying the RANTES-induced activation of T lymphocytes leading to adhesion and migration have not been fully analyzed. We investigate here the function of RANTES in the regulation of T cell adhesion, specifically the induction of homotypic aggregation. RANTES induced the expression of many important cell surface adhesion and activation receptors in a normal human T cell clone and peripheral blood T lymphocytes, including members of the beta 1 and beta 2 integrin family, CD44, CD50, and CD28. Up-regulation of these markers correlated with RANTES-stimulated homotypic adhesion of T cells. This homotypic aggregation event was RANTES dose-dependent, prolonged, and pertussis toxin-independent, but herbimycin A-sensitive, suggesting that it involves signaling through alternative (G alpha i protein-independent) pathways. Using specific monoclonal antibodies, the homotypic aggregation event was shown to be lymphocyte function-associated antigen-1 (LFA-1)-dependent, with no observable interaction through alpha 4 or beta 1 integrins. Intercellular adhesion molecule-3 (ICAM-3) and possibly ICAM-1 participate as LFA-1 ligands. Additionally, RANTES phosphorylated the beta chain of LFA-1 1-2 min following stimulation. These results imply a specific role for the chemokine RANTES in T cell activation and intercellular adhesion.
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PMID:RANTES stimulation of T lymphocyte adhesion and activation: role for LFA-1 and ICAM-3. 917 93

To characterize the adhesion cascade that directs lymphocyte homing to peripheral lymph nodes (PLNs), we investigated the molecular mechanisms of lymphocyte interactions with the microvasculature of subiliac lymph nodes. We found that endogenous white blood cells and adoptively transferred lymph node lymphocytes (LNCs) tethered and rolled in postcapillary high endothelial venules (HEVs) and to a lesser extent in collecting venules. Similarly, firm arrest occurred nearly exclusively in the paracortical HEVs. Endogenous polymorphonuclear (PMNs) and mononuclear leukocytes (MNLs) attached and rolled in HEVs at similar frequencies, but only MNLs arrested suggesting that the events downstream of primary rolling interactions critically determine the specificity of lymphocyte recruitment. Antibody inhibition studies revealed that L-selectin was responsible for attachment and rolling of LNCs, and that LFA-1 was essential for sticking. LFA-1-dependent arrest was also abolished by pertussis toxin, implicating a requirement for G alpha i--protein-linked signaling. alpha 4 integrins, which play a critical role in lymphocyte homing to Peyer's Patches, made no significant contribution to attachment, rolling, or sticking in resting PLNs. Velocity analysis of interacting LNCs revealed no detectable contribution by LFA-1 to rolling. Taken together, our results suggest that lymphocyte- HEV interactions within PLNs are almost exclusively initiated by L-selectin followed by a G protein-coupled lymphocyte-specific activation event and activation-induced engagement of LFA-1. These events constitute a unique adhesion cascade that dictates the specificity of lymphocyte homing to PLNs.
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PMID:Molecular mechanisms of lymphocyte homing to peripheral lymph nodes. 943 78

Nefiracetam (DM-9384) is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and poststroke vascular-type dementia. Because the cholinergic system plays an important role in cognitive functions and Alzheimer's disease dementia, the present study was conducted to elucidate the mechanism of action of nefiracetam and aniracetam on neuronal nicotinic acetylcholine receptors (nnAChRs). Currents were recorded from rat cortical neurons in long-term primary culture using the whole-cell, patch-clamp technique. Two types of currents were evoked by acetylcholine (ACh): alpha-bungarotoxin-sensitive, alpha 7-type currents and alpha-bungarotoxin-insensitive, alpha 4 beta 2-type currents. Although nefiracetam and aniracetam inhibited alpha 7-type currents only weakly, these nootropic agents potentiated alpha 4 beta 2-type currents in a very potent and efficacious manner. Nefiracetam at 1 nM and aniracetam at 0.1 nM reversibly potentiated alpha 4 beta 2-type currents to 200 to 300% of control. Nefiracetam at very high concentrations (approximately 10 microM) also potentiated alpha 4 beta 2-type currents but to a lesser extent, indicative of a bell-shaped dose-response relationship. Nefiracetam markedly increased the saturating responses induced by high concentrations of ACh. However, human alpha 4 beta 2 subunits expressed in human embryonic kidney cells were inhibited rather than potentiated by nefiracetam. The specific protein kinase A inhibitors (H-89, KT5720, and peptide 5-24) and protein kinase C inhibitors (chelerythrine, calphostin C, and peptide 19--63) did not prevent nefiracetam from potentiating alpha 4 beta 2-type currents, indicating that these protein kinases are not involved in nefiracetam action. The nefiracetam potentiating action was not affected by 24-h pretreatment of neurons with pertussis toxin, but was abolished by cholera toxin. Therefore, G(s) proteins, but not G(i)/G(o) proteins, are involved in nefiracetam potentiation. These results indicate that nnAChRs are an important site of action of nefiracetam and G(s) proteins may be its crucial target.
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PMID:Nootropic drug modulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons. 1125 10

Nefiracetam is a new pyrrolidone nootropic drug that is being developed for clinical use in the treatment of post-stroke vascular-type and Alzheimer's-type dementia. Among a few neuroreceptors that have been identified as potential targets of nootropics, neuronal nicotinic acetylcholine receptors (nnAChRs) are deemed the most important since they are related to learning, memory, and Alzheimer's disease dementia. We have recently found potent stimulating action of nefiracetam on nnAChRs. Rat cortical neurons in long-term primary culture expressed nnAChRs. Whole-cell patch clamp experiments revealed two types of currents induced by ACh, alpha-bungarotoxin (alpha-BuTX)-sensitive, rapidly desensitizing, alpha 7-type currents and alpha-BuTX-insensitive, slowly desensitizing, alpha 4 beta 2-type currents. Although alpha 7-type currents were only weakly inhibited by nefiracetam, alpha 4 beta 2-type currents were potently and efficaciously potentiated by nefiracetam. Nefiracetam at 0.1 nM reversibly potentiated ACh-induced currents to 200-300% of control. Very high concentrations (about 10 microM) also potentiated these currents, but to a lesser extent, indicative of the bell-shaped dose-response relationship known to occur for nefiracetam, even in animal behavior experiments. Three specific inhibitors of each of PKA and PKC did not prevent nefiracetam from potentiating ACh-induced currents, indicating that these protein kinases are not involved in nefiracetam action. Pretreatment with pertussis toxin did not alter nefiracetam potentiation, indicating Gi/Go proteins are not involved. Pretreatment with cholera toxin did abolish nefiracetam potentiation. Thus, nefiracetam potentiation is mediated via Gs proteins. In conclusion, nefiracetam stimulates alpha 4 beta 2-type nnAChRs via Gs proteins at nanomolar concentrations. The potentiation of alpha 4 beta 2-type nnAChRs is thought to be at least partially responsible for cognitive enhancing action.
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PMID:Post-stroke dementia. Nootropic drug modulation of neuronal nicotinic acetylcholine receptors. 1146 69

The steps involved in lymphocyte homing to the white pulp cords of the spleen are poorly understood. We demonstrate here that the integrins lymphocyte function associated (LFA)-1 and alpha 4 beta 1 make essential and mostly overlapping contributions necessary for B cell migration into white pulp cords. T cell entry to the white pulp is also reduced by blockade of LFA-1 and alpha 4 beta 1. The LFA-1 ligand, intercellular adhesion molecule 1 is critical for lymphocyte entry and both hematopoietic cells and radiation-resistant cells contribute to this requirement. Vascular cell adhesion molecule 1 contributes to the alpha 4 beta 1 ligand requirement and a second ligand, possibly fibronectin, also plays a role. By contrast with the entry requirements, antigen-induced movement of B cells from follicles to the outer T zone is not prevented by integrin blocking antibodies. Comparison of the distribution of integrin-blocked B cells and B cells treated with the G alpha i inhibitor, pertussis toxin, early after transfer reveals in both cases reduced accumulation in the inner marginal zone. These observations suggest that chemokine receptor signaling and the integrins LFA-1 and alpha 4 beta 1 function together to promote lymphocyte transit from the marginal zone into white pulp cords.
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PMID:Integrin-dependence of lymphocyte entry into the splenic white pulp. 1256 19