Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Macrophage-derived chemokine (MDC/CC chemokine ligand 22 (CCL22)) mediates its cellular effects principally by binding to its receptor CCR4, and together they constitute a multifunctional chemokine/receptor system with homeostatic and inflammatory roles in the body. We report the CCL22-induced accumulation of phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P(3)) in the leukemic T cell line CEM. CCL22 also had the ability to chemoattract human Th2 cells and CEM cells in a pertussis toxin-sensitive manner. Although the PI(3,4,5)P(3) accumulation along with the pertussis toxin-susceptible phosphorylation of protein kinase B were sensitive to the two phosphoinositide 3-kinase inhibitors, LY294002 and wortmannin, cell migration was unaffected. However, cell migration was abrogated with the Rho-dependent kinase inhibitor, Y-27632. These data demonstrate that although there is PI(3,4,5)P(3) accumulation downstream of CCR4, phosphoinositide 3-kinase activity is a dispensable signal for CCR4-stimulated chemotaxis of Th2 cells and the CEM T cell line.
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PMID:Activation of phosphoinositide 3-kinases by the CCR4 ligand macrophage-derived chemokine is a dispensable signal for T lymphocyte chemotaxis. 1518 60

Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes, a high-risk population for the development of a diffuse and extensive pattern of arteriosclerosis. The present study examined the effect of C-peptide on CD4(+) lymphocyte migration, an important process in early atherogenesis. C-peptide stimulated CD4(+) cell chemotaxis in a concentration-dependent manner. This process involves pertussis toxin-sensitive G-proteins as well as activation of phosphoinositide 3-kinase (PI 3-K). Biochemical analysis showed that C-peptide induced recruitment of PI 3-K to the cell membrane as well as PI 3-K activation in human CD4(+) cells. In addition, antidiabetic peroxisome proliferator-activated receptor gamma-activating thiazolidinediones inhibited C-peptide-induced CD4(+) cell chemotaxis as well as PI 3-Kgamma activation. Finally, immunofluorescence staining of thoracic artery specimen of diabetic patients showed intimal CD4(+) cells in areas with C-peptide deposition. Thus, C-peptide might deposit in the arterial intima in diabetic patients during early atherogenesis and subsequently attract CD4(+) cells to migrate into the vessel wall.
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PMID:C-peptide induces chemotaxis of human CD4-positive cells: involvement of pertussis toxin-sensitive G-proteins and phosphoinositide 3-kinase. 1522 Jan 88

Delta9-Tetrahydrocannabinol, a major psychoactive constituent of marijuana, interacts with specific receptors, i.e. the cannabinoid receptors, thereby eliciting a variety of pharmacological responses. To date, two types of cannabinoid receptors have been identified: the CB1 receptor, which is abundantly expressed in the nervous system, and the CB2 receptor, which is predominantly expressed in the immune system. Previously, we investigated in detail the structure-activity relationship of various cannabinoid receptor ligands and found that 2-AG (2-arachidonoylglycerol) is the most efficacious agonist. We have proposed that 2-AG is the true natural ligand for both the CB1 and CB2 receptors. Despite the potential physiological importance of 2-AG, not much information is available concerning its biological activities towards mammalian tissues and cells. In the present study, we examined the effect of 2-AG on morphology as well as the actin filament system in differentiated HL-60 cells, which express the CB2 receptor. We found that 2-AG induces rapid morphological changes such as the extension of pseudopods. We also found that it provokes a rapid actin polymerization in these cells. Actin polymerization induced by 2-AG was abolished when cells were treated with SR144528, a CB2 receptor antagonist, and pertussis toxin, suggesting that the response was mediated by the CB2 receptor and G(i/o). A phosphoinositide 3-kinase, Rho family small G-proteins and a tyrosine kinase were also suggested to be involved. Reorganization of the actin filament system is known to be indispensable for a variety of cellular events; it is possible that 2-AG plays physiologically essential roles in various inflammatory cells and immune-competent cells by inducing a rapid actin rearrangement.
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PMID:2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces rapid actin polymerization in HL-60 cells differentiated into macrophage-like cells. 1545 4

We have shown previously that in a heterologous mammalian expression system A549 cells, beta3-adrenoceptor (beta3-AR) stimulation regulates the activity of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The present investigation was carried out to determine the signaling pathway involved in this regulation. A549 cells were intranuclearly injected with plasmids encoding human CFTR and beta3-AR. CFTR activity was functionally assessed by microcytofluorimetry. The application of 1 microM 4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2-1 hydrochloride (CGP-12177), a beta3-AR agonist, produced a CFTR activation that was not abolished by protein kinase A inhibitors. In pertussis toxin-pretreated cells, the CFTR activation induced by CGP-12177 was abolished. The overexpression of beta-adrenoceptor receptor kinase, an inhibitor of betagamma subunits, abolished the CGP-12177-induced CFTR activation, suggesting the involvement of betagamma subunits of Gi/o proteins. The pretreatment of A549 cells with selective inhibitors of either phosphoinositide 3-kinase (PI3K), wortmannin, and 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002), or extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinase (MAPK), 2'-amino-3'-methoxyflavone (PD98059), and 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene (U0126), abolished the effects of CGP-12177 on the CFTR activity. Immunohistochemical assays showed that only the cells expressing beta3-AR exhibited MAPK activation in response to CGP-12177. Furthermore, CFTR activity increased in cells pretreated with 10% fetal bovine serum both in A549 cells injected only with CFTR and in T84 cells, which endogenously express CFTR, indicating that CFTR activity can be regulated by the MAPK independently of the beta3-AR stimulation. In conclusion, we have demonstrated that CFTR is regulated through a Gi/o/PI3K/ERK1/2 MAPK signaling cascade dependently or not on an activation of beta3-ARs. This pathway represents a new regulation for CFTR.
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PMID:Transfected beta3- but not beta2-adrenergic receptors regulate cystic fibrosis transmembrane conductance regulator activity via a new pathway involving the mitogen-activated protein kinases extracellular signal-regulated kinases. 1556 84

The stimulation of beta-adrenergic receptor (betaAR) plays a pivotal role in regulating myocardial function and morphology in the normal and failing heart. Three genetically and pharmacologically distinct betaAR subtypes, beta1AR, beta2AR, and beta3AR, are identified in various types of cells. While both beta1AR and beta2AR, the predominant betaAR subtypes expressed in the heart of many mammalian species including human, are coupled to the Gs-adenylyl cyclase-cAMP-PKA pathway, beta2AR dually activates pertussis toxin-sensitive Gi proteins. During acute stimulation, beta2AR-Gi coupling partially inhibits the Gs-mediated positive contractile and relaxant effects via a Gi-Gbetagamma-phosphoinositide 3-kinase (PI3K)-dependent mechanism in adult rodent cardiomyocytes. More importantly, persistent beta1AR stimulation evokes a multitude of cardiac toxic effects, including myocyte apoptosis and hypertrophy, via a calmodulin-dependent protein kinase II (CaMKII)-, rather than cAMP-PKA-, dependent mechanism in rodent heart in vivo and cultured cardiomyocytes. In contrast, persistent beta2AR activation protects myocardium by a cell survival pathway involving Gi, PI3K, and Akt. In this review, we attempt to highlight the distinct functionalities and signaling mechanisms of these betaAR subtypes and discuss how these subtype-specific properties of betaARs might affect the pathogenesis of congestive heart failure (CHF) and the therapeutic effectiveness of certain beta-blockers in the treatment of congestive heart failure.
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PMID:Emerging concepts and therapeutic implications of beta-adrenergic receptor subtype signaling. 1597 23

Naturally occurring single nucleotide polymorphisms have been identified in human CX3CR1, the chemokine receptor for fractalkine (FKN/CX3CL1). Individuals carrying the I249/M280 variant of CX3CR1 have a lower risk of cardiovascular disease compared with those homozygous for the common variant (V249/T280). The precise molecular basis for this phenotype is unclear, although differences in FKN binding, adhesive properties, and signaling efficiency between the CX3CR1 variants have been reported. FKN binding to CX3CR1 leads to an increase in intracellular calcium, actin rearrangement, and activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways. Regulation of these signaling pathways underlies the known roles for FKN in cell survival, proliferation, and migration. In the present study, we demonstrate that FKN stimulates phosphorylation of protein kinase B (Akt/PKB) in Chinese hamster ovary cells individually expressing the naturally occurring variants of human CX3CR1-, as well as rat CX3CR1-, but not in murine CX3CR1-expressing cells. Substitution of Pro326 in the C terminus of murine CX3CR1 with Ser (residue found in the analogous position of human CX3CR1) produced a mutant receptor that mimicked the human receptor in its ability to stimulate the phosphorylation of both Akt and extracellular signal-regulated kinase in a time-, PI3K-, and pertussis toxin-sensitive G-protein-dependent manner. These results identify a critical structural determinant of CX3CR1 important for activation of downstream signaling pathways.
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PMID:Proline 326 in the C terminus of murine CX3CR1 prevents G-protein and phosphatidylinositol 3-kinase-dependent stimulation of Akt and extracellular signal-regulated kinase in Chinese hamster ovary cells. 1616 68

Activation of naive T cells markedly up-regulates the expression of delta opioid receptors (DORs). These receptors are bound by DOR peptides released by T cells, modulating T cell functions such as interleukin-2 production, cellular proliferation, and chemotaxis. Previous studies have shown that DOR agonists [e.g., [D-Ala(2)-D-Leu(5)]-enkephalin (DADLE)] modulate T cell antigen receptor signaling through mitogen-activated protein kinases (MAPKs; i.e., extracellular signal-regulated kinases 1 and 2) and that DORs directly induce phosphorylation of activating transcription factor-2 (implicated in cytokine gene transcription) and its association with the MAPK c-jun1 NH(2)-terminal kinase (JNK). Such observations suggest that DORs may induce the phosphorylation of c-jun. These experiments were performed to test this hypothesis and determine the potential roles of phosphoinositide 3-kinase (PI3K) and Akt (protein kinase B). DADLE (10(-10) to 10(-6) M) dose-dependently induced c-jun phosphorylation. This was blocked by pertussis toxin and the DOR-specific antagonist naltindole. Fluorescence flow cytometry showed that DADLE significantly stimulated c-jun phosphorylation by T cells. DADLE stimulated phosphorylation of membrane-associated Akt; wortmannin and LY294002 ([2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one]), specific inhibitors of PI3K, abolished the DADLE-induced phosphorylation of c-jun. Finally, inhibitors of Akt and JNK blocked DADLE-induced phosphorylation of c-jun. Thus, activated DORs directly stimulate c-jun phosphorylation through a PI3K-dependent pathway in T cells, apparently involving Akt. This implies that DORs activate JNK through a novel pathway dependent on PI3K and Akt, thereby regulating the function of activator protein-1 transcription complexes containing c-jun and other transcription partners.
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PMID:delta opioid receptors stimulate Akt-dependent phosphorylation of c-jun in T cells. 1624 73

Lysophosphatidylserine (LPS) may be generated after phosphatidylserine-specific phospholipase A2 activation. However, the effects of LPS on cellular activities and the identities of its target molecules have not been fully elucidated. In this study, we observed that LPS stimulates an intracellular calcium increase in L2071 mouse fibroblast cells, and that this increase was inhibited by 1-[6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (U-73122) but not by pertussis toxin, suggesting that LPS stimulates calcium signaling via G-protein coupled receptor-mediated phospholipase C activation. Moreover, LPS-induced calcium mobilization was not inhibited by the lysophosphatidic acid receptor antagonist, (S)-phosphoric acid mono-{2-octadec-9-enoylamino-3-[4-(pyridine-2-ylmethoxy)-phenyl]-propyl} ester (VPC 32183), thus indicating that LPS binds to a receptor other than lysophosphatidic acid receptors. It was also found that LPS stimulates two types of mitogen-activated protein kinase [i.e., extracellular signal-regulated protein kinase (ERK) and p38 kinase] in L2071 cells. Furthermore, these LPS-induced ERK and p38 kinase activations were inhibited by pertussis toxin, which suggests the role of pertussis toxin-sensitive G-proteins in the process. In terms of functional issues, LPS stimulated L2071 cell chemotactic migration, which was completely inhibited by pertussis toxin, indicating the involvement of pertussis toxin-sensitive G(i) protein(s). This chemotaxis of L2071 cells induced by LPS was also dramatically inhibited by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) and by 2'-amino-3'-methoxyflavone (PD98059). This study demonstrates that LPS stimulates at least two different signaling cascades, one of which involves a pertussis toxin-insensitive but phospholipase C-dependent intracellular calcium increase, and the other involves a pertussis toxin-sensitive chemotactic migration mediated by phosphoinositide 3-kinase and ERK.
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PMID:Lysophosphatidylserine stimulates L2071 mouse fibroblast chemotactic migration via a process involving pertussis toxin-sensitive trimeric G-proteins. 1636 94

Two orphan leucine-rich repeat-containing G protein-coupled receptors were recently identified as targets for the relaxin family peptides relaxin and insulin-like peptide (INSL) 3. Human gene 2 relaxin is the cognate ligand for relaxin family peptide receptor (RXFP) 1, whereas INSL3 is the ligand for RXFP2. Constitutively active mutants of both receptors when expressed in human embryonic kidney (HEK) 293T cells signal through Galphas to increase cAMP. However, recent studies using cells that endogenously express the receptors revealed greater complexity: cAMP accumulation after activation of RXFP1 involves a time-dependent biphasic pathway with a delayed phase involving phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC) zeta, whereas the RXFP2 response involves inhibition of adenylate cyclase via pertussis toxin-sensitive G proteins. The aim of this study was to compare and contrast the cAMP signaling pathways used by these two related receptors. In HEK293T cells stably transfected with RXFP1, preliminary studies confirmed the biphasic cAMP response, with an initial Galphas component and a delayed response involving PI3K and PKCzeta. This delayed pathway was dependent upon G-betagamma subunits derived from Galphai3. An additional inhibitory pathway involving GalphaoB affecting cAMP accumulation was also identified. In HEK293T cells stably transfected with RXFP2, the cAMP response involved Galphas and was modulated by inhibition mediated by GalphaoB and release of inhibitory G-betagamma subunits. Thus, initially both RXFP1 and RXFP2 couple to Galphas and an inhibitory GalphaoB pathway. Differences in cAMP accumulation stem from the ability of RXFP1 to recruit coupling to Galphai3, release G-betagamma subunits and thus activate a delayed PI3K-PKCzeta pathway to further increase cAMP accumulation.
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PMID:Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms. 1656 7

Infection with the intracellular parasite Toxoplasma gondii renders cells resistant to multiple pro-apoptotic signals, but underlying mechanisms have not been delineated. The phosphoinositide 3-kinase (PI 3-kinase) pathway and the immediate downstream effector protein kinase B (PKB/Akt) play important roles in cell survival and apoptosis inhibition. Here, we show that Toxoplasma infection of mouse macrophages activates PKB/Akt in vivo and in vitro. In a mixed population of infected and non-infected macrophages, activation is only observed in parasite-infected cells. The PI 3-kinase inhibitors wortmannin and LY294002 block parasite-induced PKB phosphorylation. PKB activation occurs independently of Toll-like receptor adaptor protein MyD88 but uncoupling of Gi-protein-mediated signaling with pertussis toxin prevents PKB phosphorylation. Moreover, in the presence of PI 3-kinase inhibitors or pertussis toxin, not only PKB activation but also ERK1/2 activation during T. gondii infection is defective. Most importantly, the parasite's ability to induce macrophage resistance to pro-apoptotic signaling is prevented by incubation with PI 3-kinase inhibitors. This study demonstrates that T. gondii exploits host Gi-protein-dependent PI 3-kinase signaling to prevent induction of apoptosis in infected macrophages.
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PMID:Toxoplasma gondii triggers Gi-dependent PI 3-kinase signaling required for inhibition of host cell apoptosis. 1663 8


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