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)

Duodenase is a 29-kDa serine endopeptidase that displays selective trypsin- and chymotrypsin-like substrate specificity. This enzyme has been localized to epitheliocytes of Brunner's glands, and as described here, to mast cells within the intestinal mucosa and lungworm-infected lung, implying an important additional role in inflammation and tissue remodelling. In primary cultures of pulmonary artery fibroblasts, duodenase induced a concentration-dependent increase in [3H]thymidine incorporation with a maximal effect observed at 30 nm. Pretreating duodenase with soybean trypsin inhibitor abolished DNA synthesis, confirming that proteolytic activity was an essential requirement for this response. PAR1, PAR2 and PAR4 activating peptides were unable to induce [3H]thymidine incorporation in pulmonary artery fibroblasts. Likewise, pretreatment of fibroblasts with TNFalpha, known to up-regulate PAR2 expression in other systems, and IL-1beta, did not enhance the potential of duodenase to induce DNA synthesis. Furthermore, duodenase increased GTPgammaS binding to fibroblast membranes indicating that a G-protein-coupled receptor may mediate the effects of duodenase. Duodenase-induced DNA synthesis and GTPgammaS binding were both found to be inhibited by pertussis toxin, implying a role for Gi/o. Selective inhibitors of MEK1 (PD98059) and protein kinase C (GF109203X) only partially inhibited duodenase-induced DNA synthesis, but both wortmannin (100 nm) and LY294002 (10 microm) inhibited this response completely, indicating a key role for PtdIns 3-kinase. Furthermore, duodenase induced a 2.3 plus minus 0.1-fold increase in PtdIns 3-kinase activity in p85 immunoprecipitates, which was sensitive to inhibition by wortmannin. These results suggest that duodenase can induce pulmonary artery fibroblast DNA synthesis in a PtdIns 3-kinase-dependent manner via a G-protein-coupled receptor which is activated by a proteolytic mechanism.
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PMID:Proteolytic action of duodenase is required to induce DNA synthesis in pulmonary artery fibroblasts. 1185 53

(1) Thrombin, a mitogen for human cultured airway smooth muscle (HASM), has many actions that have been attributed to activation of protease-activated receptor (PARs). However, the role of PARs in the proliferative action has not been clearly identified. Moreover, thrombin elicits cytokine production in a number of cell types, but these effects have not been characterized in human ASM. (2) Thrombin (0.03-3 U ml(-1))-stimulated increases in the levels of the pro-inflammatory and fibrogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF) were observed over the same concentration range observed for thrombin-stimulated mitogenesis. (3) Inhibition of thrombin proteolytic activity, with either D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK)- or hirudin-treated thrombin (0.3 U ml(-1)) or in the presence of the thrombin serine protease-selective inhibitor, SDZ 217-766 (0.15 micro M), reduced the thrombin-stimulated GM-CSF levels by 91+/-3, 65+/-12 and 83+/-9% (n=8, P<0.05), respectively. PPACK treatment, hirudin and SDZ 217-766 inhibited thrombin-stimulated increase in cell number by 70+/-8, 63+/-11 and 69+/-8%, respectively. (4) PAR-selective peptides SFLLRN (PAR1; 10 micro M), SLIGKV (PAR2; 10 micro M), GYPGQV (PAR4; 100 micro M) or the combination of SFLLRN and GYPGQV elicited mitogenic responses of only 15% of that to thrombin and surprisingly, had no effect on GM-CSF levels (n=8). Nevertheless, inhibition of thrombin responses by pertussis toxin (50 ng ml(-1)) suggests that the PAR-independent actions also involve a G-protein-coupled receptor. (5) PAR1 receptor expression was evident by immunohistochemistry and these receptors were coupled to increases in intracellular calcium, but not to the phosphorylation of ERK or the increases in cyclin D1 protein levels that are essential for cell proliferation. Cross-desensitization of intracellular calcium increases by thrombin and the PAR1-selective peptide provides evidence that the PAR1 receptor responds to both ligands. (6) The failure of PAR-selective peptides to mimic thrombin responses together with the inhibition of thrombin responses by serine protease inhibitors suggest the involvement of novel proteolytic receptor targets for thrombin-induced mitogenesis and cytokine production.
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PMID:Protease-activated receptor (PAR)-independent growth and pro-inflammatory actions of thrombin on human cultured airway smooth muscle. 1264 88

Proteinase-activated receptors (PARs) are a family of four G protein-coupled receptors that are widely distributed in the CNS and involved in neural cell proliferation, differentiation and survival. The olfactory system undergoes continuous neurogenesis throughout life and may represent a critical target of PAR cellular actions. In the present study we investigated the functional activity of PAR1 and PAR2 in microdissected tissue preparations of olfactory nerve-glomerular layer (ON-GL), external plexiform layer (EPL) and granule cell layer (GRL) of the rat main olfactory bulb and in primary cultures of olfactory neuroepithelial cells. Activation of either PAR1 or PAR2 regulated multiple signaling pathways, including activation of pertussis-toxin sensitive Gi/o proteins, inhibition of cyclic AMP formation, stimulation of Gq/11-mediated phosphoinositide (PI) hydrolysis, phosphorylation of Ca2+/calmodulin-dependent protein kinase II and activation of the monomeric G protein Rho, predominantly in ON-GL, whereas only activation of Rho was detected in the deeper layers. Olfactory nerve lesion by nasal irrigation with ZnSO4 induced a marked decrease of PAR signaling in ON-GL. In primary cultures of olfactory neurons, double immunofluorescence analysis showed the localization of PAR1 and PAR2 in cells positive for olfactory-marker protein and neuron-specific enolase. Cell exposure to either nanomolar concentrations of thrombin and trypsin or PAR-activating peptides caused rapid neurite retraction. This study provides the first characterization of the laminar distribution of PAR1 and PAR2 signaling in rat olfactory bulb, demonstrates the presence of the receptors in olfactory sensory neurons and suggests a role of PARs in olfactory sensory neuron neuritogenesis.
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PMID:Proteinase-activated receptors 1 and 2 in rat olfactory system: layer-specific regulation of multiple signaling pathways in the main olfactory bulb and induction of neurite retraction in olfactory sensory neurons. 1743 82

The protease-activated receptors (PAR1 and PAR2) are unusual G protein-coupled receptors that are activated by distinct serine proteases and are coexpressed in many different cell types. Limited recent evidence suggests these closely related receptors regulate different physiological outputs in the same cell, although little is known about the comparative signaling pathways used by these receptors. Here we report that PAR1 and PAR2 couple to overlapping and distinct sets of G proteins to regulate receptor-specific signaling pathways involved in cell migration. In functionally PAR-null COS-7 cells, ectopically expressed PAR1 and PAR2 both form stable complexes with G alpha(q), G alpha(11), G alpha(14), G alpha(12), and G alpha(13). It is surprising that PAR1 but not PAR2 coupled to G alpha(o), G alpha(i1), and G alpha(i2). Consistent with these observations, PAR1 and PAR2 stimulation of inositol phosphate production and RhoA activation was blocked by specific inhibitors of G(q/11) and G(12/13) signaling, respectively. Both receptors stimulated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, but only PAR1 inhibited adenylyl cyclase activity, and pertussis toxin blocked PAR1 effects on both adenylyl cyclase and ERK1/2 signaling. Neu7 astrocytes express native PAR1 and PAR2 receptors that activate inositol phosphate, RhoA, and ERK1/2 signaling. However, only PAR1 inhibited adenylyl cyclase activity. PAR1 and PAR2 also stimulate Neu7 cell migration. PAR1 effects on ERK1/2 phosphorylation and cell migration were blocked both by pertussis toxin and by the mitogen-activated protein kinase kinase/ERK inhibitor [1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126)], whereas PAR2 effects were only blocked by U0126. These studies demonstrate that PAR1 and PAR2 physically and functionally link to overlapping and distinct profiles of G proteins to differentially regulate downstream signaling pathways and cell physiology.
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PMID:PAR1 and PAR2 couple to overlapping and distinct sets of G proteins and linked signaling pathways to differentially regulate cell physiology. 2021 60