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)

Thapsigargin elicits histamine release on rat mast cells, and this effect is increased if cells are pretreated with thapsigargin before the addition of external calcium. Okadaic acid does not modify the response of mast cells to thapsigargin, while sodium fluoride or the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) increases several fold the sensitivity of cells to thapsigargin. On the other hand, pertussis and cholera toxins inhibit the response to thapsigargin. Thapsigargin increases the activity of the Na(+)-H+ exchanger, this effect being blocked by fluoride and not modified by TPA. The metals cadmium and lanthanum completely block the effect of TPA or thapsigargin on the Na(+)-H+ exchanger. The influx of 45Ca in rat mast cells is not modified by thapsigargin, but if cells are treated with thapsigargin before the addition of calcium, the influx is markedly increased in the first 2 min before returning to normal. Our results indicate that exocytosis is modulated by crosstalks between intracellular calcium, cytosolic pH and external calcium.
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PMID:Effect of signal transduction pathways on the action of thapsigargin on rat mast cells. Crosstalks between cellular signalling and cytosolic pH. 751 22

Binding of activation peptide from the fifth component of C (C5a) to its receptor triggers events leading to both stimulation of cellular responses and receptor desensitization in myeloid cells. However, although transmission of a signal to pertussis toxin-sensitive G proteins is a prerequisite to neutrophil activation, we show that the process of receptor phosphorylation is mainly independent from activation of this pathway. Treatment of cells with pertussis toxin did not modify the incorporation of phosphate mediated by a saturating concentration of C5a, indicating that agonist-occupied C5aR can be fully phosphorylated, presumably by a specific G protein-coupled receptor kinase, in the absence of activation of the Gi protein. Receptor phosphorylation was transient, with a half-life of 30 to 40 min, which suggested a role for protein phosphatases in the regulation of the state of phosphorylation of C5aR in dHL60 cells. Pretreatment of cells with okadaic acid, an inhibitor of protein phosphatases 1 and 2A, increased the basal phosphorylation of unoccupied receptor and extended the phosphorylation mediated by C5a binding. Okadaic acid delayed, but did not suppress, the dephosphorylation process, which suggests either the involvement of additional phosphatase(s) or the degradation of nondephosphorylated receptors in the endocytic pathway. The data strongly suggest that internalized C5aR are recycled to the plasma membrane with a time course consistent with the kinetics of dephosphorylation. Dephosphorylation of C5aR might be essential to receptor recycling and resensitization during chemotaxis.
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PMID:Phosphorylation, dephosphorylation, and recycling of the C5a receptor in differentiated HL60 cells. 770 44

alpha 1-Adrenergic (alpha 1-AR) agents stimulate NaCl(K) cotransport and phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2]-specific phospholipase C in human trachea and nasal polyp epithelial cells. One second messenger generated by PtdIns(4,5)P2 degradation is inositol trisphosphate. We now show that diglycerides (DG) are also generated during alpha 1-AR stimulation. In cells prelabeled with [3H]arachidonic acid, alpha 1-AR agents produced a biphasic DG generation in normal and cystic fibrosis (CF) cells that is blocked by pertussis toxin. The early DG peak closely paralleled PtdIns(4,5)P2 degradation, stimulation of cotransport by phorbol 12-myristate 13-acetate (PMA), and inhibition of cotransport by the protein kinase C (PKC) inhibitor staurosporine. This suggests that cotransporter activation requires PKC-protein phosphorylation. This possibility was tested using the protein phosphatase inhibitor okadaic acid. Okadaic acid elevated bumetanide-sensitive Cl efflux. Staurosporine also blocked > 63% of okadaic-acid-stimulated Cl transport. The late DG peak did not support hormone-stimulated cotransport. The results demonstrate that DGs are a pivotal link between alpha 1-AR stimulation and NaCl(K) cotransport activation with a role for PKC and protein phosphorylation. alpha 1-AR intracellular signaling mechanisms apparently operate normally in CF cells.
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PMID:The role of protein kinase C in alpha-adrenergic regulation of NaCl(K) cotransport in human airway epithelial cells. 790 Aug 23

Protein phosphorylation was investigated in [32P]-labeled cardiomyocytes isolated from adult rat heart ventricles. The beta-adrenergic stimulation (by isoproterenol, ISO) increased the phosphorylation of inhibitory subunit of troponin (TN-I), C-protein and phospholamban (PLN). Such stimulation was largely mediated by increased adenylyl cyclase (AC) activity, increased myoplasmic cyclic AMP and increased cyclic AMP dependent protein kinase (A-kinase)-catalyzed phosphorylation of these proteins in view of the following observations: (a) dibutyryl-and bromo-derivatives of cyclic AMP mimicked the stimulatory effect of ISO on protein phosphorylation while (b) Rp-cyclic AMP was found to attenuate ISO-dependent stimulation. Unexpectedly, 8-bromo cyclic GMP was found to markedly increase TN-I and PLN phosphorylation. Both beta 1- and beta 2-adrenoceptors were present and ISO binding to either receptor was found to stimulate myocyte AC. However, the stimulation of the beta 2-AR only marginally increased while the stimulation of beta 1-AR markedly increased PLN phosphorylation. Other stimuli that increase tissue cyclic AMP levels also increased PLN and TN-I phosphorylation and these included isobutylmethylxanthine (non-specific phosphodiesterase inhibitor), milrinone (inhibits cardiotonic inhibitable phosphodiesterase, sometimes called type III or IV) and forskolin (which directly stimulates adenylyl cyclase). Cholinergic agonists acting on cardiomyocyte M2-muscarinic receptors that are coupled to AC via pertussis toxin(PT)-sensitive G proteins inhibited AC and attenuated ISO-dependent increases in PLN and TN-I phosphorylation. The in vivo PT treatment, which ADP-ribosylated Gi-like protein(s) in the myocytes, markedly attenuated muscarinic inhibitory effect on PLN and TN-I phosphorylation on one hand and, increased the beta-adrenergic stimulation, on the other. Controlled exposure of isolated myocytes to N-ethyl maleimide, also led to the findings similar to those seen following the PT treatment. Exposure of myocytes to phorbol, 12-myristate, 13-acetate (PMA) increased the protein phosphorylation, augmenting the stimulation by ISO, and such augmentation was antagonized by propranolol suggesting modulation of the beta-adrenoceptor coupled AC pathway by PMA. Okadaic acid (OA) exposure of myocytes also increased protein phosphorylation with the results supporting the roles for type 1 and 2A protein phosphatases in the dephosphorylation of PLN and TN-I. Interestingly OA treatment attenuated the muscarinic inhibitory effect which was restored by subsequent brief exposure of myocytes to PMA. While the stimulation of alpha adrenoceptors exerted little effect on the phosphorylation of PLN and TN-I, inactivation of alpha adrenoceptors by chloroethylclonidine (CEC), augmented beta-adrenergically stimulated phosphorylation. KCl-dependent depolarization of myocytes was observed to potentiate ISO-dependent increase in phosphorylation (incubation period 15 sec to 1 min) as well as to accelerate the time-dependent decline in this phosphorylation seen upon longer incubation. Verapamil decreased ISO-stimulated protein phosphorylation in the depolarized myocytes. Depolarization was found to have little effect on the muscarinic inhibitory action on phosphorylation. Prior treatment of myocytes with PMA, was found to augment ISO-stimulated protein phosphorylation in the depolarized myocytes. Such augmented increases were completely blocked by propranolol. Forskolin also stimulated PLN and TN-I phosphorylation. Prior exposure of myocytes to forskolin followed by incubation in the depolarized and polarized media showed that PLN was dephosphorylated more rapidly in the depolarized myocytes. The results support the view that both cyclic AMP and calcium signals cooperatively increase the rates of phosphorylation of TN-I and PLN in the depolarized cardiomyocytes during beta-adrenergic stimulation. (ABSTRACT TRUNCATED)
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PMID:Regulation of phospholamban and troponin-I phosphorylation in the intact rat cardiomyocytes by adrenergic and cholinergic stimuli: roles of cyclic nucleotides, calcium, protein kinases and phosphatases and depolarization. 856 20

Capacitative Ca2+ entry, a main pathway of Ca2+ entry evoked by receptor activation, is widely confirmed in various types of cells. However, the mechanism of the activation of capacitative Ca2+ entry is unknown. We checked the several candidates for the mechanism of capacitative Ca2+ entry pathway in rat glioma C6 cells using thapsigargin (TG), a microsomal Ca(2+)-ATPase inhibitor. Pretreatment with pertussis toxin did not affect the peak and sustained elevation of [Ca2+]i evoked by TG. Sodium nitroprusside and 8-bromo cyclic GMP did not affect an elevation of [Ca2+]i induced by TG. Phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), and staurosporine, an inhibitor of PKC, did not modify an increase in [Ca2+]i induced by TG. Okadaic acid, an inhibitor of phosphatase, did not affect an increase in [Ca2+]i evoked by TG. Pretreatment with colchicine and cytochalasin D, drugs disrupting cytoskeleton, had no effect on a rise of [Ca2+]i induced by TG. Genistein and erbastatin analog, inhibitors of tyrosine kinase, inhibited an elevation of [Ca2+]i evoked by TG in a dose-dependent manner. The present results suggest that tyrosine kinase regulates capacitative Ca2+ entry into rat glioma C6 cells.
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PMID:Involvement of tyrosine kinase in capacitative Ca2+ entry pathway in rat glioma C6 cells. 946 22

Three weeks after myocardial infarction (MI) in the rat, remodeled hypertrophy of noninfarcted myocardium is at its maximum and the heart is in a compensated stage with no evidence of heart failure. Our hemodynamic measurements at this stage showed a slight but insignificant decrease of +dP/dt but a significantly higher left ventricular end-diastolic pressure. To investigate the basis of the diastolic dysfunction, we explored possible defects in the beta-adrenergic receptor-G(s/i) protein-adenylyl cyclase-cAMP-protein kinase A-phosphatase pathway, as well as molecular or functional alterations of sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban (PLB). We found no significant difference in both mRNA and protein levels of sarcoplasmic reticulum Ca(2+)-ATPase and PLB in post-MI left ventricle compared with control. However, the basal levels of both the protein kinase A-phosphorylated site (Ser16) of PLB (p16-PLB) and the calcium/calmodulin-dependent protein kinase-phosphorylated site (Thr17) of PLB (p17-PLB) were decreased by 76% and 51% in post-MI myocytes (P<0.05), respectively. No change was found in the beta-adrenoceptor density, G(salpha) protein level, or adenylyl cyclase activity. Inhibition of phosphodiesterase and G(i) protein by Ro-20-1724 and pertussis toxin, respectively, did not correct the decreased p16-PLB or p17-PLB levels. Stimulation of beta-adrenoceptor or adenylyl cyclase increased both p16-PLB and p17-PLB in post-MI myocytes to the same levels as in sham myocytes, suggesting that decreased p16-PLB and p17-PLB in post-MI myocytes is not due to a decrease in the generation of p16-PLB or p17-PLB. We found that type 1 phosphatase activity was increased by 32% (P<0.05) with no change in phosphatase 2A activity. Okadaic acid, a protein phosphatase inhibitor, significantly increased p16-PLB and p17-PLB levels in post-MI myocytes and partially corrected the prolonged relaxation of the [Ca(2+)](i) transient. In summary, prolonged relaxation of post-MI remodeled myocardium could be explained, in part, by altered basal levels of p16-PLB and p17-PLB caused by increased protein phosphatase 1 activity.
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PMID:Diminished basal phosphorylation level of phospholamban in the postinfarction remodeled rat ventricle: role of beta-adrenergic pathway, G(i) protein, phosphodiesterase, and phosphatases. 1053 53

Reduction in microglial branching is a common feature in brain pathology and culminates in the transformation into small, rounded, microglia-derived phagocytes in the presence of neural debris. The molecular factors responsible for this transformation are unknown. Here we explored the effect of different classes of intra- and extracellular stimuli in vitro on the morphology of ramified microglia cultured on a confluent astrocyte substrate. These studies showed a strong dose-dependent effect for the Ca(2+) ionophore calcimycine/A21837 (50 microM) and for dibutyryl-cAMP (1 mM), with a loss of microglial ramification. Direct activation of the adenylate cyclase with forskolin (0.1 mM) also led to the disappearance of microglial branching. Okadaic acid (70 nM), the inhibitor of protein phosphatases 1 and 2A (PP1/PP2A), and pertussis toxin (12.5 microg/ml), a G(i)-protein inhibitor, also showed similar effects. No effect was observed for dibutyryl-cGMP or for UTP; addition of ATP had a moderate effect, but only at very high, probably nonphysiological concentrations (100 mM). Extracellular matrix components such as keratatan-sulfate, integrin receptor blockers, the disintegrins kistrin, echistatin, and flavoridin, or the serine protease thrombin all had no effect. Addition of prostaglandin D(2) (PGD(2)), a molecule produced by activated microglial cells, had a transforming effect, but at concentrations two orders of magnitude higher than that of established PGD(2) receptors. In summary, addition of agents causing intracellular elevation of Ca(2+) and cAMP or inhibition of G(i)-proteins and phosphatases to ramified microglia cultured on top of confluent astrocytes leads to a rapid loss of microglial branching. Signaling cascades controlled by these molecules may play an important role in the regulation of this common physiological process in the injured brain.
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PMID:Loss of microglial ramification in microglia-astrocyte cocultures: involvement of adenylate cyclase, calcium, phosphatase, and Gi-protein systems. 1246 45

Orexins are excitatory transmitters implicated in sleep disorders. Because orexins were discovered only recently, their ionic and signal transduction mechanisms have not been well clarified. We recently reported that orexin A (OXA) inhibits G protein-coupled inward rectifier K+ (GIRK) channels in cultured locus coeruleus and nucleus tuberomammillaris neurons. Other work in our laboratory revealed the existence of a novel inward rectifier K+ channel (KirNB), which is located in cholinergic neurons of the nucleus basalis (NB) and possesses unique single-channel characteristics. The mean open time is considerably shorter in KirNB than in Kir2.0 channels. Constitutive activity and a smaller unitary conductance set KirNB apart from cloned Kir3.0 channels. Previously, we found that substance P excites NB neurons by inhibiting KirNB channels. Here we show that orexins suppress KirNB channel activity, likely leading to neuronal excitation. Electrophysiological studies were performed on cultured NB neurons from the basal forebrain. OXA application decreased whole cell conductance through a pertussis toxin (PTX)-insensitive G protein. The OXA-suppressed current was inwardly rectifying with a reversal potential around E(K). Single-channel recordings of NB neurons revealed that constitutively active KirNB channels were transiently inhibited by OXA. Okadaic acid pretreatment abolished the recovery. The results suggest that OXA inhibition of KirNB is mediated by a PTX-insensitive G protein (i.e., G(q/11)), which eventually results in channel phosphorylation. Recovery from this inhibition is by dephosphorylation. These results, taken together with our previous study, suggest that orexin receptors can elicit neuronal excitation through at least two families of inward rectifier K+ channels: GIRK and KirNB channels.
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PMID:Orexin (hypocretin) effects on constitutively active inward rectifier K+ channels in cultured nucleus basalis neurons. 1526 29