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 high selectivity, low conductance, amiloride-blockable, sodium channel of the mammalian distal nephron (i.e. cortical collecting tubule) is the site of discretionary regulation which allows maintainance of total body sodium balance. In order to understand the physiological events that participate in this regulation, we have used the patch-clamp technique which allows us to measure individual Na+ channel currents and permits access to the cytosolic side of the channel-protein as well as its associated regulatory components. Most of our experiments have utilized the A6 amphibian renal cell line, which when grown on permeable supports is an excellent model for the mammalian distal nephron. Different mechanisms have been examined: (1) regulation by hormonal factors such as Anti-Diuretic Hormone (ADH) and aldosterone, (2) regulation by G-proteins, (3) modulation by protein kinase C (PK-C), and (4) modulation by products of arachidonic acid metabolism. Consistent with noise analysis of tight epithelial tissues, ADH treatment increased the number of active channels in apical membrane patches of A6 cells, without any apparent change in the open probability (Po) of the individual channels. Agents that increased intracellular cAMP mimicked the effects of ADH. In contrast, aldosterone was found to act through a dramatic increase in Po rather than through changes in channel density. Inhibition of methylation by deazaadenosine antagonizes the stimulatory effect of aldosterone. In excised inside-out patches GTP gamma S inhibits channel activity, whereas GDP beta S or pertussis toxin stimulates activity suggesting regulatory control by G-proteins. PK-C has been shown to contribute to 'feed-back inhibition' of apical Na+ conductance in tight epithelia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of renal epithelial sodium channels. 133 27

We sought to assess the effect of an increase in cAMP on sodium channels on adult rat cardiac ventricular myocytes. Sodium channels were studied with the use of the radiolabeled sodium channel-specific toxin [3H] batrachotoxinin benzoate ([3H]BTXB). Forskolin, isoproterenol, prostaglandin E1, cholera toxin, and pertussis toxin each increased cAMP levels and decreased the number of [3H]BTXB binding sites without changing the affinity of [3H]BTXB for the sodium channel. The cAMP analog 8-bromo-cyclic AMP (8-Br-cAMP) reduced the number of [3H]BTXB binding sites from 19 fmol/10(5) cells to 11 fmol/10(5) cells. [3H]BTXB binding site down-regulation was reversible, cAMP dose-dependent, and time-dependent. To test the hypothesis that the cAMP effect was mediated by cAMP-dependent phosphorylation, we determined the effect of 8-Br-cAMP on [3H]BTXB binding after preincubation of myocytes with N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide dihydrochloride (H8), a protein kinase A inhibitor. H8 inhibited 70% of the decrease in the number of [3H]BTXB binding sites induced by 8-Br-cAMP. Thus increases in intracellular cAMP in cardiac myocytes reversibly induced a decrease in the number of [3H]BTXB binding sites via cAMP-dependent protein phosphorylation, possibly of the sodium channel.
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PMID:Cyclic AMP-dependent regulation of the number of [3H]batrachotoxinin benzoate binding sites on rat cardiac myocytes. 164 46

The phosphorylation of the cardiac sodium channel by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase A leads to its inactivation. It was shown that extracellular cAMP can also modulate the sodium channel of rat, guinea pig, and frog ventricular myocytes in a rapid (less than 50 milliseconds), reversible, and dose-dependent manner. The decrease in the sodium current was accompanied by a 10- to 15-millivolt shift in the steady-state availability of the sodium channel toward more negative potentials and was inhibited by guanosine-5'-O-(2-thiodiphosphate) or pertussis toxin, suggesting that the extracellular modulation of the sodium channel by cAMP is mediated by a membrane-delimited mechanism that includes a pertussis toxin-sensitive G protein.
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PMID:Modulation of cardiac sodium channels by cAMP receptors on the myocyte surface. 165 70

The cellular mechanisms by which the hypothalamic peptide somatostatin (SRIF) inhibits Ca+(+) influx were investigated in the pituitary cell line AtT-20. Cytosolic Ca+(+) levels were measured using the fluorescent probe Quin 2. Calcium influx was stimulated by the Ca+(+) channel agonist Bay K 8644. Bay K 8644 increased Ca+(+) influx in a concentration-dependent manner and the stimulation of Ca+(+) influx was blocked by the Ca+(+) channel antagonists nifedipine and nitrendipine. SRIF analogs also blocked Bay K 8644-stimulated Ca+(+) influx. The rank order of potency of the analogs (SRIF-28 greater than D-Trp8-SRIF greater than SRIF) suggests that the effects of SRIF are mediated by SRIF-28 preferring receptors. Pretreatment of AtT-20 cells with pertussis toxin abolished SRIF's inhibition of Bay K 8644-evoked Ca+(+) influx suggesting that G proteins mediate the inhibitory effects of SRIF on Ca+(+) influx. The K+ channel antagonists tetraethylammonium, 4-aminopyridine and CsCl all stimulated Ca+(+) influx into AtT-20 cells. These agents did not alter Bay K 8644-evoked Ca+(+) influx or did they affect the ability of SRIF to inhibit Ca+(+) influx. Tetrodotoxin, the sodium channel blocker which inhibits action potential generation in AtT-20 cells, lowered basal Ca+(+) levels in AtT-20 cells but did not modify SRIF's inhibition of Bay K 8644-stimulated Ca+(+) influx. These findings suggest that SRIF receptors, linked directly to Ca+(+) channels via G proteins, may mediate SRIF's inhibition of Ca+(+) influx.
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PMID:Cellular mechanisms of somatostatin inhibition of calcium influx in the anterior pituitary cell line AtT-20. 169 31

The first step in net active transepithelial transport of sodium in tight epithelia is mediated by the amiloride-blockable sodium channel in the apical membrane. This sodium channel is the primary site for discretionary control of total body sodium and, therefore, investigating its regulatory mechanisms is important to our understanding of the physiology of fluid and electrolyte balance. Because essentially all of the regulatory sites on the channel are on the intracellular surface, patch clamp methods have proven extremely useful in the electrophysiological characterization of the sodium channel by isolating it from other channel proteins in the epithelial membrane and by allowing access to the intracellular surface of the protein. We have examined three different regulatory mechanisms. (1) Inhibition of channel activity by activation of protein kinase C; (2) activation of the channel by agents which activate G-proteins; and (3) modulation of channel kinetics and channel number by mineralocorticoids. Activation of protein kinase C by phorbol esters or synthetic diacylglycerols reduces the open probability of sodium channels. Protein kinase C can be activated in a physiological context by enhancing apical sodium entry. Actions which reduce sodium entry (low luminal sodium concentrations or the apical application of amiloride) increase channel open probability. The link between sodium entry and activation of protein kinase C appears to be mediated by intracellular calcium activity linked to sodium via a sodium/calcium exchange system. Thus, the intracellular sodium concentration is coupled to sodium entry in a negative feedback loop which promotes constant total entry of sodium. Activation of G-proteins by pertussis toxin greatly increases the open probability of sodium channels. Since channels can also be activated by pertussis toxin or GTP gamma S in excised patches, the G-protein appears to be closely linked in the apical membrane to the sodium channel protein itself. The mechanism for activation of this apical G-protein, when most hormonal and transmitter receptors are physically located on the basolateral membrane, is unclear. Mineralocorticoids such as aldosterone have at least two distinct effects. First, as expected, increasing levels of aldosterone increase the density of functional channels detectable in the apical membrane. Second, contrary to expectations, application of aldosterone increases the open probability of sodium channels. Thus aldosterone promotes the functional appearance of new sodium channels and promotes increased sodium entry through both new and pre-existant channels.
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PMID:Regulation of the amiloride-blockable sodium channel from epithelial tissue. 196 46

1. Intracellular calcium levels were measured in cultured cerebellar granule cells of the rat by use of the fluorescent dye, indo-1/AM. 2. Intracellular calcium levels were increased by depolarizing stimuli such as N-methyl-D-aspartate (NMDA) (100 microM), glutamic acid (20 microM), and veratridine (10 microM). This increase was essentially due to entry of external calcium. 3. Riluzole (10 microM) blocked responses to all the depolarizing agents. 4. Riluzole could still block the increase in intracellular calcium evoked by NMDA or glutamic acid when sodium channels were blocked by tetrodotoxin, suggesting that this effect is not mediated by a direct action of riluzole on the voltage-dependent sodium channel. 5. Pretreatment of the cells with pertussis toxin (0.1 micrograms ml-1) did not modify the increases in intracellular calcium evoked by NMDA, glutamic acid or veratridine. 6. In pertussis toxin-treated cells, riluzole could no longer block responses to excitatory amino acids, but still blocked responses to veratridine. 7. It is concluded that riluzole has a dual action on cerebellar granule cells, both blocking voltage-dependent sodium channels and interfering with NMDA receptor-mediated responses via a pertussis toxin-sensitive mechanism. Furthermore, these two processes have been shown to be independent.
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PMID:Antagonism by riluzole of entry of calcium evoked by NMDA and veratridine in rat cultured granule cells: evidence for a dual mechanism of action. 781 19

Single-channel methods were used to examine the regulation of amiloride-blockable highly selective sodium channels by guanine nucleotide-binding proteins (G proteins). A6 cells (a renal cell line derived from Xenopus laevis kidney) were cultured on permeable collagen films, and patch recordings were made from the apical membranes of confluent cells. The predominant channel in the apical membranes is a highly selective, 4-pS, amiloride-blockable sodium channel (the Na(+)-to-K+ permeability ratio is > 30). In inside-out patches, application to the cytosolic surface of guanosine-5'-O-(2-thiodiphosphate) (GDP beta S), which deactivates G proteins, increased sodium channel activity. GDP beta S produced a sevenfold increase in channel activity. In contrast, GTP and guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S) decreased sodium channel activity to about one-twentieth of the untreated value. The effect of GTP (but not GTP gamma S) was reversible. In cell-attached patches, a 3- to 4-h exposure of the apical membrane to pertussis toxin (PTX) increased the mean open time of sodium channels approximately 2.7 times and the open probability approximately 1.6-fold, but pretreatment of apical membranes with cholera toxin (250 ng/ml) for 3-4 h had no effect on open probability or mean open time. These results imply that a PTX-sensitive G protein regulates amiloride-blockable highly selective sodium channels in the apical membranes of A6 cells and that the G protein in a GTP-bound, activated state inhibits sodium channel activity.
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PMID:G protein activation inhibits amiloride-blockable highly selective sodium channels in A6 cells. 838 28

Corticosteroid regulation of Na/K-ATPase is of key importance in the modulation of Na+ transport across renal tubular epithelia. In amphibian renal cells, aldosterone induction of Na/K-ATPase alpha 1 and beta 1 subunit gene transcription is mediated by an indirect mechanism dependent on the synthesis of a labile protein. In mammalian target cells, while both mineralo- and glucocorticoids increase the levels of Na/K-ATPase alpha 1 and beta 1 subunit mRNA and enzyme activity, they are diminished by glycyrrhetinic acid (GE), the active ingredient of licorice. To investigate the mechanisms underlying the regulation of mammalian renal Na/K-ATPase, levels of alpha 1 and beta 1 mRNA were measured in rat kidney epithelial (NRK-52E) cells treated with a range of concentrations of aldosterone, corticosterone and GE in the presence of a specific inhibitor of mRNA synthesis, dichlororibofuranosylbenzimidazole (DRB), an inhibitor of total RNA synthesis, actinomycin D (ActD), and the protein synthesis inhibitor cycloheximide (CHX). In addition, GE was co-incubated with the sodium channel antagonist benzamiloride (BZ). The increase in both alpha 1 and beta 1 mRNA levels following aldosterone and corticosterone was completely abolished by treatment with ActD and DRB, while CHX did not affect this response. Similarly, the GE-induced decrease in alpha 1 and beta 1 mRNA was also completely abolished by ActD and DRB, but not by CHX or by BZ. The half-lives of alpha 1 and beta 1 mRNA in these cells (means +/- S.E.M., n = 4), estimated from the rate of mRNA decay in the presence of DRB, were 6.8 +/- 0.3 and 4.8 +/- 0.2 h respectively. This was unaffected by GE. The inhibitory action of GE on alpha 1 and beta 1 mRNA levels was accompanied by a dose-dependent decrease in levels of intracellular cAMP (means +/- S.E.M., n = 4) from 395 +/- 28 fmol cAMP/microgram total cell protein to between 275 +/- 19 fmol/micrograms total cell protein (0.1 microM GE) and 78 +/- 11 fmol/micrograms total cell protein (10 microM GE). This was abolished following down-regulation of protein kinase C by prolonged treatment with the phorbol ester tetradecanoylphorbol-13-acetate (TPA), and by pertussis toxin (PT), but not by cholera toxin (CT). Indeed, subunit mRNA levels were increased by 8-bromo-cAMP (2.2-fold) and stimulators of adenylate cyclase activity, i.e. forskolin (2.1-fold), PT (2.1-fold) and CT (1.9-fold), but not by TPA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transcriptional regulation of Na/K-ATPase by corticosteroids, glycyrrhetinic acid and second messenger pathways in rat kidney epithelial cells. 854 17

Inflammation caused by tissue damage results in pain, reflecting an increase in excitability of the primary afferent neurons innervating the area. There is some evidence to suggest that altered function of voltage-gated sodium channels is responsible for the hyperexcitability produced by inflammatory agents, possibly acting through G-proteins, but the role of different channel subtypes has not been fully explored. The tetrodotoxin-resistant (TTX-R) sodium channel Na(v)1.9 is expressed selectively in C- and A-fibre nociceptive-type units and is upregulated by G-protein activation. In this study, we examined the effects of the inflammatory agent prostaglandin-E(2) (PGE(2)) on Na(v)1.9 current in both Na(v)1.8-null and wild-type (WT) mice and explored the role of specific G-proteins in modulation. PGE(2) caused a twofold increase in Na(v)1.9 current (p<0.05) in both systems. Steady-state activation was shifted in a hyperpolarizing direction by 6-8 mV and availability of channels by 12 mV. No differences in the activation and inactivation kinetics could be detected. The increase in current was blocked by pertussis toxin (PTX) but not cholera toxin (CTX), showing involvement of G(i/o) but not G(s) subunits. Our data indicate that Na(v)1.9 current can be increased during inflammation via a G-protein dependent mechanism and suggest that this could contribute to the regulation of electrogenesis in dorsal root ganglia (DRG) neurons.
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PMID:PGE2 increases the tetrodotoxin-resistant Nav1.9 sodium current in mouse DRG neurons via G-proteins. 1537 52

For over 50 years, concerns have been raised about the risk of pertussis vaccine-induced childhood encephalopathy and epilepsy. This article reviews the scientific literature, and the social and historical context in which the scientific, public health and societal views have not always been aligned. Large-scale studies of this issue have produced conflicting results, although the recent consensus is that the risk of vaccine-induced encephalopathy and/or epilepsy, if it exists at all, is extremely low. Risk estimates in the literature have included: risk of a febrile seizure 1 per 19,496 vaccinations; risk of an afebrile seizure 1 per 76,133 vaccinations; risk of encephalopathy after pertussis infection nil-3 cases per million vaccinations. A recent study showed that encephalopathy in 11 out of the 14 children studied, although previously attributed to vaccination, was in fact due an inherited genetic defect of the SCNIA gene that codes for the voltage gated neuronal sodium channel. This study is important because it provides a solid alternative explanation for the perceived pertussis vaccine-encephalopathy association. The interesting possibility is raised that the encephalopathy apparently due to pertussis itself may, in some cases, be due to an SCNIA mutation. It may also, by analogy, shed some light on the continuing debate about other serious long-term adverse effects of vaccination in general.
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PMID:Pertussis vaccination and epilepsy--an erratic history, new research and the mismatch between science and social policy. 1809 46


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