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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Direct effects of islet-activating protein (IAP), pertussis toxin, on membrane preparations from rat heart tissues were studied. The native IAP was without effect, but its A-protomer, an active subunit, was effective after reduction of disulfide bonds in the peptide chain; it catalyzed ADP-ribosylation of the membrane Mr = 41,000 protein. Simultaneously, muscarinic receptor-mediated inhibition of adenylate cyclase was abolished. Carbachol, an agonist of muscarinic receptors, bound to membranes with the Hill coefficient smaller than unity. The affinity for the carbachol binding was lowered and the Hill coefficient was increased by guanylylimidodiphosphate (Gpp(NH)p), reflecting the muscarinic receptor coupling to the guanine nucleotide regulatory protein (N). Carbachol bound to the A-promoter-treated membranes with a lower affinity and a higher Hill coefficient, and these kinetic values were not altered by Gpp(NH)p, indicating that treatment of membranes with the A-protomer of IAP uncoupled muscarinic receptors from N. This IAP-sensitive N is Ni involved in the cyclase inhibition. Neither beta-adrenergic activation of adenylate cyclase nor beta-agonist binding to membranes was affected by the A-protomer of IAP. Thus, N (Ns) coupled to beta-receptors is not the site of its action. Although the affinity and the Hill coefficient for beta-agonist binding was not affected by preactivated cholera toxin either, the effect of Gpp(NH)p to alter these kinetic parameters was much smaller in the cholera toxin-treated membranes than in non-treated membranes. Thus, cholera toxin modified beta-receptor coupling to Ns in a manner quite different from IAP-induced modification of muscarinic receptor coupling to Ni.
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PMID:Functional uncoupling of muscarinic receptors from adenylate cyclase in rat cardiac membranes by the active component of islet-activating protein, pertussis toxin. 668 24

1. Whole-cell patch-clamp technique was used to study the beta-adrenergic and cholinergic regulation of the inwardly rectifying K+ conductance (gK1) in isolated guinea-pig ventricular myocytes. 2. In Cl(-)-free solutions or in the presence of 9-anthracenecarboxylic acid or Co2+, bath-applied isoprenaline (Iso) partially inhibited the steady-state whole-cell conductance (gss) calculated from the steady-state current (Iss)-voltage (Iss-V) curve at membrane voltages (Vm) negative to the equilibrium potential for potassium (EK). Iss was also inhibited at Vm positive to EK when the extracellular [K+] was 20 mM. The Iso-sensitive component of gss exhibited the characteristics of the inwardly rectifying K+ conductance (gK1). 3. The Iso-induced inhibition of gK1 was reversible, concentration dependent, blocked by propranolol, mimicked by both forskolin and dibutyryl cAMP, and prevented by including a cAMP-dependent protein kinase (PKA) inhibitor in the pipette solution. These findings suggest that PKA mediates the Iso-induced inhibition of gK1. 4. The apparent dissociation constant (KD) for the concentration dependence of Iso-induced inhibition was 0.035 microM and the Hill coefficient was approximately 1.0. A maximal Iso concentration (1 microM) inhibited gK1 by 40 +/- 4.1% (mean +/- S.E.M.; n = 13). 5. Bath application of acetylcholine (ACh, 0.1 microM or more) antagonized the Iso-induced (1 microM) inhibition of gK1; [ACh] > 1.0 microM antagonized 88 +/- 2.1% (n = 10) of the inhibition. ACh increased the KD for Iso to inhibit Iso-sensitive gK1 and also reduced the maximal Iso-induced inhibition. 6. ACh-induced antagonism could be abolished by pre-incubating myocytes with pertussis toxin (PTX), suggesting that a muscarinic receptor-coupled, PTX-sensitive G protein, Gi, is involved. 7. ACh (10 microM) also antagonized approximately 70% of the dibutyryl cyclic AMP (1 mM)-induced inhibition of gK1 (n = 3), suggesting that the ACh-induced antagonism involves more than simply inhibiting the Iso-mediated activation of adenylyl cyclase via the activated Gi. 8. Intracellularly applied okadaic acid (OkA, 1 microM) did not alter gK1 (control = 134 +/- 5.1 nS vs. OkA = 136 +/- 6.1 nS), but the Iso-induced decrease in gK1 was less (P < 0.001) with OkA present (42.1 +/- 2.4 nS, n = 5) than when absent (54.0 +/- 2.2 nS, n = 10). However, ACh (10 microM) failed to antagonize Iso-induced inhibition with OkA present, suggesting involvement of a protein phosphatase.
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PMID:beta-adrenergic and cholinergic modulation of the inwardly rectifying K+ current in guinea-pig ventricular myocytes. 747 26

We studied the role of cyclic guanosine monophosphate (cGMP) as a mediator of the reduction of L-type calcium current (ICa) induced by muscarinic receptor stimulation and by nitric oxide in isolated guinea-pig ventricular cells using the whole-cell patch-clamp technique. Our results show that when the level of cyclic adenosine monophosphate was increased by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), stimulation of a pertussis-toxin (PTX)-sensitive muscarinic receptor by carbachol (1 microM) reduced the calcium current increase from 80.6 +/- 23.5% to 19.8 +/- 9.6% over the control and this effect was prevented by methylene blue (10 microM), an inhibitor of the soluble guanylate cyclase. Pipette solution containing 10 microM cGMP reduced the enhancement of ICa by IBMX from 121.9 +/- 11.6% to 14.2 +/- 5.4% above the control. Sodium nitroprusside (10 microM), a spontaneous donor of nitric oxide, and consequently a stimulator of soluble guanylate cyclase, also reduced IBMX-stimulated ICa from 115.2 +/- 13.2% to 32.2 +/- 6.9% above control and the sodium nitroprusside effect was also suppressed by methylene blue. The latter two reagents were ineffective on basal ICa.
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PMID:Guanylate-cyclase-mediated inhibition of cardiac ICa by carbachol and sodium nitroprusside. 751 32

Stimulation of excitatory receptors in smooth muscle often leads to the opening of ROCC. These channels exhibit considerable permeability to Ca2+, and they have been regarded as the most probable candidate for the "receptor-operated Ca2+ entry" pathway. The muscarinic receptor ROCC in guinea pig ileum (mROCC) have a unitary conductance of -25pS and are activated through a pertussis toxin-sensitive G protein. mROCC permeate Ca2+ and Ba2+ several fold more preferably than monovalent cations, and they are inhibited by various types of K channel blockers, diphenylamine-2-carboxylate derivatives and even by nicardipine and D-600 at high concentrations. mROCC are efficiently regulated by various physiological factors including the membrane potential, intracellular Ca2+ concentration, external pH and osmolarity. The effective ranges of these factors span their dynamic ranges under physiological conditions. In addition to these properties, mROCC have several sites sensitive to external polyvalent cations. The alpha 1-adrenergic receptor ROCC in rabbit portal vein resemble mROCC in many respects, e.g., the unitary conductance, ionic selectivity, activation kinetics, sensitivity to polyvalent cations and voltage-dependence. These complex characteristics of ROCC suggest that they play other roles in addition to being just a passive cation permeable pore in agonist-mediated Ca2+ mobilization in smooth muscle.
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PMID:[Biophysical and pharmacological characterization of receptor-operated nonselective cation channels (ROCC) and their regulatory mechanisms in smooth muscle]. 753 99

Although the neurotoxicity of organophosphorus compounds is generally attributed to inhibition of acetylcholinesterase, recent reports have indicated that direct interactions with muscarinic receptors and signal transduction may be an additional mechanism of neurotoxicity. We have previously shown that the organophosphorus insecticide O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphorothioate (chlorpyrifos) binds directly to muscarinic receptors and inhibits adenylate cyclase of rat striatum. We have further pursued those results in this study by investigating the effect of chlorpyrifos oxon in NG108-15 neuroblastoma-glioma cells and Chinese hamster ovary cells transfected with cDNA for human m2 or m4 muscarinic receptor subtypes. At millimolar concentrations, chlorpyrifos oxon inhibited [3H]QNB binding in all cell lines. Likewise, [3H]CD binding was inhibited in NG108-15 and CHO-Hm2 cells. When the effect of chlorpyrifos oxon on adenylate cyclase was examined, the oxon was found to inhibit adenylate cyclase at millimolar concentrations. Though this effect on cyclase required greater concentrations of oxon than the comparable effect in striatal cells, it displayed the common characteristic of being atropine-insensitive, suggesting that the effect on cyclase was not muscarinic receptor dependent. The inhibition of adenylate cyclase produced by chlorpyrifos oxon was not eliminated in pertussis toxin treated cells, lending further support to the idea that it is not a receptor-mediated event, and suggesting a potential direct interaction of chlorpyrifos oxon with the adenylate cyclase molecule.
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PMID:In vitro effect of chlorpyrifos oxon on muscarinic receptors and adenylate cyclase. 756 87

We tested lysophosphatidic acid (LPA) known to induce inositol phosphate generation and calcium signals as well as rearrangements of the cytoskeleton and mitogenic responses in fibroblasts, for its ability to activate phospholipase C in an exocrine cell system, the salt-secreting cells from the avian nasal salt gland. LPA (> 10 nmol/l) caused the generation of inositol phosphates from membrane-bound phosphatidylinositides. The resulting calcium signals resembled those generated upon activation of muscarinic receptors, the physiological stimulus triggering salt secretion in these cells. However, close examination of the LPA-mediated calcium signals revealed that the initial calcium spike induced by high concentrations of LPA (> 10 mumol/l) may contain a component that is not dependent upon generation of inositol (1,4,5)-trisphosphate (Ins(1,4,5)P3) and may result from calcium influx from the extracellular medium induced by LPA in a direct manner. Low concentrations of LPA (< 10 mumol/l), however, induce inositol phosphate generation, Ins(1,4,5)P3-mediated release of calcium from intracellular pools and calcium entry. These effects seem to be mediated by a specific plasma membrane receptor and a G protein transducing the signal to phospholipase C in a pertussis-toxin-insensitive manner. Signaling pathways of the muscarinic receptor and the putative LPA-receptor seem to merge at the G-protein level as indicated by the fact that carbachol and LPA trigger hydrolysis of the same pool of phosphatidylinositol (4,5)-bisphosphate (PIP2) and mobilize calcium from the same intracellular stores.
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PMID:Lysophosphatidic acid induces inositol phosphate and calcium signals in exocrine cells from the avian nasal salt gland. 759 41

1. The effect of muscarinic receptor stimulation on voltage-gated calcium channel currents was examined in whole-cell voltage-clamped smooth muscle cells of the guinea-pig ileum. 2. In cells voltage clamped at -60 mV and in which calcium channel currents (ICa) were elicited repeatedly by depolarizing pulses (25 ms duration, 0.25 Hz frequency) to 0 mV, carbachol (CCh, 10 microM) induced an inward current (ICCh) and were suppressed ICa, in a biphasic manner; an initial transient component was followed by a more sustained one. 3. A calcium channel current (IBa), when Ba2+ was used as a charge carrier, was also suppressed by CCh in a biphasic manner, as with ICa. The sustained phase of the IBa suppression was significantly smaller than that of the ICa suppression, suggesting that Ca2+ entry exerts a potentiating effect on the current suppression. 4. CCh had little or no effect on calcium channel currents (ICa and IBa) in cells dialysed with a pipette solution containing EGTA (20 mM). 5. Inclusion of GDP-beta-S (1 mM) in the pipette solution abolished ICCh and the suppression of IBa. With GTP-gamma-S (10 microM) in the pipette, the sustained phase of the IBa suppression remained almost unchanged even after removal of CCh. 6. Pretreatment with 2 micrograms ml-1 pertussis toxin (PTX), which abolished ICCh, did not change noticeably the initial transient and sustained phases of IBa suppression. 7. Neomycin (100 microM) or heparin (5 mg ml-1) in the pipette each abolished the initial transient component of ICCh as well as the initial transient phase of IBa suppression. 8. The biphasic effect of CCh on IBa was observed in the presence of either staurosporine (1 microM) or 1-(5-isoquinolinesulphonyl)-2-methylpiperazine (100 microM). Phorbol 12-myristate 13-acetate and phorbol 12,13-dibutyrate (up to 10 microM) had no inhibitory effect on ICa and IBa. 9. The results suggest that stimulation of the muscarinic receptor causes a biphasic suppression of the voltage-gated calcium channel currents through a PTX-insensitive G protein in guinea-pig ileal smooth muscle cells. The initial transient phase may be brought about by the release of Ca2+ from internal storage sites, and the sustained phase by a Ca(2+)-dependent mechanism which is independent of the phosphatidylinositol pathway.
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PMID:Inhibitory effect of muscarinic receptor activation on Ca2+ channel current in smooth muscle cells of guinea-pig ileum. 762 77

1. Ca2+ channel modulation by muscarine was investigated in primary cultured embryonic rat hippocampal neurons using the whole-cell variant of the patch-clamp technique. 2. Muscarine produced a reversible and concentration-dependent decrease in the Ba2+ current amplitude. In 65% of neurons sensitive to the agonist, current inhibition was time and voltage dependent, being maximal between -20 and 0 mV and decreasing at depolarizing potentials. In the remaining 35% of neurons, the effects of muscarine were voltage independent, inhibition being constant in a wide potential range between -20 and +80 mV. 3. Different receptors might be involved in the two modes of modulation. Muscarine-induced voltage-dependent inhibition of Ba2+ current was best suppressed by the muscarinic receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine methiodide (81% suppression), while voltage-independent inhibition was best suppressed by AFDX116 (75% suppression). 4. In cells treated with omega-conotoxin (omega-CgTX), the voltage-independent mode of inhibition was strongly prevented, suggesting that the two modulatory mechanisms (voltage dependent and voltage independent) operate on separate classes of high-voltage-activated (HVA) Ca2+ channels. 5. A pertussis toxin-sensitive G-protein is involved in both modes of action of muscarine, since both modes were prevented by pretreatment of the cells with 50 ng ml-1 pertussis toxin. 6. Both modes of modulation were mimicked in different cells by intracellular application of GTP-gamma-S. However, the onset of voltage-independent inhibition was about 5 times slower than that of voltage-dependent inhibition, suggesting involvement of a more complex metabolic pathway for the former mode of channel modulation. 7. Relief of the voltage-dependent inhibition was obtained by depolarizing voltage prepulses and occurred with kinetics that depended on agonist concentration. 8. The voltage-dependent inhibition could be simulated by a kinetic model in which the time course of Ca2+ entry was assumed to be regulated by both the concentration of muscarine and membrane potential.
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PMID:Muscarine inhibits high-threshold calcium currents with two distinct modes in rat embryonic hippocampal neurons. 765 Jun 8

Bath application of the muscarinic receptor agonist, muscarine, produced a concentration-dependent depression of synaptic activity in the dentate gyrus of hippocampal slices. A concentration of 10 microM muscarine produced a reversible depression that could be competitively antagonized by the muscarinic receptor antagonist pirenzepine. However, other muscarinic receptor subtype (M1-M3) antagonists could also block the effects of muscarine. The rank order of antagonist potency was: 4-diphenylacetoxy-N-methyl-piperidine methiodide (M3/M1 antagonist) > pirenzepine (M1) > AFDX-116 (M2). The depression produced by 10 microM muscarine was not affected by in vivo pretreatment with pertussis toxin, and therefore was not mediated by a pertussis toxin-sensitive G-protein. In addition, high concentrations of muscarine did not affect either basal or isoproterenol-stimulated accumulation of cyclic AMP from slices of dentate gyrus. Muscarine also produced a concentration-dependent blockade of the induction of norepinephrine-induced long-lasting potentiation in the dentate gyrus. Norepinephrine-induced long-lasting potentiation is a form of long-lasting plasticity induced in medial perforant path synapses by beta-adrenergic agonists such as isoproterenol. The muscarinic blockade of norepinephrine-induced long-lasting potentiation was also prevented by pretreatment with pirenzepine. Based on these pharmacological data, we conclude that muscarinic depression of evoked responses, as well as blockade of norepinephrine-induced long-lasting potentiation, involves activation of either M3 or M1, but not M2, muscarinic receptors. These data also demonstrate that in addition to modulating normal synaptic transmission, muscarinic receptors may also play an important role in modulating synaptic plasticity.
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PMID:Muscarinic depression of synaptic transmission and blockade of norepinephrine-induced long-lasting potentiation in the dentate gyrus. 768 52

The inhibitory pathway of cardiac cAMP-dependent protein kinase regulated Cl- conductance was investigated using the whole-cell configuration of patch-clamp techniques in single guinea pig ventricular myocytes. Pertussis toxin-sensitive G proteins (Gi), mediating the signal transductions between muscarinic receptors and adenylate cyclase, have a substantial tonic activity even in the absence of muscarinic receptor modulators. Muscarinic agonists or antagonists (like atropine) either increase or decrease this basal activity of Gi by altering the proportion of active and inactive forms of the receptors. Similar to L-type Ca-channel currents, the Cl- conductance showed a transient over-recovery upon cessation of brief muscarinic receptor stimulation by carbachol (CCh) (rebound). Atropine alone enhanced the Cl- conductance elicited by low concentrations of Iso (reverse agonist). After washout of atropine, the over-suppression of the conductance was observed as a mirror image of CCh-induced rebound (reverse rebound). Both types of rebound became prominent when cell dialysis with pipette solutions containing 100 microM GTP was minimized with high-resistance pipettes. Endogenous GTP is therefore an intracellular modulator, and not simply a mediator, of Gi-dependent signal transduction.
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PMID:Inhibitory pathway of cardiac PKA-dependent Cl- conductance via pertussis toxin-sensitive G proteins. 775 28


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