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)

Atrial and ventricular adenylate cyclase activity and atrial membrane potentials were measured in hearts from hatched chicks at 2-3 days after intravenous administration of pertussis toxin (0.5-1.0 micrograms, total) or saline. Both in atrium and ventricle, treatment with pertussis toxin antagonized inhibition by carbachol of basal and isoproterenol-stimulated adenylate cyclase activity without changing either basal or isoproterenol-stimulated adenylate cyclase. In atria from pertussis toxin-treated animals (5.4 mM potassium), carbachol hyperpolarized the resting membrane by 0.3 +/- 0.3 mV (n = 9) and did not increase resting potassium conductance. In contrast, carbachol hyperpolarized the resting membrane by 4.5 +/- 0.8 mV (n = 11) and increased resting potassium conductance more than 4-fold in saline-treated animals. Carbachol did not significantly affect the atrial action potential peak or duration at 50% repolarization of pertussis toxin-treated animals. This muscarinic agonist reduced action potential peak by 7.8 +/- 1.2 mV and the duration at 50% repolarization by 22.1 +/- 3.0 msec in atria from saline-treated animals. Pertussis toxin treatment also prevented the negative inotropic effect and the inhibition of calcium-dependent action potentials caused by carbachol in atrial muscle. Neither the affinity nor the maximal specific binding of [3H]quinuclidinyl benzilate in ventricular homogenates was changed by pertussis toxin treatment. The apparent affinity of carbachol for muscarinic receptor was slightly (approximately 2-fold) diminished in pertussis toxin-treated animals. The inhibition of carbachol-induced hyperpolarization by pertussis toxin treatment implicates a guanosine 5'-triphosphate-dependent protein (Ni or a similar protein) as an essential link that permits muscarinic receptor to regulate atrial potassium channels.
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PMID:Pertussis toxin treatment blocks hyperpolarization by muscarinic agonists in chick atrium. 241 29

An adenosine receptor has been characterized to unambiguously demonstrate that the inhibitory guanine nucleotide regulatory protein, Gi, of 1321N1 human astrocytoma cells is fully capable of functionally coupling to adenylate cyclase. Adenosine receptor agonists attenuated cyclic AMP accumulation by 35 to 75% with the order of potency of N6(R-phenylisopropyl)-adenosine greater than adenosine = 2-chloroadenosine greater than N6-methyladenosine = N6-benzyladenosine. 3-Isobutyl-1-methylxanthine competitively antagonized the effect of adenosine receptor agonists. Adenylate cyclase activity measured in cell-free preparations from 1321N1 cells was inhibited by N6(R-phenylisopropyl)-adenosine. Pretreatment of 1321N1 cells with pertussis toxin blocked both adenosine receptor-mediated inhibition of adenylate cyclase activity and attenuation of cyclic AMP accumulation. In contrast to the effects on responses to adenosine receptor agonists, 3-isobutyl-1-methylxanthine noncompetitively antagonized muscarinic receptor-mediated attenuation of cyclic AMP accumulation and pertussis toxin had no effect. These data are consistent with the ideas that Gi is fully functional in 1321N1 cells and links inhibitory adenosine receptors to adenylate cyclase, and that the muscarinic receptor of these cells couples to the phosphoinositide response system, but is incapable of functionally coupling through Gi to inhibit adenylate cyclase.
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PMID:Adenosine and muscarinic cholinergic receptors attenuate cyclic AMP accumulation by different mechanisms in 1321N1 astrocytoma cells. 242 Sep 67

Our previous experiments in membranes prepared from rat heart and brain led us to suggest that the binding of agonists to the muscarinic receptors and to the Na+ channels is a coupled event mediated by guanine nucleotide binding protein(s) [G-protein(s)]. These in vitro findings prompted us to employ synaptoneurosomes from brain stem tissue to examine (i) the binding properties of [3H]acetylcholine at resting potential and under depolarization conditions in the absence and presence of pertussis toxin; (ii) the binding of [3H]batrachotoxin to Na+ channel(s) in the presence of the muscarinic agonists; and (iii) muscarinically induced 22Na+ uptake in the presence and absence of tetrodotoxin, which blocks Na+ channels. Our findings indicate that agonist binding to muscarinic receptors is voltage dependent, that this process is mediated by G-protein(s), and that muscarinic agonists induce opening of Na+ channels. The latter process persists even after pertussis toxin treatment, indicating that it is not likely to be mediated by pertussis toxin sensitive G-protein(s). The system with its three interacting components--receptor, G-protein, and Na+ channel--is such that at resting potential the muscarinic receptor induces opening of Na+ channels; this property may provide a possible physiological mechanism for the depolarization stimulus necessary for autoexcitation or repetitive firing in heart or brain tissues.
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PMID:G-protein mediates voltage regulation of agonist binding to muscarinic receptors: effects on receptor-Na+ channel interaction. 245 May 66

Isolated, cultured arterial endothelial cells express an acetylcholine (ACh)-activated K+ current in addition to an inward rectifier current whose conductance is unaffected by ACh. The cholinergic K+ current is specifically blocked by atropine (1 microM) and shows single saturation kinetics with ACh (half-maximal stimulation 51 nM ACh). Unlike the cardiac muscarinic receptor-gated K+ channel, its stimulation appears independent of a pertussis toxin-sensitive GTP-binding protein. Activation of the endothelial muscarinic K+ current resulting in hyperpolarization may represent an initial component of the vasodilatory effect of ACh.
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PMID:Muscarinic-activated K+ current in bovine aortic endothelial cells. 245 60

Stimulation of muscarinic cholinergic receptors in SK-N-SH human neuroblastoma cells resulted in a 1.5-4 fold increase in intracellular cAMP levels. This unusual response was sensitive to atropine and pirenzepine but insensitive to pertussis toxin. It was observable regardless of whether basal, PGE1- or forskolin-stimulated cAMP levels were measured. The half-maximal concentration for carbachol-stimulation of cAMP levels (6 microM) was similar to that for the previously determined carbachol-induced stimulation of phosphoinositide turnover in these cells, suggesting that the former is mediated by the latter. These data indicate that cross-talk between the phosphoinositide turnover system and the adenylate cyclase system results in increased cAMP levels in SK-N-SH cells in response to muscarinic receptor stimulation.
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PMID:Muscarinic receptor-mediated increase in cAMP levels in SK-N-SH human neuroblastoma cells. 245 66

This study examines the mechanism of guanine nucleotide-binding protein (G protein) coupling of receptors to phospholipase C. The Xenopus oocyte has a muscarinic receptor-activated Cl- current that is mediated by inositol 1,4,5-trisphosphate. Modulation of the muscarinic receptor-evoked Cl- current was examined under voltage clamp in oocytes injected with resolved G-protein subunits. The presence of an alpha subunit of G proteins in oocytes was shown by pertussis toxin-labeling of a 41-kDa band in oocyte membranes. The presence of the beta subunit of G proteins was demonstrated by immunoblotting experiments with an antiserum (U-49) that is specific for the beta subunit. Pertussis toxin treatment of oocytes resulted in the uncoupling of muscarinic receptors from activation of the Cl- current. Cells microinjected with 1.5 ng of human erythrocyte beta gamma-subunit complex or 1.0 ng of bovine brain beta gamma-subunit complex showed approximately a 95% reduction in the evoked Cl- current. Cells injected with equal volumes of protein storage vehicle showed no change in response. Cells injected with boiled beta gamma subunits, bovine serum albumin, or resolved alpha subunits also showed no reduction in response. Cells injected with various concentrations of beta gamma subunits showed a concentration dependence with half-maximal inhibition of the muscarinic activated Cl- current at about 10 nM. Cells injected with 1.0 ng of bovine brain beta gamma subunits could not respond to bath-applied agonist but could generate the Cl- current on intracellular injection of inositol 1,4,5-trisphosphate. These observations suggest that there is a G protein responsible for muscarinic receptor-mediated signal transduction through phospholipase C and that it is an alpha beta gamma heterotrimer. It appears that the mode of action of the G protein in the phospholipase C system may be similar to that of the hormone-activated adenylyl cyclase.
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PMID:Beta gamma subunits of GTP-binding proteins inhibit muscarinic receptor stimulation of phospholipase C. 246 57

The interaction of cholinergic agonists and antagonists with smooth muscle muscarinic receptors has been investigated by measurement of displacement of the muscarinic antagonist [3H]QNB (quinuclidinyl benzilate) in membranes prepared from toad stomach. The binding of [3H]QNB was saturable, reversible and of high affinity (KD = 423 pM). The muscarinic receptor subtypes present in gastric smooth muscle were classified by determining the relative affinities for the selective antagonists pirenzepine (M1), AF-DX 116 (M2) and 4-DAMP (M3). The results from these studies indicate the presence of a heterogeneous population of muscarinic receptor subtypes, with a majority (88%) exhibiting characteristics of M3 receptors and a much smaller population (12%) exhibiting characteristics of M2 receptors. The binding curve for the displacement of [3H]QNB binding by the agonist oxotremorine was complex and was consistent with presence of two affinity states: 24% of the receptors had a high affinity (KD = 4.7 nM) for oxotremorine and 76% displayed nearly a 1,000-fold lower affinity (KD = 4.4 microM). When oxotremorine displacement of [3H]QNB binding was determined in the presence GTP gamma S, high affinity binding was abolished, indicating that high affinity agonist binding may represent receptors coupled to G proteins. Moreover, pertussis toxin pretreatment of membranes also abolished high affinity agonist binding, indicating that the muscarinic receptors are coupled to pertussis toxin-sensitive G proteins. Reaction of smooth muscle membranes with pertussis toxin in the presence [32P]NAD caused the [32P]-labelling of a 40 dD protein that may represent the alpha subunit(s) of G proteins that are known to by NAD-ribosylated by the toxin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of agonists and selective antagonists with gastric smooth muscle muscarinic receptors. 249 69

In mammalian heart, vagal stimulation or the direct application of acetylcholine produces profound direct effects on the electro-physiologic characteristics of atrial myocytes. At the tissue level, these effects are observed as shortening of atrial action potential duration. Despite anatomic, biochemical, and physiologic evidence for significant vagal input to the mammalian ventricle, similar direct effects of acetylcholine on the ventricular action potential have been difficult to demonstrate. Chronic denervation via cervical vagotomy is one method that has been shown to render previously unresponsive ventricular myocytes sensitive to acetylcholine, but the molecular mechanism has not been defined. In the experiments described, selective cardiac para-sympathectomy was performed on mongrel dogs. Five to seven days after parasympathectomy, the dogs were sacrificed, electrophysiologic responses to acetylcholine were measured, and sarcolemmal vesicles were prepared. After parasympathectomy, ventricular myocytes were responsive to the effects of acetylcholine, manifested as shortening of the action potential duration. A quantitative and functional assessment of the transmembrane signalling mechanisms of the muscarinic receptor was carried out. After parasympathectomy, the density of muscarinic receptors in the sarcolemma was increased, compared with control ventricles. After parasympathectomy, ventricular sarcolemma displayed significant increases in both basal and oxotremorine-stimulated GTPase activity. ADP-ribosylation revealed significantly increased quantities of the pertussis toxin substrates Gi and Go. The quantity of ADP ribose incorporated was correlated with the increased level of GTPase activity in control and oxotremorine-stimulated membranes. Quantitation of the alpha and beta gamma subunits of the guanine nucleotide-binding proteins by immunoblot confirmed the increase in density of inhibitory guanine nucleotide-binding proteins following parasympathectomy. The results offer new insights into possible mechanisms of altered electrophysiologic responsiveness to acetylcholine following cardiac parasympathectomy.
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PMID:Selective parasympathectomy increases the quantity of inhibitory guanine nucleotide-binding proteins in canine cardiac ventricle. 250 54

The pertussis toxin-sensitive G proteins (guanine nucleotide binding proteins)-muscarinic receptor interactions in 18-day fetal to adult rat hearts were studied. The collective concentration of these G proteins was measured by pertussis toxin-dependent ADP-ribosylation and decreased from 1.5 pmol of [32P]ADP-ribose/mg of protein in the fetal heart to 0.5 pmol of [32P]ADP-ribose/mg of protein in 21-day postpartum and older animals in a nonlinear pattern. The muscarinic receptor density diminished 2-fold from 400 fmol/mg in 1-day-old neonate to 200 fmol/mg of protein in adult hearts in a linear manner. The receptor affinity for the agonist oxotremorine and the effect of guanine nucleotide on that affinity were monitored in heart preparations of the various ages. The IC50 value for oxotremorine/[3H]quinuclidinylbenzilate competition curves in the absence or presence of guanine nucleotide increased gradually with age. Modeling of the competition curves from 1-day-old neonate and adult preparations suggested the receptor has two oxotremorine affinity states in both age groups but the ability of guanine nucleotide to shift receptors from the higher affinity state increases with age. [3H] Oxotremorine binding to the higher affinity state had KD values of 95 and 170 pM in neonate and adult heart preparations. The concentration of 5'-guanylylimidodiphosphate which caused 50% displacement of [3H]oxotremorine binding was 1.3 and 0.22 microM in neonate and adult tissue. These results suggest that although the quantity of the G proteins and muscarinic receptors diminish with development, the sensitivity of the G protein:muscarinic receptor complex to guanine nucleotide increases.
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PMID:Developmental changes of the G proteins-muscarinic cholinergic receptor interactions in rat heart. 250 74

Intracellular recording from hippocampal CA1 pyramidal cells was used to characterize the pharmacological properties of muscarinic responses. Results obtained with the M1 antagonist pirenzepine and the M2 antagonist gallamine suggest that an M1 muscarinic receptor is involved in the muscarinic-induced membrane depolarization and blockade of the afterhyperpolarization (AHP). On the other hand, an M2 receptor may be involved in the cholinergic depression of the EPSP and the blockade of the potassium current termed the M-current. Pretreatment of hippocampi with pertussis toxin did not prevent any of the muscarinic responses suggesting that a pertussis toxin-sensitive G-protein is not involved. The M-current, in contrast to the other muscarinic actions, was unaffected by muscarinic agonists which are weak at increasing phosphoinositide (PI) turnover and actually blocked the action of full agonists. This finding suggests that stimulation of PI turnover may be involved in the blockade of the M-current. Although activation of protein kinase C with phorbol esters has little effect on the M-current, intracellular application of inositol trisphosphate did reduce the M-current. We were unable to establish any clear relationship between biochemical effector systems and the muscarinic receptor subtypes.
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PMID:Pharmacological characterization of muscarinic responses in rat hippocampal pyramidal cells. 253 6


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