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)

Acute myocardial ischaemia frequently is complicated by ventricular tachyarrhythmias. These arrhythmias are in part due to an increased susceptibility of myocardial cells to adenylyl cyclase stimulation by catecholamines [1]. As adenylyl cyclase underlies an endogenous dual regulation by stimulatory and inhibitory receptor systems, adenylyl cyclase stimulation can be counteracted by the activation of receptors like the muscarinic M2 receptor [2]. Therefore, the effect of myocardial ischaemia on muscarinic receptor and "inhibitory" guanine nucleotide binding proteins (G(i)) mediated inhibition of adenylyl cyclase was studied. During 5 min of myocardial ischaemia, carbachol mediated inhibition of forskolin and isoproterenol stimulated adenylyl cyclase was reduced by 30% and 50%, respectively. Hormone independent inhibition of adenylyl cyclase by the nonhydrolyzable GTP-analogue guanosine 5'-[beta gamma-imido]triphosphate (Gpp(NH)p) was reduced by 46%. In contrast, the amount of G(i), as determined by pertussis toxin catalyzed ADP-ribosylation, remained constant during 15 min of ischaemia. The impaired function of muscarinic receptor linked signal transduction during early myocardial ischaemia could contribute to the occurrence of ischaemia induced tachyarrhythmias by a reduced ability to counteract adenylyl cyclase activation.
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PMID:Reduced adenylyl cyclase inhibition by carbachol and GTP during acute myocardial ischaemia. 163 72

Decreased airway relaxation to beta-adrenoceptor stimulation has been hypothesized as a potential mechanism leading to enhanced bronchoconstrictor responsiveness in asthma. In addressing potential mechanisms underlying this phenomenon, the relative contributions of beta-adrenoceptor-coupled transmembrane signaling mechanisms were examined in isolated rabbit tracheal smooth muscle (TSM) passively sensitized with serum from atopic asthmatic patients and in TSM comparably exposed to non-atopic (control) human serum. During half-maximal isometric contraction of the tissues with acetylcholine, relative to control TSM, the sensitized tissues exhibited significant attenuation of both their maximal relaxation (Rmax) and sensitivity (i.e., -log 50% Rmax) to cumulative administration of isoproterenol (P < 0.001) or prostaglandin (PG)E2 (P < 0.001). In contrast, the relaxation responses to forskolin, a diterpene that directly activates adenylate cyclase, were similar in both tissue groups. Extended studies demonstrated that the attenuated relaxation to isoproterenol and PGE2 in sensitized TSM was 1) ablated by pretreatment with the muscarinic M2-receptor antagonists methoctramine (10(-6) M) or gallamine (10(-4) M); 2) also inhibited by pretreatment with pertussis toxin (100 ng/ml), which ADP ribosylates the inhibitory G protein (G(i)) negatively coupled to adenylate cyclase activation; and 3) associated with diminished adenosine 3',5'-cyclic monophosphate accumulation in response to isoproterenol administration. Moreover, based on Western immunoblot analysis, we found that G(i) protein expression was increased in membrane fractions from sensitized TSM, related to enhanced expression of the G(i) alpha 3 subunit. Collectively, these observations provide new evidence that the impaired beta-adrenoceptor-mediated relaxation in atopic sensitized airways is associated with increased muscarinic M2 receptor/G(i) protein-coupled expression and function.
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PMID:Mechanism of impaired beta-adrenoceptor responsiveness in atopic sensitized airway smooth muscle. 749 84

The key event in receptor-catalyzed activation of heterotrimer G proteins is binding of GTP, which leads to subunit dissociation generating GTP-bound alpha subunits and free beta gamma complexes. We have previously identified a mutation that abolished GTP binding in G alpha o (S47C) and demonstrated that the mutant retained the ability to bind beta gamma and could act in a dominant negative fashion when expressed in Xenopus oocytes (Slepak, V.Z., Quick, M.W., Aragay, A.M., Davidson, N., Lester, H.A., and Simon, M.I. (1993) J. Biol. Chem. 268, 21889-21894). In the current work, we investigated the effects of the homologous mutant of G alpha i2 (S48C) upon signaling pathways reconstituted in transiently transfected COS-7 cells. We found that expression of the G alpha i2 S48C mutant prevented stimulation of phospholipase C (PLC) beta 2 by free beta gamma subunit complexes. This effect of G alpha i S48C was not readily reversible in contrast to the inhibitory effect of wild-type G alpha i2, which could be reversed upon activation of the cotransfected muscarinic M2 receptor, presumably by release of beta gamma from the G protein heterotrimer. Coexpression of G alpha i S48C or the wild-type G alpha i2 also dramatically decreased G16-mediated stimulation of PLC by C5a in the cells transfected with cDNAs encoding C5a receptor and G alpha 16. Activation of PLC via endogenous Gq or G11 in the presence of alpha 1C adrenergic receptors was similarly attenuated by coexpression of G alpha i or G alpha i S48C. Pertussis toxin treatment of the transfected cells enhanced the inhibition of the receptor-stimulated PLC by wild-type G alpha i subunits but did not influence the effects of the dominant negative mutant. The enhancement of the wild-type G alpha i inhibitory effect by pertussis toxin can be explained by stabilization of G alpha i binding to beta gamma as a result of ADP-ribosylation, while G alpha i S48C mutant binds beta gamma irreversibly even without pertussis toxin treatment. Therefore, a feasible mechanism to rationalize the attenuation of the G alpha 16 and Gq/11-mediated activation of PLC by cotransfected G alpha i is the competition between G alpha i and G alpha 16 or Gq/11 for the beta gamma complexes, which are necessary for the G protein coupling with receptors. These experiments provide new evidence for the role of beta gamma in the integration of signals controlling phosphoinositide release through different G alpha families.
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PMID:Functional analysis of a dominant negative mutant of G alpha i2. 787 52

The muscarinic M2 receptor that normally couples via Gi to inhibit adenylyl cyclase was made to couple to Gs by exchange of its third intracellular loop for the comparable domain of the beta 2-adrenoceptor. In HeLa cells transfected with the recombinant M2 beta i-3 cDNA, the chimaeric receptor showed carbachol-mediated activation of adenylyl cyclase (EC50 = 73 nM) that was blocked by atropine, but not by propranolol. The chimaeric receptor was shown to mediate a carbachol-stimulated, Bordetella pertussis toxin-sensitive GTPase activity in membranes of transfected HeLa cells. Interestingly, stimulation of adenylyl cyclase by carbachol was 2-fold higher in transfected cells that had been pretreated with pertussis toxin. These data suggested that the M2 beta i-3 receptor was able to couple to both Gi and Gs, and that the ability to recognise and stimulate Gi did not involve the third cytoplasmic loop of M2. We investigated peptide elements taken from the second intracellular loop of the M2 receptor for their ability to mediate activation of Gi and found that a nine amino acid peptide representing the C-terminal sequence, VKRTTKMAG-NH2 (V9G), was capable of inhibiting forskolin-stimulated adenylyl cyclase by up to 18% and could stimulate high affinity GTPase activity of rat brain membranes by 32%. Further, V9G was shown to cause a doubling of the initial rate of [35S]GTP gamma S binding to purified bovine brain Gi/Go in reconstituted phospholipid vesicles. These data identify a domain on the second intracellular loop of the muscarinic M2 receptor that is involved in the selection of a pertussis toxin-sensitive G protein.
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PMID:Activation of Gi protein by peptide structures of the muscarinic M2 receptor second intracellular loop. 805 Apr 79

We measured endogenous noradrenaline (NA) overflow from a vascularly perfused rat stomach in vitro. The stomach was perfused with Krebs-Ringer solution containing 10 microM pargyline. Periarterial nerves, which contain postganglionic sympathetic nerves, around the left gastric artery were stimulated for 1 min with square-wave pulses of 2 msec duration, 2.5 to 5.0 Hz, supramaximal intensity (10 mA). Oxotremorine (10(-8) to 10(-6) M) concentration-dependently inhibited the periarterial nerve stimulation-evoked NA overflow under the presence of 10(-6) M phentolamine. Bilateral vagus nerve stimulation (5 Hz, 2 msec duration, 10 mA, for 1 min) reduced the evoked NA overflow. Oxotremorine (10(-7) M)-induced inhibition of NA overflow was attenuated by atropine, methoctramine (muscarinic M2 receptor antagonist), 4-diphenylacetoxy-N-methylpiperidine (M3 receptor antagonist) and pirenzepine (M1 receptor antagonist) with the following potency; atropine > methoctramine > 4-diphenylacetoxy-N-methylpiperidine >> pirenzepine. The oxotremorine-induced inhibition was attenuated by N-ethylmaleimide (3 x 10(-5) M for 50 min), but was not affected by pertussis toxin pretreatment (10 micrograms/rat, for 4 days). However, this pretreatment with pertussis toxin abolished completely negative chronotropic and inotropic effects of oxotremorine in rat atria. These results suggest that NA release from gastric sympathetic nerve terminals is inhibited by activation of muscarinic M2 receptor, and this receptor-mediated inhibitory mechanisms are insensitive to pertussis toxin.
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PMID:Cholinergic M2 muscarinic receptor-mediated inhibition of endogenous noradrenaline release from the isolated vascularly perfused rat stomach. 842 50

Short periods of ischemia render the myocardium more resistant to a subsequent prolonged coronary occlusion resulting in a reduction of infarct size. This cardioprotective mechanism has been called ischemic preconditioning. Acute myocardial ischemia results in a rapid decline of high energy phosphates. After short periods of ischemia the high energy phosphate levels are better preserved and the increase of lactate is slower during the prolonged subsequent ischemia in the preconditioned group compared to control. The duration of ischemia needed for induction of the protective effect is 2.5 min in dogs and 20 min in our swine model. In porcine myocardium the protection is lost about 1 h after induction and a renewal is not possible at that time, but is 24 h later. For rabbits or dogs, but not in pigs, a late protection 24 h after induction or preconditioning has been shown ("second window of protection"). Adenosine or adenosine A1 receptor agonists, muscarinic M2 receptor agonists, alpha 1-receptor agonists and bradykinin B2 receptor agonists as well as opening of the K+ATP-channel substitute for ischemia in the induction of protection. Activation of protein kinase C results in protection in rats and rabbits, but not in dogs or pigs. Inhibition of protein kinase C translocation or kinase activity results in a loss of the protection induced by preceding ischemia. After blockade of the K+ATP-channel the protection induced by adenosine A1 receptor activation is lost. Therefore opening of the K+ATP-channel is a prerequisite for induction of the protective effect. Inhibition of the inhibitory G-protein by pertussis toxin has been shown to result in a loss of protection, therefore the Gi-protein seems to be involved in the evolution of protection. In humans during coronary angioplasty anginal pain and lactate production during a second balloon occlusion is diminished without any change in the regional myocardial perfusion. This adaptation is inhibited by blockade of the K+ATP-channel or of the adenosine A1 receptor. Intermittent cross-clamping before a longer occlusion during open-heart surgery results in a better preservation of high energy phosphates compared to controls without preceding short ischemia. These observations support the hypothesis that ischemic preconditioning also occurs in humans. Angina pectoris preceding the myocardial infarction may have preconditioned the human heart against the subsequent myocardial infarction, but studies concerning the influence of angina pectoris on short-term outcome after thrombolysis are conflicting. In the future, ischemic preconditioning or preconditioning with drugs may prolong the duration of ischemia tolerated without necrosis and improve the prognosis of patients by reducing the infarct size.
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PMID:-Myocardial protection by preconditioning. Experimental and clinical significance-. 865 Sep 86

1. Cytosolic Ca2+ concentration ([Ca2+]i) during exposure to acetylcholine or caffeine was measured in mouse duodenal myocytes loaded with fura-2. Acetylcholine evoked a transient increase in [Ca2+]i followed by a sustained rise which was rapidly terminated after drug removal. Although L-type Ca2+ currents participated in the global Ca2+ response induced by acetylcholine, the initial peak in [Ca2+]i was mainly due to release of Ca2+ from intracellular stores. 2. Atropine, 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, a muscarinic M3 antagonist), pirenzepine (a muscarinic M1 antagonist), methoctramine and gallamine (muscarinic M2 antagonists) inhibited the acetylcholine-induced Ca2+ release, with a high affinity for 4-DAMP and atropine and a low affinity for the other antagonists. Selective protection of muscarinic M2 receptors with methoctramine during 4-DAMP mustard alkylation of muscarinic M3 receptors provided no evidence for muscarinic M2 receptor-activated [Ca2+]i increase. 3. Acetylcholine-induced Ca2+ release was blocked by intracellular dialysis with a patch pipette containing either heparin or an anti-phosphatidylinositol antibody and by external application of U73122 (a phospholipase C inhibitor). 4. Acetylcholine-induced Ca2+ release was insensitive to external pretreatment with pertussis toxin, but concentration-dependently inhibited by intracellular dialysis with a patch pipette solution containing an anti-alpha q/alpha 11 antibody. An antisense oligonucleotide approach revealed that only the Gq protein was involved in acetylcholine-induced Ca2+ release. 5. Intracellular applications of either an anti-beta com antibody or a peptide corresponding to the G beta gamma binding domain of the beta-adrenoceptor kinase 1 had no effect on acetylcholine-induced Ca2+ release. 6. Our results show that, in mouse duodenal myocytes, acetylcholine-induced release of Ca2+ from intracellular stores is mediated through activation of muscarinic M3 receptors which couple with a Gq protein to activate a phosphatidylinositol-specific phospholipase C.
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PMID:Specific Gq protein involvement in muscarinic M3 receptor-induced phosphatidylinositol hydrolysis and Ca2+ release in mouse duodenal myocytes. 917 86

We investigated the effects of pertussis toxin on contraction in field-stimulated guinea pig ileum in the absence and presence of isoproterenol. Field-stimulation elicited pertussis toxin-insensitive contractions. Cumulative addition of isoproterenol produced a maximal 52% reduction in the contractile response. Following pertussis toxin-treatment, the maximal inhibitory effect of isoproterenol increased to 83%. Pertussis toxin had no effect on the ability isoproterenol to inhibit contractions elicited by histamine agonists. Our results suggest that the increased effectiveness of isoproterenol in pertussis toxin-treated ileum is due to an uncoupling of the muscarinic M2 receptor contractile mechanism.
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PMID:Pertussis toxin increases isoproterenol induced relaxation in field-stimulated ileum. 1008 68

In the human heart, as in the heart of several other species, muscarinic receptors are predominantly of the M2-subtype that couple via a pertussis toxin-sensitive Gi-protein to inhibit adenylyl cyclase. However, it is not clear whether an additional muscarinic receptor subtype exists in the human heart. In human right atrium, stimulation of muscarinic M2 receptors causes direct negative inotropic and chronotropic effects; in human ventricular myocardium, however, the negative inotropic effect can be only achieved when basal force of contraction has been pre-stimulated by cyclic AMP-elevating agents such as beta-adrenoceptor agonists, forskolin or phosphodiesterase inhibitors (indirect effect); this has been shown in various in vitro and in vivo studies. Evidence has accumulated that in chronic heart failure vagal activity is decreased. Cardiac muscarinic M2 receptor density and functional responsiveness (inhibition of adenylyl cyclase activity and negative inotropic effects), however, are not considerably changed when compared with non-failing hearts although cardiac Gi-activity is increased.
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PMID:Muscarinic receptors in the failing human heart. 1044 75

Over the last decade, several lines of evidence have shown that both muscarinic M2 and M3 receptors are postjunctionally expressed in many smooth muscles, including the gastrointestinal tract. Although in vitro data suggests that both receptors are functional in that they inhibit adenylate cyclase activity and activate non-selective cation channels, few studies support a role in vivo. Thus, data from procedures that ablate the signaling pathway of the muscarinic M2 receptor, including receptor antagonism, pertussis toxin pretreatment reveal little effect on gastrointestinal smooth muscle responsiveness to muscarinic agonists. Recently, information from knockout mice, lacking either M2 or M3 receptor, indicate reveal a role for both subtypes. However, the contribution of the M2 receptor appears greater in the ileum than in the urinary bladder. Therapeutically, non-selective, as well as selective M3 receptor antagonists are being clinically studied, although it remains to be shown which is the optimal approach to disorders of smooth muscle motility.
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PMID:Muscarinic receptors and gastrointestinal tract smooth muscle function. 1139 28


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