UMLS:C0043167 - FACTA Search

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

In the rat pituitary cell line GH3, carbachol inhibits PRL secretion in a pertussis toxin-sensitive manner. For elucidation of the underlying mechanisms, we studied the effect of carbachol on voltage-dependent Ca2+ currents. Under voltage-clamp conditions, carbachol inhibited whole-cell Ca2+ currents by about 25%. This inhibitory action of carbachol was not observed in cells treated with pertussis toxin, indicating the involvement of a pertussis toxin-sensitive G-protein. In membranes of GH3 cells, carbachol stimulated a pertussis toxin-sensitive high-affinity GTPase. In immunoblot experiments with peptide antisera, we identified two forms of the Gi alpha-subunit (41 and 40 kDa) and two forms of the Go alpha-subunit (40 and 39 kDa). The 40-kDa Gi alpha-subunit was recognized by an antibody specific for the Gi2 alpha-subunit, and the 39-kDa Go alpha-subunit was detected by an antibody specific for the Go2 alpha-subunit. Incubation of membranes with the photoreactive GTP analog [alpha-32P]GTP azidoanilide resulted in photo-labelling of 40- and 39-kDa pertussis toxin substrates comigrating with G-protein alpha-subunits of the corresponding molecular masses. Carbachol dose-dependently stimulated incorporation of the photoreactive GTP analog into the 39-kDa pertussis toxin substrate and, to a lesser extent, into 40-kDa pertussis toxin substrates. The data indicate that muscarinic receptors of GH3 cells couple preferentially to Go, which is likely to be involved in the inhibition of secretion, possibly by conferring an inhibitory effect to voltage-dependent Ca2+ channels.
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PMID:Inhibition of voltage-dependent Ca2+ currents and activation of pertussis toxin-sensitive G-proteins via muscarinic receptors in GH3 cells. 165 34

Phosphatidylinositol (PI) turnover via muscarinic acetylcholine (mACh) receptor was investigated using the cerebral cortex from adult rats. Activities in the cerebral cortex, hippocampus and striatum from senescent rats were compared with those from adult rat. Carbachol (1 mM)-stimulated [3H]IP accumulation in the presence of 10 mM LiCl was inhibited by pirenzepine more potently than by AF-DX 116. Although the displacing activity of carbachol for [3H]pirenzepine binding was decreased by 50 microM GTP gamma S, pretreatment of slices with pertussis toxin (PTX, 0.01-1.0 micrograms/ml) did not affect the carbachol-induced [3H]IP accumulation. In the slices from all 3 tissues, cerebral cortex, hippocampus and striatum, both incorporation of [3H]inositol and carbachol-stimulated [3H]IP accumulation were reduced at 28 months compared to those at 2 months. Furthermore, the Bmax values of [3H]pirenzepine binding in membranes from these three regions were diminished at the senescent stage. Taken together, the results suggest that an M1-subtype of muscarinic acetylcholine receptor could be involved in PI turnover via GTP-binding proteins insensitive to PTX. Age-related changes in M1-receptor mediated PI turnover seem to be in part due to the decreased number of M1-receptors with increasing age in the cerebral cortex, hippocampus and striatum; and some qualitative changes also seem to have occurred in the hippocampus of senescent rats in the mACh receptor-PI turnover system.
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PMID:M1 acetylcholine receptor-mediated phosphatidylinositol turnover in adult and senescent rat brain slices. 166 17

1. Apparent affinity constants (KD) for prenalterol, an agonist of low intrinsic efficacy at beta 1-adrenoceptors in rat left atria, have been determined by use of receptor desensitization and functional antagonism induced by isoprenaline and carbachol, respectively. The values obtained have been compared to those values estimated with the irreversible beta-adrenoceptor antagonist, bromoacetylalprenololmenthane (BAAM). 2. The -log KD values for prenalterol estimated by desensitization or irreversible antagonism ranged from 6.8-7.1 and 6.2-7.1, respectively. 3. Carbachol produced functional antagonism of the response to prenalterol even though it was removed before addition of prenalterol. This effect was mediated by M2-muscarinic receptors. Pretreatment of animals with pertussis toxin did not affect the functional antagonism elicited by carbachol. The apparent KD value obtained after pre-exposure to carbachol (6.8) was similar to those estimated by use of either alkylation with BAAM or desensitization with isoprenaline (see above). 4. It is concluded that acute desensitization or functional antagonism of responses to agonists of low intrinsic efficacy provides a means to estimate apparent KD constants. This approach could be useful to characterize receptors for which an irreversible antagonist may not be available.
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PMID:Desensitization and functional antagonism by beta-adrenoceptor and muscarinic receptor agonists, respectively: a comparison with receptor alkylation for calculation of apparent agonist affinity. 168 May 17

Pretreatment of 1321N1 human astrocytoma cells with phorbol 12-myristate-13-acetate or other activators of protein kinase C led to 2.5- to 5-fold increases (sensitization) in subsequent stimulation by forskolin of intracellular cyclic AMP accumulation. These compounds caused much smaller or no increases in receptor-mediated stimulation of cyclic AMP accumulation induced by isoproterenol and by prostaglandin E1. Carbachol and histamine, agonists acting at receptors coupled to polyphosphoinositide turnover in these cells, induced less sensitization of subsequent stimulation by forskolin but greater sensitization of stimulation by isoproterenol and by prostaglandin E1. The specificities of various analogs of phorbol 12-myristate-13-acetate, for induction of sensitization of forskolin stimulation were consistent with involvement of protein kinase C. The effects of protein kinase inhibitors and of down-regulation of protein kinase C activity also indicated involvement of protein kinase C in sensitization of forskolin stimulation, although additional mechanisms are likely to be involved in sensitization of isoproterenol stimulation. Neither pertussis toxin pretreatment nor inclusion of isobutylmethylxanthine during assays of cyclic AMP accumulation were able to prevent or mimic these sensitization phenomena, suggesting that the primary site of modification responsible for sensitization is neither the inhibitory guanine nucleotide-binding protein nor cyclic AMP phosphodiesterase. Sensitization was only observed in assays with intact cells. These results, together with those from our previous study describing protein kinase C-mediated desensitization of broken cell adenylate cyclase activity, indicate that activation of protein kinase C leads to multiple changes in the receptor-stimulated adenylate cyclase signal transduction pathway of these cells.
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PMID:Protein kinase C activators sensitize cyclic AMP accumulation by intact 1321N1 human astrocytoma cells. 168 54

Adenylate cyclase activity can be stimulated in goldfish retina by forskolin, GTP, NaF, dopamine and serotonin. Pharmacological characterisation of the dopamine and serotonin responses shows them to be mediated through specific receptors. A synergistic increase in the level of C-AMP is observed following application of forskolin together with NaF, GTP, dopamine, or serotonin. Dopamine and serotonin with or without GTP produce an additive response. When NaF and GTP are both together their combined effect in elevating C-AMP levels in the presence or absence of forskolin is less than additive. These results suggest that forskolin may be interacting with a Gs protein as well as directly stimulating adenylate cyclase. Increases in the level of C-AMP observed following application of forskolin or dopamine are decreased by carbachol in a dose-dependent manner. The carbachol response is blocked by pertussis toxin and is insensitive to the phosphodiesterase inhibitor, IBMX, suggesting an involvement of a Gi protein. Carbachol attenuation of elevated C-AMP levels is inhibited by atropine while pirenzapine has little effect suggesting the presence of a M2-type receptor.
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PMID:Effects of GTP, forskolin, sodium fluoride, serotonin, dopamine, and carbachol on adenylate cyclase in Teleost retina. 169 28

Carbachol induces a novel tetrodotoxin-resistant Na+ current in guinea pig ventricular myocytes bathed in Tyrode's solution with 20 mM Cs+. This action of carbachol, which initiates a series of reactions that culminates in a catecholamine-independent positive inotropic effect, occurs through muscarinic rather than nicotinic cholinoceptive sites. The concentrations of muscarinic antagonists required to suppress the carbachol-induced current by 50% were 2.1 nM, 270 nM, and 1700 nM for atropine, AF-DX 116, and pirenzepine, respectively. These results indicate that an M2-selective antagonist, AF-DX 116, is more potent than an M1-selective antagonist, pirenzepine, as an inhibitor. The M1-selective agonist McN-A-343 did not induce an inward current and blocked that caused by carbachol, in a rapid and reversible manner. This finding is also consistent with the conclusion that the muscarinic receptor involved in the regulation of myocardial Na+ channels by carbachol cannot be distinguished from the M2 subtype of such receptors. Treatment with pertussis toxin did not affect the ability of carbachol to induce an inward current in ventricular myocytes and reversed the current activated by carbachol in atrial cells from outward to inward. The electrophysiological and pharmacological nature of the carbachol-induced current in ventricular myocytes is very similar to that of the acetylcholine-induced current in Xenopus oocytes transfected with porcine M2, but not M1, muscarinic receptors. In both preparations, Na+ is the dominant charge carrier, intracellular Ca2+ is not involved in opening the Na+ channel, and an M2 receptor is involved.
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PMID:Carbachol activates a novel sodium current in isolated guinea pig ventricular myocytes via M2 muscarinic receptors. 170 71

We have investigated the modulatory action of carbachol on intracellular cAMP levels in human neuroblastoma SH-SY5Y cells. Carbachol enhanced forskolin-stimulated cAMP levels in a dose-dependent manner (EC50 = 3 microM). The enhancing effect of carbachol was completely inhibited by pirenzepine and atropine. Pertussis toxin treatment of the cells partially affected the ability of carbachol. Furthermore, carbachol also enhanced the effect of vasoactive intestinal peptide (EC50 = 3 microM)-, adenosine- and prostaglandin E1-stimulated cAMP levels. The enhancing response of carbachol was sensitive to trifluoperazine but insensitive to calphostin C. These results suggest that the mechanism for carbachol-induced cAMP levels may act, at least in part, through the activation of calmodulin system in SH-SY5Y cells. Hence we describe for the first time a synergistic interaction between calmodulin- and cAMP-dependent signal transduction pathway mediated by carbachol in neuron-derived cell line.
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PMID:Carbachol enhances forskolin-stimulated cyclic AMP accumulation via activation of calmodulin system in human neuroblastoma SH-SY5Y cells. 171 84

Serotonin 5-HT1A receptors have been reported to be negatively coupled to muscarinic receptor-stimulated phosphoinositide turnover in the rat hippocampus. In the present study, we have investigated further the pharmacological specificity of this negative control and attempted to elucidate the mechanism whereby 5-HT1A receptor activation inhibits the carbachol-stimulated phosphoinositide response in immature or adult rat hippocampal slices. Various 5-HT1A receptor agonists were found to inhibit carbachol (10 microM)-stimulated formation of total inositol phosphates in immature rat hippocampal slices with the following rank order of potency (IC50 values in nM): 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (11) greater than ipsapirone (20) greater than gepirone (120) greater than RU 24969 (140) greater than buspirone (560) greater than 1-(m-trifluoromethylphenyl)piperazine (1,500) greater than methysergide (5,644); selective 5-HT1B, 5-HT2, and 5-HT3 receptor agonists were inactive. The potency of the 5-HT1A receptor agonists investigated as inhibitors of the carbachol response was well correlated (r = 0.92) with their potency as inhibitors of the forskolin-stimulated adenylate cyclase in guinea pig hippocampal membranes. 8-OH-DPAT (10 microM) fully inhibited the carbachol-stimulated formation of inositol di-, tris-, and tetrakisphosphate but only partially antagonized (-40%) inositol monophosphate production. The effect of 8-OH-DPAT on carbachol-stimulated phosphoinositide turnover was not prevented by addition of tetrodotoxin (1 microM), by prior destruction of serotonergic afferents, by experimental manipulations causing an increase in cyclic AMP levels (addition of 10 microM forskolin), or by changes in membrane potential (increase in K+ concentration or addition of tetraethylammonium). Prior intrahippocampal injection of pertussis toxin also failed to alter the ability of 8-OH-DPAT to inhibit the carbachol response. Carbachol-stimulated phosphoinositide turnover in immature rat hippocampal slices was inhibited by the protein kinase C activators phorbol 12-myristate 13-acetate (10 microM) and arachidonic acid (100 microM). Moreover, the inhibitory effect of 8-OH-DPAT on the carbachol response was blocked by 10 microM quinacrine (a phospholipase A2 inhibitor) but not by BW 755C (100 microM), a cyclooxygenase and lipoxygenase inhibitor. These results collectively suggest that 5-HT1A receptor activation inhibits carbachol-stimulated phosphoinositide turnover by stimulating a phospholipase A2 coupled to 5-HT1A receptors, leading to arachidonic acid release. Arachidonic acid could in turn activate a gamma-protein kinase C with as a consequence an inhibition of carbachol-stimulated phosphoinositide turnover. This inhibition may be the consequence of a phospholipase C phosphorylation and/or a direct effect on the muscarinic receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Potential mechanisms involved in the negative coupling between serotonin 5-HT1A receptors and carbachol-stimulated phosphoinositide turnover in the rat hippocampus. 184 78

We undertook the present studies to explore the mechanisms by which carbachol inhibits the release of somatostatin-like immunoreactivity (SLI) from D cells. D cells were isolated from canine fundic mucosa by collagenase/EDTA dispersion followed by counterflow elutriation. Carbachol inhibited the release of SLI induced by forskolin, dibutyryl 3':5' cyclic adenosine monophosphate (cAMP), pentagastrin (PG), and 12-0-tetradecanoyl-phorbol-13-acetate in a fashion that could be prevented by pertussis toxin (PT) pretreatment of the D cells. Pertussis toxin also prevented the carbachol-induced inhibition of forskolin-stimulated cAMP generation and PG-stimulated [Ca2+]i mobilization. These data indicate that pertussis toxin sensitive inhibitory guanine nucleotide binding proteins mediate many of carbachol's inhibitory actions on D cells.
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PMID:Mechanisms for muscarinic inhibition of somatostatin release from canine fundic D cells. 197 5

Carbachol has been shown to produce a biphasic response in rat left atria. At low concentrations, carbachol depresses basal inotropy, while at high doses a positive inotropic effect is observed. The negative inotropic response can be selectively eliminated by pretreatment of rats with pertussis toxin. The aim of these studies was to determine whether or not evidence could be obtained to show that different muscarinic receptors produced these different biochemical responses to the agonist carbachol. Schild analysis was used to measure the equilibrium dissociation constant of the antagonist-receptor complex for antagonism of the negative inotropy to carbachol by atropine, scopolamine 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and AF-DX 116. The antagonism of the positive inotropic response to carbachol by these antagonists was studied in atria from rats pretreated with pertussis toxin where the negative inotropy was nearly completely abolished. In general, it was found that the antagonists did not produce simple competitive blockade of the positive inotropy but rather a nominal shift to the right of the dose-response curves followed by a depression of maximal responses. However, it was found that when pA2 or pKb values could be calculated, they coincided with those determined for the antagonism of the negative inotropy to carbachol. The conclusion drawn from these experiments was that no evidence was obtained to disprove the null hypothesis that a common receptor, interacting with two G-proteins, mediates these two effects of carbachol in rat left atria. The implications of these data for the classification of drug receptors with agonists is discussed.
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PMID:Promiscuous or heterogeneous muscarinic receptors in rat atria? I. Schild analysis with simple competitive antagonists. 209 99

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