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)

The muscarinic receptors in a B82 cell line which were transfected with the rat m1 muscarinic receptor gene (cTB10 cells) were studied by using radioligand binding assays. Their possible coupling to the hydrolysis of inositol lipids and cyclic AMP formation were also investigated. [(-)-[3H]Quinuclidinyl benzilate [(-)-[3H]QNB] binding to the intact cTB10 cells was saturable and displaceable by 1 microM atropine sulfate. The Kd and maximum binding values of (-)-[3H]QNB from saturation studies were 12 pM and 17 fmol/10(6) cells, respectively. Inhibition studies of (-)-[3H]QNB binding to intact cTB10 cells suggested that these muscarinic receptors are of the M1 type defined by their high affinity for pirenzepine and low affinity for AF-DX 116 [11-[2-diethylamino methyl-1-piperidinylacetyl]-5,11-dihydro-6H-pyrido(2,3-b) (1,4)benzodiazepine-6-one]. The muscarinic agonist carbachol stimulated [3H]inositol monophosphate accumulation in the cTB10 cells, which could be reversed by the muscarinic antagonists atropine, pirenzepine or AF-DX 116. The rank order of potency of the muscarinic antagonists in inhibiting carbachol-stimulated [3H]inositol monophosphate accumulation was atropine greater than pirenzepine greater than AF-DX 116, in agreement with that from ligand/(-)-[3H]QNB competition experiments. Pertussis toxin and 4 beta-phorbol, 12-beta-myristate, 13-alpha-acetate reduced carbachol-stimulated [3H]inositol monophosphate accumulation. Prostaglandin E1 stimulated cyclic AMP formation in the cTB10 cells. Carbachol at the concentration of 10 mM exhibited no stimulatory or inhibitor effect on the basal or prostaglandin E1-stimulated cyclic AMP formation. These results suggest that the muscarinic receptors encoded by the transfected m1 gene in the cTB10 cells are of the M1 type and are coupled to the hydrolysis of inositol lipids, possibly via a pertussis toxin sensitive G protein.
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PMID:Pharmacological characterization of the M1 muscarinic receptors expressed in murine fibroblast B82 cells. 253 6

The involvement of G regulatory proteins in muscarinic receptor signal transduction was examined in electrically permeabilized rat submandibular acinar cells. The guanine nucleotide analog, GTP gamma S, caused the dose dependent hydrolysis of membrane phosphatidylinositol 4,5-bisphosphate to release IP3. This response was insensitive to pertussis toxin treatment and was duplicated by NaF but not by GDP beta S. Enhanced IP3 synthesis was observed with a combination of GTP gamma S and carbachol. Exogenous IP3, as well as carbachol and GTP gamma S, provoked the release of sequestered 45Ca2+ from non-mitochondrial stores. In intact cells, carbachol significantly reduced the level of cyclic AMP induced by the beta-adrenergic agonist, isoproterenol, to 69% of its normal value. Pertussis toxin abolished this inhibitory action of carbachol on cyclic nucleotide levels. These results suggest that muscarinic receptors are coupled to two separate G regulatory proteins in submandibular mucous acini-the pertussis toxin-insensitive Gp of the phosphoinositide transduction pathway associated with elevated cytosolic calcium levels, and the pertussis toxin-sensitive Gi inhibitory protein of the adenylate cyclase complex.
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PMID:G regulatory proteins and muscarinic receptor signal transduction in mucous acini of rat submandibular gland. 253 96

This laboratory has reported recently that muscarinic receptor-stimulated release of norepinephrine from pheochromocytoma (PC12) cells is dependent upon an influx of Ca2+ through a Ca2+ channel that is regulated by a pertussis toxin-sensitive GTP-binding protein (G-protein) (Inoue, K., and Kenimer J. G. (1988) J. Biol. Chem. 263, 8157-8161). In the present study, we have examined the role of phosphoinositide hydrolysis in this mechanism. The muscarinic agonist methacholine was shown to stimulate phosphoinositide hydrolysis by a mechanism that was sensitive to pertussis toxin inhibition. When assayed in the absence of Ca2+, muscarinic-stimulated norepinephrine release but not phosphoinositide hydrolysis was blocked. Conversely, muscarinic-stimulated phosphoinositide hydrolysis but not norepinephrine release was blocked in cells preincubated with phorbol 12,13-dibutyrate. In contrast to several previous hypotheses that suggested that muscarinic-stimulated neurotransmitter release is dependent upon phosphoinositide hydrolysis, our results suggest that these two muscarinic-stimulated processes are independent events in PC12 cells. Inhibition studies with muscarinic receptor subtype-specific antagonists suggest that norepinephrine release is regulated by an M2 subtype muscarinic receptor and that phosphoinositide hydrolysis is regulated by an M3 subtype muscarinic receptor.
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PMID:Muscarinic-stimulated norepinephrine release and phosphoinositide hydrolysis in PC12 cells are independent events. 254 76

Forskolin and vasoactive intestinal polypeptide (VIP) were shown to increase cyclic AMP accumulation in a human neuroblastoma cell line, SK-N-SH cells. The alpha 2-adrenergic agonist UK 14304 decreased forskolin-stimulated cyclic AMP levels by 40 +/- 2%, with an EC50 of 83 +/- 20 nM. This response was blocked by pretreatment with pertussis toxin (PT) (EC50 = 1 ng/ml) or by the alpha 2-antagonists yohimbine, idazoxan, and phentolamine. Antagonist IC50 values were 0.3 +/- 0.1, 2.2 +/- 0.3, and 1.4 +/- 0.1 microM, respectively. This finding suggests the presence of normal inhibitory coupling of SK-N-SH cell alpha 2-adrenergic receptors to adenylate cyclase via the inhibitory GTP-binding protein species, Gi. Muscarinic receptors in many target cell types are coupled to inhibition of adenylate cyclase. However, in SK-N-SH cells, muscarinic agonists synergistically increased (67-95%) the level of cyclic AMP accumulation elicited by forskolin or VIP. EC50 values for carbamylcholine (CCh) and oxotremorine facilitation of the forskolin response were 1.2 +/- 0.2 and 0.3 +/- 0.1 microM, respectively. Pharmacological studies using the muscarinic receptor subtype-preferring antagonists 4-diphenylacetoxy-N-methylpiperidine, pirenzepine, and AF-DX 116 indicated mediation of this response by the M3 subtype. IC50 values were 14 +/- 1, 16,857 +/- 757, and 148,043 +/- 16,209 nM, respectively. CCh-elicited responses were unaffected by PT pretreatment. Muscarinic agonist binding affinity was indirectly measured by the ability of CCh to compete for [3H]quinuclidinyl benzilate binding sites on SK-N-SH cell membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alpha 2-adrenergic and muscarinic cholinergic receptors have opposing actions on cyclic AMP levels in SK-N-SH human neuroblastoma cells. 254 24

The action of carbamoylcholine (Cchol), NaF and other agonists on the generation of inositol phosphates (IPs) was studied in dog thyroid slices prelabelled with myo-[2-3H]inositol. The stimulation by Cchol (0.1 microM-0.1 mM) of IPs accumulation through activation of a muscarinic receptor [Graff, Mockel, Laurent, Erneux & Dumont (1987) FEBS Lett. 210, 204-210] was pertussis- and cholera-toxin insensitive. Ins(1,4,5)P3, Ins(1,3,4)P3 and InsP4 were generated. NaF (5-20 mM) also increased IPs generation (Graff et al., 1987); this effect was potentiated by AlCl3 (10 microM) and unaffected by pertussis toxin. Although phorbol dibutyrate (5 microM) abolished the cholinergic stimulation of IPs generation (Graff et al., 1987), it did not affect the fluoride-induced response. Cchol and NaF did not require extracellular Ca2+ to exert their effect, and neither KCl-induced membrane depolarization nor ionophore A23187 (10 microM) had any influence on basal IPs levels, or on cholinergic stimulation. However, more stringent Ca2+ depletion with EGTA (0.1 or 1 mM) decreased basal IPs levels as well as the amplitude of the stimulation by Cchol without abolishing it. Dibutyryl cyclic AMP, forskolin, cholera toxin and prostaglandin E1 had no effect on basal IPs levels and did not decrease the response to Cchol. Iodide (4 or 40 microM) also strongly decreased the cholinergic action on IPs, this inhibition being relieved by methimazole (1 mM). Our data suggest that Cchol activates a phospholipase C hydrolysing PtdIns(4,5)P2 in the dog thyroid cell in a cyclic AMP-independent manner. This activation requires no extracellular Ca2+ and depends on a GTP-binding protein insensitive to both cholera toxin and requires no extracellular Ca2+ and depends on a GTP-binding protein insensitive to both cholera toxin and pertussis toxin. The data are consistent with a rapid metabolism of Ins(1,4,5)P3 to Ins(1,3,4)P3 via the Ins(1,4,5)P3 3-kinase pathway, followed by dephosphorylation by a 5-phosphomonoesterase. Indeed, a Ca2+-sensitive InsP3 3-kinase activity was demonstrated in tissue homogenate. Stimulation of protein kinase C and an organified form of iodine inhibit the Cchol-induced IPs generation. The negative feedback of activated protein kinase C could be exerted at the level of the receptor or of the receptor-G-protein interaction.
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PMID:Stimulation of generation of inositol phosphates by carbamoylcholine and its inhibition by phorbol esters and iodide in dog thyroid cells. 255 11

The classification of muscarinic receptors into M1 and M2 subtypes and the involvement of guanine nucleotide binding proteins (G-proteins) as major mediators of receptor information transduction in the cholinergic and other neurotransmitter systems have prompted us to undertake studies both at receptor and postreceptor levels that may shed light on the importance of these new findings to the pharmacotherapy of manic-depressive illness and of extrapyramidal syndromes. We searched for patterns of muscarinic selectivity among the commonly used anticholinergics (biperiden, procyclidine, trihexyphenidyl, benztropine, and methixen) through radioligand receptor studies in various rat tissues. The drugs showed a range of selectivity, from the totally nonselective methixen to the highly M1-selective biperiden. Sinus arrhythmia measurements were undertaken in psychiatric patients treated with different antiparkinsonian anticholinergics. The extent of sinus arrhythmia suppression was inversely correlated with the degree of M1 selectivity of the drugs used, advocating the use of M1-selective antiparkinsonian anticholinergics like biperiden in the treatment of extrapyramidal side effects. The implications of muscarinic receptor subclassification were further extended to include postreceptor phenomena. We have directly studied G-protein function by measuring cholinergic agonist-induced increases in guanosine triphosphate (GTP) binding to these proteins. This cholinergic agonistic effect was shown to be exerted by G-proteins other than Gs (the adenylate cyclase stimulatory G-protein), i.e., Gi (the adenylate cyclase inhibitory G-protein) or Gp [the G-protein activating phosphatidylinositol (PI) turnover], as ribosylation by pertussis toxin abolished this cholinergic effect, whereas it was unaffected by cholera toxin. Pertussis toxin-blockable, carbamylcholine-induced increases in GTP binding capacity were found to be mediated through M1 muscarinic receptors, as M1-selective antagonists were 100-fold more effective than M2 selective antagonists in blocking carbamylcholine effects. Moreover, carbamylcholine effect was exclusively detected in tissues predominantly populated by M1 receptors. Our results thus suggest that carbamylcholine-induced increases in GTP binding are exerted through M1 receptors interacting with Gp. At therapeutically efficacious concentrations, lithium completely blocked carbamylcholine-induced increases in GTP binding capacity in both in vitro and in vivo experiments.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Muscarinic receptor subclassification and G-proteins: significance for lithium action in affective disorders and for the treatment of the extrapyramidal side effects of neuroleptics. 256 9

Muscarinic acetylcholine receptor subtypes m1, m3 and m5 couple strongly to phosphatidylinositol turnover and hence to intracellular Ca2+ concentration via pertussis toxin (PTX) sensitive and insensitive G proteins. The m2 and m4 muscarinic receptor subtypes strongly inhibit adenylyl cyclase production via PTX sensitive G proteins. Additionally, the cardiac M2 receptor is closely coupled to a K+ current (IK.ACh). To characterize this functional diversity more completely, we measured the ACh-induced Ca2+ responses of cells transfected with the muscarinic receptor subtypes m1, m2, m3 and m4. As expected, cells transfected with m1 or m3 receptors exhibited large dose-dependent increases in Ca2+ in response to ACh application. Unexpectedly, cells transfected with m2 or m4 receptors also exhibited increases in Ca2+ in response to agonist application. The m2- or m4-coupled responses were smaller in amplitude, required higher concentrations of agonist and were much more sensitive to PTX treatment when compared to m1- or m3-coupled responses. We discuss this remarkable diversity of function in terms of the receptor subtype's coupling to G proteins.
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PMID:Diverse functions of muscarinic acetylcholine receptor subtypes. 269 20

The effects of acetylcholine (ACh) were examined on the naturally occurring slow action potentials (APs) of the isolated, organ-cultured, spontaneously beating sinoatrial (SA) node of the rabbit, in the presence or absence of pertussis toxin. The sensitivity of the SA-node preparations to ACh was not altered after 24 h incubation in organ culture medium. Activation of the muscarinic receptor hyperpolarized the cells and reduced the frequency of spontaneous activity at low concentrations (1 X 10(-6) and 3 X 10(-6) M), and completely abolished automaticity at higher concentrations (1 X 10(-5) M). However, stimulated activity was maintained. Increased concentrations (1 X 10(-4) M) of ACh completely abolished excitability. When the SA-node preparations were cultured in the presence of 0.5 micrograms/mL pertussis toxin, concentrations of ACh as high as 1 X 10(-4) M had no effect on the AP parameters and frequency of spontaneous activity. The results indicate that inactivation of G proteins by pertussis toxin caused inhibition of the ACh effects on the automaticity of the SA node. In addition, the blocking effect of ACh to the naturally occurring slow APs was also inhibited by pertussis toxin. We conclude that in the rabbit SA node, the effects of ACh on automaticity and on the slow channels are mediated by G protein.
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PMID:Acetylcholine inhibition in rabbit sinoatrial node is prevented by pertussis toxin. 276 98

Acetylcholine inhibits FSH-induced cAMP accumulation in cultured Sertoli cells from immature hamsters. This action of acetylcholine is mimicked by muscarinic cholinergic agonists with a rank order of carbachol greater than acetylcholine greater than arecoline greater than pilocarpine. The carbachol-induced inhibition of stimulated cAMP accumulation is blocked by atropine greater than pirenzepine but not by d-tubocurarine, indicating an apparent muscarinic receptor similar to that found in other peripheral tissues. The fact that pirenzepine is less effective as an inhibitor of the carbachol effect than atropine further defines the muscarinic effect as of the M2 subtype. The ability of carbachol to inhibit FSH-induced cAMP accumulation is blocked by pertussis toxin, which inhibits the action of the Ni inhibitory transducer of adenylate cyclase. These data indicate that cultured Sertoli cells from immature hamsters contain an M2 type muscarinic cholinergic receptor that is negatively coupled to the adenylate cyclase system through the inhibitory Ni transducer.
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PMID:Cholinergic inhibition of cAMP accumulation in Sertoli cells cultured from immature hamsters. 282 40

The rat M1 muscarinic receptor gene was cloned and expressed in a rat cell line lacking endogenous muscarinic receptors. Assignment of the cloned receptors to the M1 class was pharmacologically confirmed by their high affinity for the M1-selective muscarinic antagonist pirenzepine and low affinity for the M2-selective antagonist AF-DX-116. Guanylyl imidodiphosphate [Gpp(NH)p] converted agonist binding sites on the receptor, from high-affinity to the low-affinity state, thus indicating that the cloned receptors couple to endogenous G-proteins. The cloned receptors mediated both adenylate cyclase inhibition and phosphoinositide hydrolysis, but by different mechanisms. Pertussis toxin blocked the inhibition of adenylate cyclase (indicating coupling of the receptor to inhibitory G-protein), but did not affect phosphoinositide turnover. Furthermore, the stimulation of phosphoinositide hydrolysis was less efficient than the inhibition of adenylate cyclase. These findings demonstrate that cloned M1 receptors are capable of mediating multiple responses in the cell by coupling to different effectors, possibly to different G-proteins.
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PMID:Cloned M1 muscarinic receptors mediate both adenylate cyclase inhibition and phosphoinositide turnover. 284 74

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