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  • 1
    Electronic Resource
    Electronic Resource
    Distinct Internalization of M2 Muscarinic Acetylcholine Receptors Confers Selective and Long-Lasting Desensitization of Signaling to Phospholipase C (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 74 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Although M1-M4 muscarinicacetylcholine receptors (mAChRs) in HEK-293 cells internalize on agoniststimulation, only M1, M3, and M4 but notM2 mAChRs recycle to the plasma membrane. To investigate thefunctional consequences of this phenomenon, we compared desensitization andresensitization of M2 versus M4 mAChRs. Treatment with 1mM carbachol for 1 h at 37°C reduced numbers of cell surfaceM2 and M4 mAChRs by 40-50% and M2 andM4 mAChR-mediated inhibition of adenylyl cyclase, intracellularCa2+ concentration ([Ca2+]i) increases, andphospholipase C (PLC) activation by 60-70%. Receptor-mediated inhibition ofadenylyl cyclase and [Ca2+]i increases significantlyresensitized within 3 h. However, M4 but not M2mAChR-mediated PLC activation resensitized. At 16°C, M2mAChR-mediated [Ca2+]i increases and PLC stimulationdesensitized to a similar extent as at 37°C. However, at 16°C, whereM2 mAChR internalization is negligible, both M2 mAChRresponses resensitized, demonstrating that M2 mAChR resensitizationproceeds at the plasma membrane. Examination of M2 mAChR responsesfollowing inactivation of cell surface mAChRs by quinuclidinyl benzilaterevealed substantial receptor reserve for coupling to[Ca2+]i increases but not to PLC. We conclude thatM2 mAChR internalization induces long-lasting PLC desensitization predominantly because receptor loss is not compensated for by receptor recycling or receptor reserve.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0741721.x
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  • 2
    Electronic Resource
    Electronic Resource
    Synthetic α-adrenergic agonists are potent α-adrenergic blockers in human platelets (1978)
    [s.l.] : Nature Publishing Group
    Nature 274 (1978), S. 819-820 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Figure 1 shows the effects of phenylephrine, methoxamine, clonidine and xylometazoline on adrenaline-induced platelet aggregation in comparison with the effects of two typical a-adrenergic antagonists, phentolamine and phenoxybenzamine. Phentolamine completely blocked adrenaline-induced aggregation ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/274819a0
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  • 3
    Electronic Resource
    Electronic Resource
    Binding characteristics and functional G protein coupling of muscarinic acetylcholine receptors in rat duodenum smooth muscle membranes (1992)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 345 (1992), S. 7-15 
    Details
    ISSN: 1432-1912
    Keywords: Rat duodenum ; Muscarinic receptors ; M2/M4/M1 subtypes ; Catalytic G protein activation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The non-selective labelled antagonist [3H]N-methyl-scopolamine ([3H]NMS) was used to identify muscarinic acetylcholine receptors in rat duodenum smooth muscle membranes. Saturation and kinetic experiments revealed a binding site with a KD-value of 0.2–0.3 nmol/l and a receptor concentration (Bmax) of 100 fmol/mg protein. The affinities of eight selective muscarinic antagonists were determined and compared with those at M1 (rat cerebral cortex), M2 (rat heart), M3 (rat submandibular gland) and M4 (data from Dörje et al. 1991) receptors. The “M2-selective” agent AF-DX 116, the group of “M2/M4-selective” compounds himbacine, AF-DX 384, AQ-RA 741 and methoctramine but also the “M3-selective” HHSiD showed affinities corresponding to M2 and/or M4 sites. The intermediate affinity of 4-DAMP favours a mixed M2/M4 receptor population mainly containing M2 receptors. Two compounds, pirenzepine and AQ-RA 741, displayed biphasic displacement curves indicating the presence of a small population of putative M1 receptors. The rat duodenum antagonist binding profile, however, is not consistent with the presence of M3 receptors. We further demonstrate a concentration-dependent stimulation of [35S]GTP[S] binding to duodenal G proteins by the muscarinic agonist oxotremorine. Estimation of the binding parameters of GTP[S] in absence and presence of oxotremorine provided evidence for a catalytic activation of G proteins by agonist-activated muscarinic receptors in rat duodenal membranes and a strong signal amplification on the G protein level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00175462
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  • 4
    Electronic Resource
    Electronic Resource
    Agonist-induced down-regulation of the m4 muscarinic acetylcholine receptor occurs without changes in receptor mRNA steady-state levels (1994)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 350 (1994), S. 507-513 
    Details
    ISSN: 1432-1912
    Keywords: Muscarinic receptor subtypes ; Gene regulation ; RNA ; Down-regulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The regulation of m4 muscarinic acetylcholine receptor mRNA expression by receptor activation was studied in NIE-115 neuroblastoma and AtT-20 pituitary cells that endogeneously express the m4 muscarinic receptor. Receptor concentration was measured by binding of the muscarinic receptor radioligand [3H]quinuclidinyl benzilate, and RNA-RNA solution hybridization/RNase protection assay with a m4 receptor-specific [32P]-cRNA probe was used to evaluate the levels of receptor mRNA. Treatment of both cell lines with a receptor-saturating concentration of the agonist carbachol decreased receptor number. However, there was no change in steady-state levels of m4 mAChR mRNA in both cell lines. Determination of mRNA stability in the presence of the transcription blocker actinomycin D revealed that carbachol treatment increased half-life of receptor mRNA in N1E-115 cells, but not in AtT-20 cells, suggesting that receptor activation can regulate m4 receptor mRNA stability dependently on cell type. Analysis of receptor degradation kinetics in the presence of the protein synthesis inhibitor cycloheximide showed that receptor down-regulation in N1E-115 and AtT-20 cells is sufficiently accounted for by increased receptor degradation. These results indicate than m4 muscarinic receptor down-regulation is substantially different from that of the muscarinic receptor subtypes m2 and m3 which is reported to be associated with agonist-induced reduction in receptor mRNA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00173020
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  • 5
    Electronic Resource
    Electronic Resource
    Differential calcium signalling by m2 and m3 muscarinic acetylcholine receptors in a single cell type (1995)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 352 (1995), S. 469-476 
    Details
    ISSN: 1432-1912
    Keywords: Muscarinic acetylcholine receptor subtypes ; G proteins ; Intracellular Ca2+ ; Phospholipase C ; Pertussis toxin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have compared muscarinic acetylcholine receptor (mAChR) coupling to phospholipase C (PLC) and increases in cytoplasmic Ca2+ concentration [Ca2+]i in human embryonic kidney (HEK) cells, stably expressing either the human m3 or m2 receptor subtype. In m3 mAChR-expressing cells, carbachol stimulated inositol phosphate (InsP) formation and increased [Ca2+]i with EC50 values of about 2 μM and 30 nM, respectively. Maximal inositol 1,4,5-trisphosphate (InsP3) production (about fourfold) was rapid (15 s) and stable for 2 min. Maximal increases in [Ca2+]i were 300–350 nM and mainly, almost 90%, due to influx of extracellular Ca2+. The efficacy of pilocarpine for stimulating InsP andCa2+ responses was not significantly different from that of carbachol. All m3 mAChR-mediated responses were pertussis toxin (PTX)-insensitive. In m2 mAChR-expressing cells, carbachol stimulated InsP formation and increased [Ca2+]i with EC50 values of about 20 μM and 7 μM, respectively. Maximal InsP formation was only 10–15% of that observed in m3 mAChR-expressing cells, whereas maximal elevations of [Ca2+]i were similar in both cell types. Formation of InsP3 was rapid (15 s to 2 min) and about twofold above basal. In contrast to m3 mAChR activation, [Ca2+]i increases induced by m2 mAChR activation were exclusively due to Ca2+ mobilization from intracellular stores.The efficacy of pilocarpine for stimulating InsP and Ca2+ responses was 50% and 20% of the efficacy of carbachol, respectively. PTX treatment did not affect m2 mAChR-induced PLC stimulation, but reduced the m2 mAChR-mediated increases in [Ca2+]i to 50%. In conclusion, m3 and m2 mAChRs stably expressed in HEK cells can induce similar cellular responses; however, they do so by activating apparently distinct signalling pathways. While coupling of m2 mAChR to PLC occurs in a PTX-insensitive manner, coupling to mobilization of Ca2+ from intracellular stores is partly PTX-sensitive and this may occur at least partly independent of PLC activation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00169379
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  • 6
    Electronic Resource
    Electronic Resource
    A role for Rho in receptor- and G protein-stimulated phospholipase C Reduction in phosphatidylinositol 4,5-bisphosphate by Clostridium difficile toxin B (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 354 (1996), S. 87-94 
    Details
    ISSN: 1432-1912
    Keywords: Muscarinic receptor ; Phospholipase C ; Rho ; Clostridium difficile toxin B ; C3 exoenzyme ; Phosphatidylinositol 4,5-bisphosphate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Receptors coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins) activate phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)-hydrolyzing phospholipase C (PLC) enzymes by activated α or free βγ subunits of the relevant G proteins. To study whether low molecular weight G proteins of the Rho family are involved in receptor signalling to PLC, we examined the effect of Clostridium difficile toxin B, which glucosylates and thereby inactivates Rho proteins, on the regulation of PLC activity in human embryonic kidney (HEK) cells stably expressing the m3 muscarinic acetylcholine receptor (mAChR) subtype. Toxin B treatment of HEK cells did not affect basal PLC activity, but potently and efficiently inhibited mAChR-stimulated inositol phosphate formation. PLC activation by the endogenously expressed thrombin receptor and by the direct G protein activators, AlF inf4 sup− and guanosine 5′-[γ-thio]triphosphate (GTPγS), studied in intact and permeabilized cells, respectively, were also inhibited by toxin B treatment. C3 exoenzyme, which ADP-ribosylates Rho proteins, mimicked the inhibitory effect of toxin B on GTPγS-stimulated PLC activity. Finally, both toxin B and C3 exoenzyme significantly reduced, by 40 to 50%, the total level of PtdIns(4,5)P2 in HEK cells, without affecting the levels of phosphatidylinositol and phosphatidylinositol 4-phosphate. Accordingly, when PLC activity was measured with exogenous PtdIns(4,5)P2 as enzyme substrate, Ca2+- as well as GTPγS- or A1F inf4 sup− -stimulated PLC activities were not altered by prior toxin B treatment. In conclusion, evidence is provided that toxin B and C3 exoenzyme, apparently by inactivating Rho proteins, inhibit G protein-coupled receptor signalling to PLC, most likely by reducing the cellular substrate supply.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00178707
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  • 7
    Electronic Resource
    Electronic Resource
    Identification of G protein-coupled receptors potently stimulating migration of human transitional-cell carcinoma cells (1997)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 769-776 
    Details
    ISSN: 1432-1912
    Keywords: Key words LPA ; Thrombin ; Migration ; Bladder ; cancer cells ; J82 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The expression of G protein-coupled receptors inducing calcium mobilization and stimulating cell migration was examined in human transitional-cell carcinoma (J82) cells. Measurements of cytoplasmic Ca2+ concentration ([Ca2+]i) and phospholipase C activity indicated that these cells express several calcium-mobilizing receptors, including those for lysophosphatidic acid (LPA), thrombin, bradykinin, bombesin and histamine, of which only the LPA response was sensitive (∼ 50%) to pertussis toxin (PTX). Migration of J82 cells was strongly stimulated by LPA and thrombin, by 5- to 20-fold, whereas bradykinin, bombesin and histamine were ineffective. Migration induced by either LPA or thrombin was inhibited by the actin cytoskeleton-disrupting agent, cytochalasin B, by the Rho protein-inactivating Clostridium difficile toxin B, by preventing [Ca2+]i transients with an intracellular calcium-chelating agent, and by the phorbol ester, phorbol 12-myristate 13-acetate, which also blocked the LPA- and thrombin-induced [Ca2+]i increases. On the other hand, ADP-ribosylation of Gi type G proteins by PTX abrogated the migratory response to LPA, without affecting the thrombin effect. Similarly, raising cAMP levels inhibited, by about 50%, the LPA- but not the thrombin-induced J82 cell migration. In conclusion, human transitional-cell carcinoma (J82) cells express various G protein-coupled, calcium-mobilizing receptors, out of which only those for LPA and thrombin stimulate cell migration, indicating that phospholipase C-derived second messengers per se are not sufficient for initiating this response. The complex signal transduction processes leading to LPA- and thrombin-stimulated motility of these human carcinoma cells apparently involve several common, essential factors, such as [Ca2+]i changes and Rho protein-regulated reorganization of the cytoskeleton, as well as some distinct components, most notably distinct subtypes of heterotrimeric G proteins and apparently also distinct cAMP-sensitive targets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00005117
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  • 8
    Electronic Resource
    Electronic Resource
    Sodium regulation of agonist and antagonist binding to β-adrenoceptors in intact and Ns-deficient membranes (1986)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 333 (1986), S. 124-129 
    Details
    ISSN: 1432-1912
    Keywords: β-Adrenoceptors ; Sodium ; Adenylate cyclase ; Guanine nucleotides ; GTP-binding proteins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Agonist binding to various hormone receptors mediating adenylate cyclase inhibition is decreased by sodium ions. We studied the influence of Na+ on agonist and antagonist binding to β-adrenoceptors in membrane preparations of guinea pig lung, S49 lymphoma wild-type cells (WT) and their Ns-deficient cyc− variants by measuring binding of the antagonist, [125I]iodocyanopindolol ([125I]CYP). At 37° C, sodium decreased the receptor affinity for the agonist, isoproterenol, in all three membrane preparations. In lung and WT membranes, Na+ steepened the shallow agonist competition curves in a manner similar to and synergistic with guanine nucleotides. When binding was performend at 4° C, sodium regulation but not guanine nucleotide regulation of agonist binding was preserved. At the low temperature, [125I]CYP affinity was reduced, and sodium increased [125I]CYP binding in both Ns-containing and Ns-deficient membranes by increasing the antagonist affinity without significant change in total receptor number. Compared to Na+, Li+ and K+ were much less potent and efficient in decreasing agonist and increasing antagonist binding. Na+ and Mg2+ had opposite effects on agonist binding in the Ns-containing lung and WT membranes but not in the Ns-deficient cyc− membranes. The data indicate that sodium not only regulates binding of inhibitory hormone receptors but also agonist and antagonist binding to the adenylate cyclase stimulatory β-adrenoceptor. The finding that sodium regulation of β-adrenoceptor binding is also observed in the Ns α2 cyc− membranes, furthermore, indicates that the target of sodium is not the α-subunit of Ns but possibly a component common to both types of receptor systems regulating adenylate cyclase activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00506514
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  • 9
    Electronic Resource
    Electronic Resource
    Differential calcium signalling by m2 and m3 muscarinic acetylcholine receptors in a single cell type (1995)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 352 (1995), S. 469-476 
    Details
    ISSN: 1432-1912
    Keywords: Key words Muscarinic acetylcholine receptor subtypes ; G proteins ; Intracellular Ca2+ ; Phospholipase C ; Pertussis toxin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We have compared muscarinic acetylcholine receptor (mAChR) coupling to phospholipase C (PLC) and increases in cytoplasmic Ca2+ concentration [Ca2+]i in human embryonic kidney (HEK) cells, stably expressing either the human m3 or m2 receptor subtype. In m3 mAChR-expressing cells, carbachol stimulated inositol phosphate (InsP) formation and increased [Ca2+]i with EC50 values of about 2 μM and 30 nM, respectively. Maximal inositol 1,4,5-trisphosphate (InsP3) production (about fourfold) was rapid (15 s) and stable for 2 min. Maximal increases in [Ca2+]i were 300–350 nM and mainly, almost 90%, due to influx of extracellular Ca2+. The efficacy of pilocarpine for stimulating InsP and Ca2+ responses was not significantly different from that of carbachol. All m3 mAChR-mediated responses were pertussis toxin (PTX)-insensitive. In m2 mAChR-expressing cells, carbachol stimulated InsP formation and increased [Ca2+]i with EC50 values of about 20 μM and 7 μM, respectively. Maximal InsP formation was only 10–15% of that observed in m3 mAChR-expressing cells, whereas maximal elevations of [Ca2+]i were similar in both cell types. Formation of InsP3 was rapid (15 s to 2 min) and about twofold above basal. In contrast to m3 mAChR activation, [Ca2+]i increases induced by m2 mAChR activation were exclusively due to Ca2+ mobilization from intracellular stores. The efficacy of pilocarpine for stimulating InsP and Ca2+ responses was 50% and 20% of the efficacy of carbachol, respectively. PTX treatment did not affect m2 mAChR-induced PLC stimulation, but reduced the m2 mAChR-mediated increases in [Ca2+]i to 50%. In conclusion, m3 and m2 mAChRs stably expressed in HEK cells can induce similar cellular responses; however, they do so by activating apparently distinct signalling pathways. While coupling of m2 mAChR to PLC occurs in a PTX-insensitive manner, coupling to mobilization of Ca2+ from intracellular stores is partly PTX-sensitive and this may occur at least partly independent of PLC activation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00169379
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  • 10
    Electronic Resource
    Electronic Resource
    Association of a human G-protein β3 subunit variant with hypertension (1998)
    [s.l.] : Nature Publishing Group
    Nature genetics 18 (1998), S. 45-48 
    Details
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Hypertension is a common disorder of multifactorial origin that constitutes a major risk factor for cardiovascular events such as stroke and myocardial infarction. Previous studies demonstrated an enhanced signal transduction via pertussis toxin-sensitive G proteins in lymphoblasts and fibroblasts ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/ng0198-45
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