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Martin C. Michel - One of the best experts on this subject based on the ideXlab platform.
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signal transduction underlying Carbachol induced contraction of human urinary bladder
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Tim Schneider, Charlotte Fetscher, Susanne Krege, Martin C. MichelAbstract:The present study was designed to reexamine the muscarinic acetylcholine receptor subtype mediating Carbachol-induced contraction of human urinary bladder and to investigate the underlying signal transduction. Based upon the nonselective tolterodine, the highly M(2)-selective (R)-4-[2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl]piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M(3)-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M(3) receptors. The phospholipase C inhibitor 1-(6-[([17beta]-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione (U 73,122) (1-10 microM) did not significantly affect Carbachol-stimulated bladder contraction. The phospholipase D inhibitor butan-1-ol relative to its negative control butan-2-ol (0.3% each) caused small but detectable inhibition of Carbachol-induced bladder contraction. The Ca(2+) entry blocker nifedipine (10-100 nM) strongly inhibited Carbachol-induced bladder contraction. In contrast, 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SK&F 96,365) (1-10 microM), an inhibitor of store-operated Ca(2+) channels, caused little inhibition. The protein kinase C inhibitor bisindolylmaleimide I (1-10 microM) did not significantly affected Carbachol-induced bladder contraction. In contrast, trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide (Y 27,632) (1-10 microM), an inhibitor of rho-associated kinases, concentration dependently and effectively attenuated the Carbachol responses. We conclude that Carbachol-induced contraction of human urinary bladder via M(3) receptors largely depends on Ca(2+) entry through nifedipine-sensitive channels and activation of a rho kinase, whereas phospholipase D and store-operated Ca(2+) channels contribute only in a minor way. Surprisingly, phospholipase C or protein kinase C do not seem to be involved to a relevant extent.
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signal transduction underlying Carbachol induced contraction of rat urinary bladder i phospholipases and ca2 sources
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Tim Schneider, Peter Hein, Martin C. MichelAbstract:We have reexamined the muscarinic receptor subtype mediating Carbachol-induced contraction of rat urinary bladder and investigated the role of phospholipase (PL)C, D, and A2 and of intra- and extracellular Ca2+ sources in this effect. Based on the nonsubtype-selective tolterodine, the highly M2 receptor-selective ( R )-4-{2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl}-piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M3 receptor-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M3 receptors. Carbachol stimulated inositol phosphate formation in rat bladder slices, and this was abolished by the phospholipase C inhibitor 1-(6-[([17β]-3-methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-1 H -pyrrole-2,5-dione (U 73,122; 10 μM). Nevertheless, U 73,122 (1–10 μM) did not significantly affect Carbachol-stimulated bladder contraction. Carbachol had only little effect on PLD activity in bladder slices, but the PLD inhibitor butan-1-ol, relative to its negative control butan-2-ol (0.3% each), caused detectable inhibition of Carbachol-induced bladder contraction. The cytosolic PLA2 inhibitor arachidonyltrifluoromethyl ketone weakly inhibited Carbachol-induced contraction at a concentration of 300 μM, but the cyclooxygenase inhibitor indomethacin (1–10 μM) remained without effect. The Ca2+ entry blocker nifedipine (10–100 nM) almost completely inhibited Carbachol-induced bladder contraction. In contrast, 1-[β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1 H -imidazole HCl (SKF 96,365; 10 μM), an inhibitor of store-operated Ca2+ channels, caused little inhibition. We conclude that Carbachol-induced contraction of rat bladder largely depends on Ca2+ entry through nifedipine-sensitive channels and, perhaps, PLD, PLA2, and store-operated Ca2+ channels, whereas cyclooxygenase and, surprisingly, also PLC are not involved to a relevant extent.
Colin W Taylor - One of the best experts on this subject based on the ideXlab platform.
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cyclic amp recruits a discrete intracellular ca2 store by unmasking hypersensitive ip3 receptors
Cell Reports, 2017Co-Authors: Vera Konieczny, Stephen C Tovey, Stefania Mataragka, David L Prole, Colin W TaylorAbstract:Summary Inositol 1,4,5-trisphosphate (IP 3 ) stimulates Ca 2+ release from the endoplasmic reticulum (ER), and the response is potentiated by 3′,5′-cyclic AMP (cAMP). We investigated this interaction in HEK293 cells using Carbachol and parathyroid hormone (PTH) to stimulate formation of IP 3 and cAMP, respectively. PTH alone had no effect on the cytosolic Ca 2+ concentration, but it potentiated the Ca 2+ signals evoked by Carbachol. Surprisingly, however, the intracellular Ca 2+ stores that respond to Carbachol alone could be both emptied and refilled without affecting the subsequent response to PTH. We provide evidence that PTH unmasks high-affinity IP 3 receptors within a discrete Ca 2+ store. We conclude that Ca 2+ stores within the ER that dynamically exchange Ca 2+ with the cytosol maintain a functional independence that allows one store to be released by Carbachol and another to be released by Carbachol with PTH. Compartmentalization of ER Ca 2+ stores adds versatility to IP 3 -evoked Ca 2+ signals.
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parathyroid hormone controls the size of the intracellular ca2 stores available to receptors linked to inositol trisphosphate formation
Journal of Biological Chemistry, 2000Co-Authors: Alison D Short, Colin W TaylorAbstract:In HEK 293 cells stably expressing type 1 parathyroid (PTH) receptors, PTH stimulated release of intracellular Ca2+ stores in only 27% of cells, whereas 96% of cells responded to Carbachol. However, in almost all cells PTH potentiated the response to Carbachol by about 3-fold. Responses to Carbachol did not desensitize, but only the first challenge in Ca2+-free medium caused an increase in [Ca2+]i, indicating that the Carbachol-sensitive Ca2+ stores had been emptied. Subsequent addition of PTH also failed to increase [Ca2+]i, but when it was followed by Carbachol there was a substantial increase in [Ca2+]i. A similar potentiation was observed between ATP and PTH but not between Carbachol and ATP. Intracellular heparin inhibited responses to Carbachol and PTH, and pretreatment with ATP and Carbachol abolished responses to PTH, suggesting that the effects of PTH involve inositol trisphosphate (IP3) receptors. PTH neither stimulated detectable IP3 formation nor affected the amount formed in response to ATP or Carbachol. PTH stimulated cyclic AMP formation, but this was not the means whereby PTH potentiated Ca2+ signals. We suggest that PTH may regulate Ca2+ mobilization by facilitating translocation of Ca2+ between discrete intracellular stores and that it thereby regulates the size of the Ca2+ pool available to receptors linked to IP3 formation.
Barbara E Slack - One of the best experts on this subject based on the ideXlab platform.
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the m3 muscarinic acetylcholine receptor is coupled to mitogen activated protein kinase via protein kinase c and epidermal growth factor receptor kinase
Biochemical Journal, 2000Co-Authors: Barbara E SlackAbstract:The acetylcholine analogue Carbachol rapidly activated mitogen-activated protein kinase (MAPK), and caused tyrosine phosphorylation of the adapter protein p52 Shc and the epidermalgrowth factor (EGF) receptor, in human embryonic kidney cells stably expressing m3 muscarinic receptors. The protein kinase C (PKC) inhibitor GF109203X caused a significant partial inhibition of m3 receptor-mediated activation of MAPK. The PKC-independent MAPK activity elicited by Carbachol in the presence of GF109203X was reproducibly abolished by AG1478, an inhibitor of EGF-receptor tyrosine kinase activity, and by the Src tyrosine kinase inhibitor PP1. In a subset of these experiments, GF109203X concomitantly increased Carbachol-induced tyrosine phosphorylation of p52 Shc and the EGF receptor. In co-stimulation experiments, Carbachol and EGF activated MAPK in a non-additive fashion; moreover, EGF-induced association of Shc with the phosphorylated EGF receptor was inhibited by Carbachol. This effect of Carbachol was blocked by GF109203X. The results indicate that MAPK activation by m3 receptor stimulation is regulated by two pathways; one dependent on PKC, and the other mediated via the EGF receptor and Src. Moreover, the EGF-receptor-dependent pathway may be subject to negative-feedback regulation via m3 receptor-coupled activation of PKC.
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tyrosine phosphorylation dependent stimulation of amyloid precursor protein secretion by the m3 muscarinic acetylcholine receptor
Journal of Biological Chemistry, 1995Co-Authors: Barbara E Slack, Jeffrey Breu, Magdalena A Petryniak, Kakul Srivastava, Richard J WurtmanAbstract:Abstract Stimulation of m1 and m3 muscarinic acetylcholine receptors, which are coupled to phosphoinositide hydrolysis and protein kinase C activation, has been shown to increase the release of soluble amyloid precursor protein derivatives (APPs). The effect is mimicked by phorbol esters, which directly activate protein kinase C. Using human embryonic kidney cells expressing individual muscarinic receptor subtypes, we found that stimulation of APPs release by the muscarinic agonist Carbachol was only partially reduced by a specific inhibitor of protein kinase C (the bisindolylmaleimide GF 109203X), while the response to phorbol 12-myristate 13-acetate (PMA) was abolished. The increase in APPs release elicited by Carbachol and PMA was accompanied by elevated tyrosine phosphorylation of several proteins and reduced by tyrosine kinase inhibitors; GF 109203X significantly reduced the stimulation of tyrosine phosphorylation by Carbachol and PMA. Inhibition of protein tyrosine phosphatases by vanadyl hydroperoxide markedly increased cellular tyrosine phosphorylation and enhanced APPs release as effectively as PMA and Carbachol. Direct phosphorylation of amyloid precursor protein on tyrosine residues following treatment with Carbachol, PMA, or vanadyl hydroperoxide was not observed. The results implicate both tyrosine phosphorylation and protein kinase C-dependent mechanisms in the regulation of APPs release by G protein-coupled receptors, and suggest that Carbachol and PMA increase APPs release from human embryonic kidney cells expressing m3 muscarinic receptors via partially divergent pathways that converge at a tyrosine phosphorylation-dependent step.
Tim Schneider - One of the best experts on this subject based on the ideXlab platform.
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signal transduction underlying Carbachol induced contraction of human urinary bladder
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Tim Schneider, Charlotte Fetscher, Susanne Krege, Martin C. MichelAbstract:The present study was designed to reexamine the muscarinic acetylcholine receptor subtype mediating Carbachol-induced contraction of human urinary bladder and to investigate the underlying signal transduction. Based upon the nonselective tolterodine, the highly M(2)-selective (R)-4-[2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl]piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M(3)-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M(3) receptors. The phospholipase C inhibitor 1-(6-[([17beta]-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione (U 73,122) (1-10 microM) did not significantly affect Carbachol-stimulated bladder contraction. The phospholipase D inhibitor butan-1-ol relative to its negative control butan-2-ol (0.3% each) caused small but detectable inhibition of Carbachol-induced bladder contraction. The Ca(2+) entry blocker nifedipine (10-100 nM) strongly inhibited Carbachol-induced bladder contraction. In contrast, 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SK&F 96,365) (1-10 microM), an inhibitor of store-operated Ca(2+) channels, caused little inhibition. The protein kinase C inhibitor bisindolylmaleimide I (1-10 microM) did not significantly affected Carbachol-induced bladder contraction. In contrast, trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide (Y 27,632) (1-10 microM), an inhibitor of rho-associated kinases, concentration dependently and effectively attenuated the Carbachol responses. We conclude that Carbachol-induced contraction of human urinary bladder via M(3) receptors largely depends on Ca(2+) entry through nifedipine-sensitive channels and activation of a rho kinase, whereas phospholipase D and store-operated Ca(2+) channels contribute only in a minor way. Surprisingly, phospholipase C or protein kinase C do not seem to be involved to a relevant extent.
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signal transduction underlying Carbachol induced contraction of rat urinary bladder i phospholipases and ca2 sources
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Tim Schneider, Peter Hein, Martin C. MichelAbstract:We have reexamined the muscarinic receptor subtype mediating Carbachol-induced contraction of rat urinary bladder and investigated the role of phospholipase (PL)C, D, and A2 and of intra- and extracellular Ca2+ sources in this effect. Based on the nonsubtype-selective tolterodine, the highly M2 receptor-selective ( R )-4-{2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl}-piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M3 receptor-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M3 receptors. Carbachol stimulated inositol phosphate formation in rat bladder slices, and this was abolished by the phospholipase C inhibitor 1-(6-[([17β]-3-methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-1 H -pyrrole-2,5-dione (U 73,122; 10 μM). Nevertheless, U 73,122 (1–10 μM) did not significantly affect Carbachol-stimulated bladder contraction. Carbachol had only little effect on PLD activity in bladder slices, but the PLD inhibitor butan-1-ol, relative to its negative control butan-2-ol (0.3% each), caused detectable inhibition of Carbachol-induced bladder contraction. The cytosolic PLA2 inhibitor arachidonyltrifluoromethyl ketone weakly inhibited Carbachol-induced contraction at a concentration of 300 μM, but the cyclooxygenase inhibitor indomethacin (1–10 μM) remained without effect. The Ca2+ entry blocker nifedipine (10–100 nM) almost completely inhibited Carbachol-induced bladder contraction. In contrast, 1-[β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1 H -imidazole HCl (SKF 96,365; 10 μM), an inhibitor of store-operated Ca2+ channels, caused little inhibition. We conclude that Carbachol-induced contraction of rat bladder largely depends on Ca2+ entry through nifedipine-sensitive channels and, perhaps, PLD, PLA2, and store-operated Ca2+ channels, whereas cyclooxygenase and, surprisingly, also PLC are not involved to a relevant extent.
Hideo Kanaide - One of the best experts on this subject based on the ideXlab platform.
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the mechanism for the contraction induced by leukotriene c4 in guinea pig taenia coli
British Journal of Pharmacology, 2001Co-Authors: Satoshi Ieiri, Junji Nishimura, Katsuya Hirano, Sachiyo Suita, Hideo KanaideAbstract:The mechanism underlying the LTC4-induced contraction of guinea-pig taenia coli was determined using the simultaneous measurements of [Ca2+]i and force in whole muscle preparations. Additional experiments were performed in receptor coupled permeabilized preparation. For comparison purposes, the contraction which was induced by a typical G-protein mediated agonist, Carbachol was also characterized. LTC4 induced a contraction in the guinea-pig taenia coli in a concentration-dependent manner. The maximal response was obtained at 100 nM and the EC50 value was 5.4±1.9 nM. Both LTC4 and Carbachol induced increases in [Ca2+]i and force. The maximum force induced by 100 nM LTC4 was significantly smaller than that induced by 10 μM Carbachol, although an increase in [Ca2+]i produced by both agonists was similar. In the permeabilized preparations, Carbachol, but not LTC4, induced an additional force development at a fixed Ca2+ concentration. LTC4 induced no increase in [Ca2+]i and force in the Ca2+-free solution, while Carbachol induced transient increases in both [Ca2+]i and force in a Ca2+-free solution. Both diltiazem and SK&F 96365 significantly inhibited the LTC4− and Carbachol-induced increases in [Ca2+]i and force in normal PSS. The inhibitory pattern of [Ca2+]i by these drugs was also similar. We thus conclude that LTC4 induces the contraction of the guinea-pig taenia coli mainly through Ca2+ influx via both the diltiazem-sensitive and SK&F 96365-sensitive Ca2+ channels, without affecting either the Ca2+-sensitivity or the intracellular Ca2+ release. These results indicated that the mechanism underlying the LTC4-induced contraction differs greatly from that for conventional G-protein mediated agonists, such as Carbachol. British Journal of Pharmacology (2001) 133, 529–538; doi:10.1038/sj.bjp.0704122