Biological properties of a specific G<i>α</i><sub>q/11</sub> inhibitor, YM‐254890, on platelet functions and thrombus formation under high‐shear stress

Uemura, Toshio; Kawasaki, Tomihisa; Taniguchi, Masatoshi; Moritani, Yumiko; Hayashi, Kazumi; Saito, Tetsu; Takasaki, Jun; Uchida, Wataru; Miyata, Keiji

doi:10.1038/sj.bjp.0706711

Cited by 58 publications

(51 citation statements)

References 35 publications

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“…YM-254890 has been reported to block agonist-induced activation of G q/11 -type G-proteins in various tissues or cells [17,23,27,34]. We confirmed this blocking activity in preparations used for the present study, where YM-254890 abolished carbachol-evoked contractions mediated by intracellular Ca 2+ release that is known to involve G q/11 -type Gproteins [3,12,13].…”

Section: Discussionsupporting

confidence: 78%

Muscarinic Receptor Subtypes Mediating Ca2+ Sensitization of Intestinal Smooth Muscle Contraction: Studies with Receptor Knockout Mice

Suguro

Matsuyama

Tanahashi

et al. 2010

The Journal of Veterinary Medical Science

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ABSTRACT. In the present study, we have characterized muscarinic receptor subtypes that mediate carbachol-induced Ca 2+ sensitization of contraction in intestinal smooth muscle, using mutant mice lacking M 2 or M 3 muscarinic receptors or both receptor subtypes. In -toxinpermeabilized muscle strips from wild-type (WT) mice, isometric tension responses to Ca 2+ applied cumulatively (pCa 7.0-5.0) were increased when the muscarinic agonist carbachol (100 M) was added to the medium, as judged from shifts of pCa-tension curves in both 50% effective concentration (EC 50 ) and maximum response (E max ) of pCa-tension curve. In preparations from M 2 -knockout (KO) mice, pCa-tension curves were also shifted by carbachol (100 M), and the extents of the EC 50 and E max changes resembled those observed in preparations from WT mice. In preparations from M 3 -KO or M 2 /M 3 -double KO mice, however, no significant changes in pCa-tension curves were obtained after carbachol application. ] c to increase the MLCK/ MLCP activity ratio, resulting in enhanced contractions compared to those without receptor activation [21].In intestinal smooth muscles, acetylcholine and its derivatives such as carbachol, activate muscarinic receptors, inducing Ca 2+ sensitization as well as cytosolic Ca 2+ mobilization and contraction [6,29]. Among the five muscarinic receptor subtypes (M 1 -M 5 ), the M 2 and M 3 are predominantly expressed in intestinal smooth muscles [2]. By using muscarinic receptor antagonists with limited subtype selectivity, Murthy et al. [14] suggested that acetylcholineinduced Rho kinase activation and PKC activation in rabbit intestinal smooth muscles is mediated by the M 3 subtype, leading to Ca 2+ sensitization. However, such pharmacological studies often remain inconclusive because of the poor subtype selectivity of available muscarinic antagonists. For example, pharmacological studies suggested that carbacholevoked contractions are exclusively mediated by M 3 receptors, whereas recent studies using muscarinic receptor knockout mice implicated both M 3 and M 2 receptors in this response [30,31].Therefore, in the present study, using M 2 -knockout (KO) or M 3 -KO or M 2 /M 3 -double KO mice and wild type (WT) mice, we examined the activity of carbachol in inducing Ca 2+ sensitization in -toxin-permeabilized smooth muscles of the small intestine. In general, M 2 and M 3 muscarinic receptors are coupled preferentially with G i/o -and G q/11 -type G-proteins, respectively. We also examined whether the carbacholinduced Ca 2+ sensitization was affected by YM-254890, a selective inhibitor of G q/11 -type G-protein activity [23,26].

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Section: Discussionsupporting

confidence: 78%

Muscarinic Receptor Subtypes Mediating Ca2+ Sensitization of Intestinal Smooth Muscle Contraction: Studies with Receptor Knockout Mice

Suguro

Matsuyama

Tanahashi

et al. 2010

The Journal of Veterinary Medical Science

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“…1E) (25). To determine the signaling mechanism involved in fucoidan-induced platelet activation, we used the selective G q inhibitor YM-254890 (26,27) or the pan SFK inhibitor PP2 (28). Platelets pretreated with YM-254890 had only a minimum reduction in aggregation in comparison with the full inhibition of aggregation to AYPGKF ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Fucoidan Is a Novel Platelet Agonist for the C-type Lectin-like Receptor 2 (CLEC-2)

Manne

Getz

Hughes

et al. 2013

Journal of Biological Chemistry

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Background: Fucoidan was tested as a novel drug for hemophilia, but its effect on platelets has not been studied. Results: We show that fucoidan activates human and mouse platelets and that activation is blocked in CLEC-2 knock-out murine platelets. Conclusion: Fucoidan is a novel agonist for the CLEC-2. Significance: Understanding the effects of fucoidan on platelets can help in designing efficient drugs for hemophilia.

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“…In fact, PLC␤3-deficient mice exhibit an almost complete loss of serotonin-or ␣-Me-5-HT-induced scratching. By contrast, the PLC␤3-deficient mutant mice respond normally to ET-1, SLIGRL-NH 2 (a protease-activated receptor 2 agonist) and U-46619 (a thromboxane A2 receptor agonist), despite the fact that the cognate receptors corresponding to these ligands also signal via G␣q-PLC␤ (22)(23)(24). Therefore, we conclude that G␣q-coupled pruritic compounds elicit an itch response through at least 2 different G␣q pathways: one is PLC␤3-dependent and the other is PLC␤3-independent.…”

Section: The Molecular Specificity Of G␣q-plc␤ Intracellular Signalinmentioning

confidence: 99%

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

Isowa

Park

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

395

437

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The mechanisms that generate itch are poorly understood at both the molecular and cellular levels despite its clinical importance. To explore the peripheral neuronal mechanisms underlying itch, we assessed the behavioral responses (scratching) produced by s.c. injection of various pruritogens in PLC␤3-or TRPV1-deficient mice. We provide evidence that at least 3 different molecular pathways contribute to the transduction of itch responses to different pruritogens: 1) histamine requires the function of both PLC␤3 and the TRPV1 channel; 2) serotonin, or a selective agonist, ␣-methylserotonin (␣-Me-5-HT), requires the presence of PLC␤3 but not TRPV1, and 3) endothelin-1 (ET-1) does not require either PLC␤3 or TRPV1. To determine whether the activity of these molecules is represented in a particular subpopulation of sensory neurons, we examined the behavioral consequences of selectively eliminating 2 nonoverlapping subsets of nociceptors. The genetic ablation of MrgprD ؉ neurons that represent Ϸ90% of cutaneous nonpeptidergic neurons did not affect the scratching responses to a number of pruritogens. In contrast, chemical ablation of the central branch of TRPV1 ؉ nociceptors led to a significant behavioral deficit for pruritogens, including ␣-Me-5-HT and ET-1, that is, the TRPV1-expressing nociceptor was required, whether or not TRPV1 itself was essential. Thus, TRPV1 neurons are equipped with multiple signaling mechanisms that respond to different pruritogens. Some of these require TRPV1 function; others use alternate signal transduction pathways.itch ͉ PLCb3 ͉ scratching

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Biological properties of a specific Gα_q/11 inhibitor, YM‐254890, on platelet functions and thrombus formation under high‐shear stress

Cited by 58 publications

References 35 publications

Muscarinic Receptor Subtypes Mediating Ca2+ Sensitization of Intestinal Smooth Muscle Contraction: Studies with Receptor Knockout Mice

Muscarinic Receptor Subtypes Mediating Ca2+ Sensitization of Intestinal Smooth Muscle Contraction: Studies with Receptor Knockout Mice

Fucoidan Is a Novel Platelet Agonist for the C-type Lectin-like Receptor 2 (CLEC-2)

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

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Biological properties of a specific Gαq/11 inhibitor, YM‐254890, on platelet functions and thrombus formation under high‐shear stress

Cited by 58 publications

References 35 publications

Muscarinic Receptor Subtypes Mediating Ca2+ Sensitization of Intestinal Smooth Muscle Contraction: Studies with Receptor Knockout Mice

Muscarinic Receptor Subtypes Mediating Ca2+ Sensitization of Intestinal Smooth Muscle Contraction: Studies with Receptor Knockout Mice

Fucoidan Is a Novel Platelet Agonist for the C-type Lectin-like Receptor 2 (CLEC-2)

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

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Biological properties of a specific Gα_q/11 inhibitor, YM‐254890, on platelet functions and thrombus formation under high‐shear stress