Pasteurella multocida Toxin-induced Activation of RhoA Is Mediated via Two Families of Gα Proteins, Gαq and Gα12/13

Orth, J.; Lang, Simona; Taniguchi, Masatoshi; Aktories, Klaus

doi:10.1074/jbc.m507203200

Cited by 68 publications

(85 citation statements)

References 46 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%

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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%

“…In HEK293 cells, the action of YM-254890 to block carbachol-induced IP 3 production lasted at least 30 min after its wash-out [17].…”

Section: Methodsmentioning

confidence: 99%

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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“…PMT activates Gα q , Gα 12-13 subunits of heterotrimeric G-proteins, through conversion of the GDP-into the GTP-form by a yet undefined mechanism. GTP-Gα q dissociates from the Gβγ complex and then stimulates PLCβ1, which, in its turn, catalyses the hydrolysis of PIP 2 (phosphatidylinositol 4,5-bisphosphate) into IP 3 (inositol triphosphate) and diacylglycerol, leading to subsequent Ca 2+ mobilization, PKC (protein kinase C) activation and downstream signalling (Wilson et al, 1997;Zywietz et al, 2001;Orth et al, 2005).…”

Section: Toxin That Modulates Plcmentioning

confidence: 99%

Bacterial protein toxins and lipids: role in toxin targeting and activity

Geny

Popoff

2006

Biology of the Cell

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All bacterial toxins, which globally are hydrophilic proteins, interact first with their target cells by recognizing a surface receptor, which is either a lipid or a lipid derivative, or another compound but in a lipid environment. Intracellular active toxins follow various trafficking pathways, the sorting of which is greatly dependent on the nature of the receptor, notably lipidic receptor or receptor embedded into a distinct environment such as lipid microdomains. Numerous other toxins act locally on cell membrane. Indeed, phospholipase activity is a common mechanism shared by several membrane‐damaging toxins. In addition, many toxins active intracellularly or on cell membrane modulate host cell phospholipid pathways. Unusually, a few bacterial toxins require a lipid post‐translational modification to be active. Thereby, lipids are obligate partners of bacterial toxins.

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“…Studies using G␣ q/11 -deficient mouse embryonic fibroblasts (MEFs) indicate that G␣ q , but not the closely related G␣ 11 , is activated by PMT (13,14). In addition to G␣ q , PMT activates G␣ 13 of the G 12/13 family, resulting in formation of stress fibers and activation of the small GTPase RhoA (15). More recently, we observed that PMT is also a potent activator of G␣ i , converting the G protein into a PTx-insensitive state (16).…”

mentioning

confidence: 99%

Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation

Orth

Preuß

Fester

et al. 2009

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

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103

123

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Pasteurella multocida toxin is a major virulence factor of Pasteurella multocida, which causes pasteurellosis in men and animals and atrophic rhinitis in rabbits and pigs. The Ϸ145 kDa protein toxin stimulates various signal transduction pathways by activating heterotrimeric G proteins of the G␣ q, G␣i, and G␣12/13 families by using an as yet unknown mechanism. Here, we show that Pasteurella multocida toxin deamidates glutamine-205 of G␣ i2 to glutamic acid. Therefore, the toxin inhibits the intrinsic GTPase activity of G␣ i and causes persistent activation of the G protein. A similar modification is also evident for G␣ q, but not for the closely related G␣ 11, which is not a substrate of Pasteurella multocida toxin. Our data identify the ␣-subunits of heterotrimeric G proteins as the direct molecular target of Pasteurella multocida toxin and indicate that the toxin does not act like a protease, which was suggested from its thiol protease-like catalytic triad, but instead causes constitutive activation of G proteins by deamidase activity.bacterial protein toxin ͉ Gi protein ͉ posttranslational modification ͉ transglutaminase

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Pasteurella multocida Toxin-induced Activation of RhoA Is Mediated via Two Families of Gα Proteins, Gαq and Gα12/13

Cited by 68 publications

References 46 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

Bacterial protein toxins and lipids: role in toxin targeting and activity

Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation

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