Thromboxane A2-induced contraction of rat caudal arterial smooth muscle involves activation of Ca2+ entry and Ca2+ sensitization: Rho-associated kinase-mediated phosphorylation of MYPT1 at Thr-855, but not Thr-697

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dc.contributor.authorWilson, D.
dc.contributor.authorSusnjar, M.
dc.contributor.authorKiss, E.
dc.contributor.authorSutherland, C.
dc.contributor.authorWalsh, M.
dc.date.issued2005
dc.descriptionThe final version of record is available at http://www.biochemj.org/bj/toc.htm
dc.description.abstractThe signal transduction pathway whereby the TxA2 (thromboxane A2) mimetic U-46619 activates vascular smooth muscle contraction was investigated in de-endothelialized rat caudal artery. U- 46619-evoked contraction was inhibited by the TP receptor (TxA2 receptor) antagonist SQ-29548, the ROK (Rho-associated kinase) inhibitors Y-27632 and H-1152, the MLCK (myosin light-chain kinase) inhibitors ML-7, ML-9 and wortmannin, the voltagegated Ca2+-channel blocker nicardipine, and removal of extracellular Ca2+; the protein kinase C inhibitor GF109203x had no effect. U-46619 elicited Ca2+ sensitization in α-toxin-permeabilized tissue. U-46619 induced activation of the small GTPase RhoA, consistent with the involvement of ROK. Two downstream targets of ROK were investigated: CPI-17 [protein kinase C-potentiated inhibitory protein for PP1 (protein phosphatase type 1) of 17 kDa], a myosin light-chain phosphatase inhibitor, was not phosphorylated at the functional site (Thr-38); phosphorylation of MYPT1 (myosin-targeting subunit of myosin light-chain phosphatase) was significantly increased at Thr-855, but not Thr-697. U-46619-evoked contraction correlated with phosphorylation of the 20 kDa light chains of myosin. We conclude that: (i) U-46619 induces contraction via activation of the Ca2+/calmodulin/MLCK pathway and of the RhoA/ROK pathway; (ii) Thr-855 ofMYPT1is phosphorylated byROKat rest and in response to U-46619 stimulation; (iii) Thr-697 of MYPT1 is phosphorylated by a kinase other than ROK under resting conditions, and is not increased in response to U-46619 treatment; and (iv) neither ROK nor protein kinase C phosphorylates CPI-17 in this vascular smooth muscle in response to U-46619.
dc.description.statementofresponsibilityDavid P. Wilson, Marija Susnjar, Enikõ Kiss, Cindy Sutherland and Michael P. Walsh
dc.identifier.citationBiochemical Journal, 2005; 389(3):763-774
dc.identifier.doi10.1042/BJ20050237
dc.identifier.issn0264-6021
dc.identifier.issn1470-8728
dc.identifier.urihttp://hdl.handle.net/2440/34776
dc.language.isoen
dc.publisherPortland Press
dc.source.urihttps://doi.org/10.1042/bj20050237
dc.subjectCa2+ sensitization
dc.subjectL-type Ca2+ current
dc.subjectmyosin lightchain phosphatase
dc.subjectthromboxane A2
dc.subjectCPI-17
dc.subjectvascular smooth muscle
dc.titleThromboxane A2-induced contraction of rat caudal arterial smooth muscle involves activation of Ca2+ entry and Ca2+ sensitization: Rho-associated kinase-mediated phosphorylation of MYPT1 at Thr-855, but not Thr-697
dc.typeJournal article
pubs.publication-statusPublished

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