Myosin Regulatory Light Chain Diphosphorylation Slows Relaxation of Arterial Smooth Muscle

Sutherland, Cindy; Walsh, Michael P.

doi:10.1074/jbc.m112.371609

Cited by 44 publications

(61 citation statements)

References 54 publications

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“…5). Calyculin A induces a slow, sustained contraction of vascular smooth muscle through inhibition of MLCP, which unmasks the basal activities of integrin-linked kinase and zipper-interacting protein kinase, leading to phosphorylation of LC 20 at Thr-18 and Ser-19 and contraction (7). The fact that PF-431396 had no effect on calyculin A-induced contraction indicates the absence of an off-target effect of the compound downstream of LC 20 phosphorylation.…”

Section: Discussionmentioning

confidence: 81%

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A Role for the Tyrosine Kinase Pyk2 in Depolarization-induced Contraction of Vascular Smooth Muscle

Mills

Mita

Nakagawa

et al. 2015

Journal of Biological Chemistry

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Background: Depolarization-induced tonic contraction of vascular smooth muscle involves tyrosine phosphorylation. Results: Depolarization activates the Ca 2ϩ -dependent tyrosine kinase Pyk2, leading to activation of the RhoA/Rho-associated kinase pathway. Conclusion: Activation of Pyk2 is required for the sustained phase of depolarization-induced contraction. Significance: Knowledge of the mechanisms responsible for sustained contraction is crucial for identification of defects leading to disease associated with vascular contractile dysfunction.

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Section: Discussionmentioning

confidence: 81%

“…De-endothelialized caudal arterial smooth muscle strips were prepared for force measurement as described previously (3,7). Experiments were carried out with endothelium-denuded vessels to eliminate interference from endothelial cell-derived vasoactive mediators.…”

Section: Methodsmentioning

confidence: 99%

A Role for the Tyrosine Kinase Pyk2 in Depolarization-induced Contraction of Vascular Smooth Muscle

Mills

Mita

Nakagawa

et al. 2015

Journal of Biological Chemistry

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“…9A), previously identified as Ser19, as expected (e.g., Sutherland and Walsh, 2012). LC 20 phosphorylation was significantly increased at the peak of the contractile response to PE, U46619, KCl, and ET-1 (Fig.…”

Section: Resultsmentioning

confidence: 60%

“…We employed isolated rat caudal arterial smooth muscle strips as a model VSM tissue and assessed the concentration and time dependence of HS38 effects on contractile responses. Muscle strips were incubated in Ca 21 -containing HEPES buffer with HS38 or vehicle prior to addition of the type 1 and 2A phosphatase inhibitor CLa, which by inhibiting endogenous MLCP activity unmasks basal Ca 21 -independent LC 20 kinase activities to induce a slow, sustained contraction (Wilson et al, 2005b;Sutherland and a Denotes CLa (0.5 mM) alone. b Denotes CLa + HS38 (50 mM).…”

Section: Resultsmentioning

confidence: 99%

A Small Molecule Pyrazolo[3,4-d]Pyrimidinone Inhibitor of Zipper-Interacting Protein Kinase Suppresses Calcium Sensitization of Vascular Smooth Muscle

et al. 2015

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A novel inhibitor of zipper-interacting protein kinase (ZIPK) was used to examine the involvement of ZIPK in the regulation of smooth muscle contraction. Pretreatment of de-endothelialized rat caudal arterial smooth muscle strips with the pyrazolo [3,4-propanamide (HS38) decreased the velocity of contraction (time to reach half-maximal force) induced by the phosphatase inhibitor calyculin A in the presence of Ca 21 without affecting maximal force development. This effect was reversed following washout of HS38 and correlated with a reduction in the rate of phosphorylation of myosin 20-kDa regulatory light chains (LC 20 ) but not of protein kinase C-potentiated inhibitory protein for myosin phosphatase of 17 kDa (CPI-17), prostate apoptosis response-4, or myosin phosphatase-targeting subunit 1 (MYPT1), all of which have been implicated in the regulation of vascular contractility. A structural analog of HS38, with inhibitory activity toward proviral integrations of Moloney (PIM) virus 3 kinase but not ZIPK, had no effect on calyculin A-induced contraction or protein phosphorylations. We conclude that a pool of constitutively active ZIPK is involved in regulation of vascular smooth muscle contraction through direct phosphorylation of LC 20 upon inhibition of myosin light chain phosphatase activity. HS38 also significantly attenuated both phasic and tonic contractile responses elicited by phenylephrine, angiotensin II, endothelin-1, U46619, and K 1 -induced membrane depolarization in the presence of Ca 21 , which correlated with inhibition of phosphorylation of LC 20 , MYPT1, and CPI-17. These effects of HS38 suggest that ZIPK also lies downstream from G protein-coupled receptors that signal through both Ga 12/13 and Ga q/11 .

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“…23 Finally, MLCp can involve more than a single phosphorylation site with physiological implications. 15,24 In short, the statement that smooth muscle contraction is regulated solely by a Ca 2+ -dependent MLCK switch seems an incomplete depiction of this complex muscle type. However, the level of steady-state MLCp remains a strong indicator of the degree of contractile tension, at least of vascular smooth muscle.…”

Section: Article See P 562mentioning

confidence: 99%

Inhibitor κB Kinase

Ratz

2013

Circulation Research

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Myosin Regulatory Light Chain Diphosphorylation Slows Relaxation of Arterial Smooth Muscle

Cited by 44 publications

References 54 publications

A Role for the Tyrosine Kinase Pyk2 in Depolarization-induced Contraction of Vascular Smooth Muscle

A Role for the Tyrosine Kinase Pyk2 in Depolarization-induced Contraction of Vascular Smooth Muscle

A Small Molecule Pyrazolo[3,4-d]Pyrimidinone Inhibitor of Zipper-Interacting Protein Kinase Suppresses Calcium Sensitization of Vascular Smooth Muscle

Inhibitor κB Kinase

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