Nitric Oxide-Induced Decrease in Calcium Sensitivity of Resistance Arteries Is Attributable to Activation of the Myosin Light Chain Phosphatase and Antagonized by the RhoA/Rho Kinase Pathway

Bolz, Steffen‐Sebastian; Vogel, Lukas; Sollinger, Daniel; Derwand, Roland; Wit, Cor de; Loirand, Gervaise; Pohl, Ulrich

doi:10.1161/01.cir.0000074202.19612.8c

Cited by 123 publications

(113 citation statements)

References 27 publications

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“…The ability of 8-Br-cGMP to dramatically reverse GTP-␥S or agonist-induced activation of RhoA͞Rho-kinase mediated Ca 2ϩ sensitization of force and (8) demonstrates the antagonistic roles of RhoA͞Rho-kinase and cyclic nucleotide-signaling pathways. However, PKG-induced Ca 2ϩ desensitization can also be shown in preparations where the RhoA͞ROK mechanism is inactive (24), and PKG can also increase MLCP activity through interaction between the leucine zipper motifs of PKG1␣ and MYPT1 (6). Because GTP-␥S-induced Ca 2ϩ sensitization did not change with deletion of telokin, it is unlikely that telokin is inhibiting the RhoA͞Rho-kinase pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, results support the hypothesis (3) that in vivo, telokin-induced Ca 2ϩ desensitization and associated decreases in RLC 20 phosphorylation are mediated by acceleration of MLCP activity rather than inhibition of MLCK. NO-induced Ca 2ϩ desensitization in resistance arteries (24) is also thought to reflect activation of MLCP. In the present study, we now show directly that MLCP activity is significantly greater in whole homogenates from WT ileal SM than from telokin KO homogenates, whereas neither MYPT1 nor MLCK content differed.…”

Section: Discussionmentioning

confidence: 99%

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Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca ²⁺ and decreased cGMP-induced relaxation

Khromov¹,

Wang²,

Choudhury³

et al. 2006

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

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Cyclic nucleotides can relax smooth muscle without a change in [Ca 2؉ ]i, a phenomenon termed Ca 2؉ desensitization, contributing to vasodilation, gastrointestinal motility, and airway resistance. The physiological importance of telokin, a 17-kDa smooth musclespecific protein and target for cyclic nucleotide-induced Ca 2؉ desensitization, was determined in telokin null mice bred to a congenic background. Telokin null ileal smooth muscle homogenates compared to wild type exhibited an Ϸ30% decrease in myosin light-chain phosphatase (MLCP) activity, which was reflected in a significant leftward shift (up to 2-fold at pCa 6.3) of the Ca 2؉ force relationship accompanied by an increase in myosin light-chain phosphorylation. No difference in the Ca 2؉ force relationship occurred in telokin WT and knockout (KO) aortas, presumably reflecting the normally Ϸ5-fold lower telokin content in aorta vs. ileum smooth muscle. Ca 2؉ desensitization of contractile force by 8-Br-cGMP was attenuated by 50% in telokin KO intestinal smooth muscle. The rate of force relaxation reflecting MLCP activity, in the presence of 50 M 8-Br-cGMP, was also significantly slowed in telokin KO vs. WT ileum and was rescued by recombinant telokin. Normal thick filaments in telokin KO smooth muscles indicate that telokin is not required for filament formation or stability. Results indicate that a primary role of telokin is to modulate force through increasing MLCP activity and that this effect is further potentiated through phosphorylation by cGMP in telokin-rich smooth tissues. S mooth muscle (SM) myosin II ATPase activity and associated contraction is activated by actin only when Ser-19 of the myosin regulatory light chain (RLC 20 ) is phosphorylated. The extent of RLC 20 phosphorylation is a reflection of the balance between Ca 2ϩ calmodulin-dependent myosin light-chain kinase (MLCK) and myosin light-chain phosphatase (MLCP) activities. Although the major mechanism for initiating contraction is the rise in [Ca 2ϩ ] i , force can be further increased or decreased through signaling pathways that modulate MLCK and͞or MLCP activities giving rise to processes termed Ca 2ϩ sensitization or -desensitization (reviewed in ref. 1). Ca 2ϩ sensitization due to inhibition of MLCP activity is mediated by an agonist G protein-coupled, Ca 2ϩ -independent process that activates RhoA͞Rho-kinase, phosphorylates the myosin regulatory subunit of MLCP (MYPT1), and leads to increased force (1). On the other hand, cyclic nucleotideactivated kinases, in addition to decreasing cytosolic Ca 2ϩ , make a significant contribution to dephosphorylation of RLC 20 and relaxation through Ca 2ϩ -desensitization processes (2-5) and can reverse G protein-coupled Ca 2ϩ sensitization (2, 3). Interaction between the leucine zipper motifs of protein kinase G and MYPT1 leads to direct stimulation of MLCP (6). A role for this interaction in Ca 2ϩ desensitization is supported by the observation that chicken gizzard MYPT1 lacking the leucine zipper motifs is resistant to 8-BrcGMP-induced depho...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca ²⁺ and decreased cGMP-induced relaxation

Khromov¹,

Wang²,

Choudhury³

et al. 2006

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

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“…59 The ROK inhibitor Y-27632 also counteracts S1P-elicited constriction responses in canine basilar arteries 71 as well as in hamster gracilis muscle small resistance arteries. 72 The roles of RhoA/ROK pathway have been documented in several smooth muscle models, but roles of PKC in S1P-dependent contraction remain less completely characterized. When smooth muscle cells are exposed to eNOS-derived NO, cGMP-dependent protein kinase (PKG) gets activated.…”

Section: Vasoconstriction Pathways Elicited By Sphingosine-1-phosphatmentioning

confidence: 99%

“…Of note, in hamster gracilis muscle small resistance arteries, S1P induces acute translocation of the MLCP from cytosol to membrane fractions. 72 5. Sphingosine-1-phosphate overall vessel tone reactions S1P is capable of activating both vasorelaxation responses mediated by eNOS/NO in ECs and vasoconstriction responses mediated by RhoA/ROK pathways in smooth muscle cells.…”

Section: Vasoconstriction Pathways Elicited By Sphingosine-1-phosphatmentioning

confidence: 99%

Sphingosine-1-phosphate and modulation of vascular tone

Igarashi¹,

Michel²

2009

Cardiovascular Research

103

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Sphingosine-1-phosphate (S1P) is a phosphorylated product of sphingosine, the core structure of the class of lipids termed sphingolipids. S1P is a naturally occurring lipid metabolite, and usually is present at a concentration of a few 100 nanomolar in human sera. S1P has been found to exert a diverse set of physiological and pathophysiological responses in mammalian tissues through the activation of heterotrimeric G-proteins that in turn modulate the activity of various downstream effecter molecules. In blood vessels, vascular endothelial cells and smooth muscle cells express specific receptors for S1P that modulate vascular tone. This article will provide a brief overview of S1P metabolism in the vasculature and will discuss some of the pathways whereby S1P regulates intracellular signal transduction pathways in endothelial and smooth muscle cells, leading to the activation of both vasorelaxation and vasoconstriction responses.

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“…Isolated branches of the mesenteric artery system are used in many pharmacological studies of the vascular system [30][31][32] . In mesenteric artery explants from TN-XXL transgenic mice, expression was predominantly found in endothelial cells, with SMC only occasionally showing detectable expression (Fig.…”

Section: Calcium Imaging In Tissue Explantsmentioning

confidence: 99%

Biocompatibility of a genetically encoded calcium indicator in a transgenic mouse model

et al. 2012

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Engineering efforts of genetically encoded calcium indicators predominantly focused on enhancing fluorescence changes, but how indicator expression affects the physiology of host organisms is often overlooked. Here, we demonstrate biocompatibility and widespread functional expression of the genetically encoded calcium indicator Tn-XXL in a transgenic mouse model. To validate the model and characterize potential effects of indicator expression we assessed both indicator function and a variety of host parameters, such as anatomy, physiology, behaviour and gene expression profiles in these mice. We also demonstrate the usefulness of primary cells and organ explants prepared from these mice for imaging applications. Although we find mild signatures of indicator expression that may be further reduced in future sensor generations, the 'green' indicator mice generated provide a well-characterized resource of primary cells and tissues for in vitro and in vivo calcium imaging applications.

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Nitric Oxide-Induced Decrease in Calcium Sensitivity of Resistance Arteries Is Attributable to Activation of the Myosin Light Chain Phosphatase and Antagonized by the RhoA/Rho Kinase Pathway

Cited by 123 publications

References 27 publications

Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca ²⁺ and decreased cGMP-induced relaxation

Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca ²⁺ and decreased cGMP-induced relaxation

Sphingosine-1-phosphate and modulation of vascular tone

Biocompatibility of a genetically encoded calcium indicator in a transgenic mouse model

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Nitric Oxide-Induced Decrease in Calcium Sensitivity of Resistance Arteries Is Attributable to Activation of the Myosin Light Chain Phosphatase and Antagonized by the RhoA/Rho Kinase Pathway

Cited by 123 publications

References 27 publications

Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca 2+ and decreased cGMP-induced relaxation

Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca 2+ and decreased cGMP-induced relaxation

Sphingosine-1-phosphate and modulation of vascular tone

Biocompatibility of a genetically encoded calcium indicator in a transgenic mouse model

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Product

Resources

About

Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca ²⁺ and decreased cGMP-induced relaxation

Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca ²⁺ and decreased cGMP-induced relaxation