Carbachol-induced signaling through Thr696-phosphorylation of myosin phosphatase-targeting subunit 1 (MYPT1) in rat bladder smooth muscle cells

Liu, Benchun; Alwaal, Amjad; Wang, Guifang; Banie, Lia; Lin, Chen; Lin, Guo‐Hao; Lue, Tom F.

doi:10.1007/s11255-016-1303-2

Cited by 6 publications

(5 citation statements)

References 31 publications

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“…Thus, P‐MYPT‐1 is a reflection of RhoA/Rho‐kinase pathway activity, and its excessive levels in GSNOR −/− mouse bladders conceivably lead to excessive smooth muscle contraction and detrusor overactivity. A previous study reported that carbachol activates the RhoA/Rho‐kinase pathway, leading to MYPT‐1 phosphorylation at Thr‐696 and sustained contraction in rat bladder smooth muscle cells . In our present study, basal expression levels of the RhoA/Rho‐kinase pathway were unchanged, but the increased level of phospho‐MYPT‐1 is consistent with increased activity of this pathway.…”

Section: Discussionsupporting

confidence: 83%

cAMP‐dependent regulation of RhoA/Rho‐kinase attenuates detrusor overactivity in a novel mouse experimental model

Akakpo¹,

Musicki²,

Burnett³

2017

BJU International

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Objectives To investigate detrusor function and cAMP activation as a possible target for detrusor overactivity in an experimental model lacking a key denitrosylation enzyme, S-nitrosoglutathione reductase (GSNOR). Materials and Methods GSNOR-deficient (GSNOR−/−) (n=30) and wild-type (WT) mice (n=26) were treated for 7 days with the cAMP activator, colforsin (1mg/kg), or vehicle intraperitoneally. Cystometric studies or molecular analyses of bladder specimens were performed. Bladder function indices and expression levels of proteins that regulate detrusor relaxation (nitric oxide synthase pathway) or contraction (RhoA/Rho-kinase pathway) and oxidative stress were assessed. Student t-test and one-way ANOVA were used. Results GSNOR−/− mice showed a significant increase (P<0.05) in voiding and non-voiding contraction frequencies compared to WT mice (Cohen’s effect size values d = 1.82 and 2.52, respectively). Colforsin normalized these abnormalities (Cohen’s effect size values d = 1.85 and 1.28, respectively). Western blot analyses showed an up-regulation of the RhoA/Rho-kinase pathway reflected by a significant increase (P<0.05) of phosphorylated-MYPT1 expression in GSNOR−/− mouse bladders, which was reversed by colforsin treatment. An increased level (P<0.05) of gp91phox expression in bladders of GSNOR−/− mice was observed without significant change after colforsin treatment. Neuronal and endothelial nitric oxide synthase phosphorylation on Ser-1412 and Ser-1177, respectively, did not differ between GSNOR−/− and WT mouse bladders irrespective of colforsin treatment. Conclusion Impaired denitrosylation is associated with detrusor overactivity that is linked with upregulated RhoA/Rho-kinase signaling. Colforsin reverses physiologic and molecular abnormalities. This study describes a novel model of detrusor overactivity and suggests a possible basis for its treatment.

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Section: Discussionsupporting

confidence: 83%

cAMP‐dependent regulation of RhoA/Rho‐kinase attenuates detrusor overactivity in a novel mouse experimental model

Akakpo¹,

Musicki²,

Burnett³

2017

BJU International

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“…The underlying mechanism of sustained contraction is related to MYPT1 [ 13 ]. Multiple lines of evidence imply that MYPT1 may regulate the biochemical activity of MLCP through multiple mechanisms, thereby regulating MLC phosphorylation and affecting bladder smooth muscle detrusor contraction [ 14 ]. These results suggest that the pathogenesis of DBD may be closely related to MLC phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

Effect of Electroacupuncture on Bladder Dysfunction via Regulation of MLC and MLCK Phosphorylation in a Rat Model of Type 2 Diabetes Mellitus

Han

Gao

Yin

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Previous studies observed have reported that electroacupuncture (EA) is effective in relieving diabetic bladder dysfunction (DBD); however, little is known about the mechanism. Therefore, we explored the effects and mechanisms of EA on DBD in streptozotocin–high-fat diet- (STZ–HFD-) induced diabetic rats. The Sprague-Dawley male rats were divided randomly into four groups: normal group, diabetes mellitus group (DM group), DM with EA treatment group (EA group), and DM with sham EA treatment group (sham EA group). After 8 weeks of EA treatment, the body weight, serum glucose, bladder weight, and cystometrogram were evaluated. The bladder wall thickness was examined by abdominal ultrasound imaging. After the transabdominal ultrasound measurements, hematoxylin-eosin (HE) staining was used to observe the bladder mucosa layer. The bladder detrusor smooth muscle cells (SMCs) and fibroblasts were observed under transmission electron microscopy (TEM). The phospho-myosin light chain (p-MLC), phospho-myosin light chain kinase (p-MLCK), and phospho-myosin phosphatase target subunit 1 (p-MYPT1) levels in the bladder were examined using Western blot. The bladder weight, serum glucose, bladder wall thickness, volume threshold for micturition, and postvoid residual (PVR) volume in the diabetic rats were significantly higher than those in the control animals. EA treatment significantly reduced the bladder weight, bladder wall thickness, volume threshold for micturition, and PVR volume in diabetic rats. EA caused a significant increase in the MLC dephosphorylation and MLCK phosphorylation levels in the group compared to the sham EA and model groups. EA reduced the infiltration of inflammatory cells in the bladder mucosa layer of diabetic rats. In addition, EA repaired the damaged bladder detrusor muscle of diabetic rats by reducing mitochondrial damage of the SMCs and fibroblasts. Therefore, EA could reduce the bladder hypertrophy to ameliorate DBD by reversing the impairment in the mucosa layer and detrusor SMCs, which might be mainly mediated by the regulation of p-MLC and p-MLCK levels.

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“…DKK2 is generally considered to be a direct inhibitor of Wnt binding to the LRP5/LRP6 coreceptor of FZD [56]. In addition, decreased DKK2 expression is seen in melanoma cell lines and tumors [57,58]. Thirdly, Axin2 has similar biochemical and cell biological properties to Axin.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-197 Promotes Metastasis of Hepatocellular Carcinoma by Activating Wnt/β-Catenin Signaling

Wang

Lin

et al. 2018

Cell Physiol Biochem

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Background/Aims: MicroRNA-197 (miR-197) has been shown to play roles in epithelialmesenchymal transition (EMT) and metastasis. The Wnt/β-catenin pathway is associated with EMT, but whether miR-197 regulatesWnt/β-catenin remains unclear. This study was to demonstrate the role of miR-197 on the Wnt/β-catenin pathway in hepatocellular carcinoma (HCC). Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-197 in 105 HCC specimens and 15 HCC cell lines. We tested the predicted target gene of miR-197 using a genetic report system. The role of miR-197 in HCC cell invasion and migration (wound healingand cell invasion and migrationby Transwell assays) and in an HCC xenograft modelwas analyzed. Results: Using a miRNA microarray analysis of HCC specimens and compared with non-metastatic HCC, miR-197 was identified as one of the most upregulated miRNAs in metastatic HCC. miR-197 expression was positively associated with the invasiveness of HCC cell lines. Metastatic HCC cells with high miR-197 expression had Wnt/β-catenin signaling activation. High levels of miR-197 expression also promoted EMT and invasionHCC cells in vitro and in vivo. miR-197 directly targeted Axin-2, Naked cuticle 1 (NKD1), and Dickkopf-related protein 2 (DKK2), leading to inhibition of Wnt/β-catenin signaling. High miR-197 expression was found in HCC specimens from patients with portal vein metastasis;high miR-197 expression correlated to the expression of Axin2, NKD1, and DKK2. Conclusion: miR-197 promotes HCC invasion and metastasis by activating Wnt/β-catenin signaling. miR-197 could possibly be used as a prognostic marker and therapeutic target for HCC.

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Carbachol-induced signaling through Thr696-phosphorylation of myosin phosphatase-targeting subunit 1 (MYPT1) in rat bladder smooth muscle cells

Cited by 6 publications

References 31 publications

cAMP‐dependent regulation of RhoA/Rho‐kinase attenuates detrusor overactivity in a novel mouse experimental model

cAMP‐dependent regulation of RhoA/Rho‐kinase attenuates detrusor overactivity in a novel mouse experimental model

Effect of Electroacupuncture on Bladder Dysfunction via Regulation of MLC and MLCK Phosphorylation in a Rat Model of Type 2 Diabetes Mellitus

MicroRNA-197 Promotes Metastasis of Hepatocellular Carcinoma by Activating Wnt/β-Catenin Signaling

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