scholarly journals Differential volume regulation and calcium signaling in two ciliary body cell types is subserved by TRPV4 channels

2016 ◽  
Vol 113 (14) ◽  
pp. 3885-3890 ◽  
Author(s):  
Andrew O. Jo ◽  
Monika Lakk ◽  
Amber M. Frye ◽  
Tam T. T. Phuong ◽  
Sarah N. Redmon ◽  
...  
Keyword(s):  
Ciliary Body ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Fluid Secretion ◽  
Cell Types ◽  
Transient Receptor Potential Vanilloid ◽  
Intact Mouse ◽  
Transient Receptor ◽  
Hypotonic Swelling

Fluid secretion by the ciliary body plays a critical and irreplaceable function in vertebrate vision by providing nutritive support to the cornea and lens, and by maintaining intraocular pressure. Here, we identify TRPV4 (transient receptor potential vanilloid isoform 4) channels as key osmosensors in nonpigmented epithelial (NPE) cells of the mouse ciliary body. Hypotonic swelling and the selective agonist GSK1016790A (EC50 ∼33 nM) induced sustained transmembrane cation currents and cytosolic [Ca2+]i elevations in dissociated and intact NPE cells. Swelling had no effect on [Ca2+]i levels in pigment epithelial (PE) cells, whereas depolarization evoked [Ca2+]i elevations in both NPE and PE cells. Swelling-evoked [Ca2+]i signals were inhibited by the TRPV4 antagonist HC067047 (IC50 ∼0.9 μM) and were absent in Trpv4−/− NPE. In NPE, but not PE, swelling-induced [Ca2+]i signals required phospholipase A2 activation. TRPV4 localization to NPE was confirmed with immunolocalization and excitation mapping approaches, whereas in vivo MRI analysis confirmed TRPV4-mediated signals in the intact mouse ciliary body. Trpv2 and Trpv4 were the most abundant vanilloid transcripts in CB. Overall, our results support a model whereby TRPV4 differentially regulates cell volume, lipid, and calcium signals in NPE and PE cell types and therefore represents a potential target for antiglaucoma medications.

scholarly journals Novel role of transient receptor potential vanilloid 2 in the regulation of cardiac performance

2014 ◽  
Vol 306 (4) ◽  
pp. H574-H584 ◽  
Author(s):  
Jack Rubinstein ◽  
Valerie M. Lasko ◽  
Sheryl E. Koch ◽  
Vivek P. Singh ◽  
Vinicius Carreira ◽  
...  
Keyword(s):  
Vascular Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Wild Type ◽  
Transient Receptor ◽  
Systolic And Diastolic Function ◽  
Myocyte Contractility

Transient receptor potential cation channels have been implicated in the regulation of cardiovascular function, but only recently has our laboratory described the vanilloid-2 subtype (TRPV2) in the cardiomyocyte, though its exact mechanism of action has not yet been established. This study tests the hypothesis that TRPV2 plays an important role in regulating myocyte contractility under physiological conditions. Therefore, we measured cardiac and vascular function in wild-type and TRPV2−/− mice in vitro and in vivo and found that TRPV2 deletion resulted in a decrease in basal systolic and diastolic function without affecting loading conditions or vascular tone. TRPV2 stimulation with probenecid, a relatively selective TRPV2 agonist, caused an increase in both inotropy and lusitropy in wild-type mice that was blunted in TRPV2−/− mice. We examined the mechanism of TRPV2 inotropy/lusitropy in isolated myocytes and found that it modulates Ca2+ transients and sarcoplasmic reticulum Ca2+ loading. We show that the activity of this channel is necessary for normal cardiac function and that there is increased contractility in response to agonism of TRPV2 with probenecid.

Abstract 358: Transient Receptor Potential Vanilloid 2 (TRPV2) contributes to myocardial contractility and hypertrophy via sarcoplasmic reticulum calcium handling

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Jack Rubinstein ◽  
Vivek P Singh ◽  
Valerie M Lasko ◽  
Sheryl E Koch ◽  
Evangelia Kranias ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Fold Increase ◽  
Calcium Handling ◽  
Heart Weight ◽  
Transient Receptor Potential Vanilloid ◽  
Cardiomyocyte Contractility ◽  
Transient Receptor

Background: TRPV2 is a Ca2+ channel that we have recently discovered in cardiomyocytes. The absence of this channel negatively impacts baseline contractility while stimulation results in a positive inotropic response. What remains to be established is the mechanism of this receptor and its role, if any, in the development of hypertrophy. Methods and Results: We obtained isolated cardiomyocytes from wild type (WT) and TRPV2-/- (KO) mice and found that the sarcoplasmic reticulum Ca2+ content and Ca2+ transients were reduced along with fractional shortening in the KO cardiomyocytes (figure, panels A, B, C). In vivo echocardiography confirmed a decrease in ejection fraction in KO mice in comparison to the WT counterparts (panel D). The relevance of these findings was examined in 6 WT and 5 KO mice subjected to transverse aortic constriction (TAC). These mice were followed by echocardiography weekly for a total of 8 weeks post TAC. At the conclusion, the hearts were obtained for histological and molecular analyses. We demonstrated that the KO mice developed less LV hypertrophy in comparison to WT (via echocardiography and by heart weight/body weight ratios) (figure, panels E and F). Importantly, there was a 5 fold increase in TRPV2 expression assessed by PCR in TAC WT hearts, compared to WT not subjected to TAC (0.72±0.10 vs. 0.13±0.04; p<0.01). This suggests a role for TRPV2 not only in contractility, but also in the development of hypertrophy. Conclusions: We have discovered a novel cardiac channel that alters Ca2+ cycling and is capable of modulating cardiomyocyte contractility and hypertrophy, which could lead to novel therapeutic options in heart failure and hypertrophy.

scholarly journals Prof. Transient receptor potential vanilloid 4 promotes the growth of non-small cell lung cancer by regulating Foxp3

2022 ◽  
Author(s):  
Jiang-tao Pu ◽  
Tao Zhang ◽  
Kai-ming He ◽  
Deng-guo Zhang ◽  
Zhang-yu Teng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transient Receptor Potential ◽  
A549 Cells ◽  
Receptor Potential ◽  
Small Cell ◽  
Transient Receptor Potential Vanilloid ◽  
Small Cell Lung ◽  
Transient Receptor ◽  
Nsclc Patients

Objective(s): Transient receptor potential vanilloid 4 (TRPV4) participates in malignant tumor. However, the role of TRPV4 in non-small cell lung cancer (NSCLC) remains unclear. In this study, we demonstrated TRPV4 was upregulated in NSCLC tissues and NSCLC cell lines. Materials and Methods: TRPV4 level in the NSCLC patients and cell lines were detected, and its function was studied both in vivo and vitro. Results: The level of TRPV4 showed a positive correlation with tumor size of NSCLC patients. Activation TRPV4 by agonist GSK1016790A promoted cell proliferation and decreased apoptosis in A549 cells, and these effects were enhanced when the cells have overexpressed TRPV4. Moreover, GSK1016790A induced inhibitory effects on apoptosis of A549 cells was impaired when GSK1016790A used together with TRPV4 selective antagonist HC-067047, or impaired when the cells have already downregulated TRPV4 expression by TRPV4 siRNA. In vivo study, pharmacological inhibition of TRPV4 prevented A549 cells transplanted tumor growth. It was showed Foxp3 level was significantly increased in the NSCLC tissues, and showed a positive correlation with the level of TRPV4. Deactivation of TRPV4 using TRPV4 siRNA or HC-067047 significantly reduced expression of Foxp3 in GSK1016790A treated NSCLC cells. Moreover, downregulation Foxp3 by transfection of Foxp3 siRNA significantly impaired TRPV4 induced NSCLC cells proliferations in vitro. Conclusions: Antitumor effects caused by TRPV4 inhibition in NSCLC might be attributed to the suppression of Foxp3 which induced subsequent cell apoptosis. Thus, pharmacological inhibition of TRPV4 may be a promising option for NSCLC treatment.  

Activation of Transient Receptor Potential Vanilloid 3 Channel Suppresses Adipogenesis

Endocrinology ◽  
2015 ◽  
Vol 156 (6) ◽  
pp. 2074-2086 ◽  
Author(s):  
Sin Ying Cheung ◽  
Yu Huang ◽  
Hiu Yee Kwan ◽  
Hau Yin Chung ◽  
Xiaoqiang Yao
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
In Vivo Studies ◽  
Transient Receptor Potential Vanilloid ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
High Fat Diets ◽  
Transient Receptor ◽  
Fat Diets

Abstract The present study shows that activation of the transient receptor potential vanilloid 3 channel (TRPV3) suppresses adipocyte differentiation. We also found that a major functional catechin compound in green tea and cocoa, (−)-epicatechin, exerts antiadipogenic effects in the adipocytes through direct activation of TRPV3. TRPV3 was detected in the 3T3-L1 adipocytes using immunohistochemistry and semiquantitative PCR. TRPV3 activation by activators (−)-epicatechin and diphenylborinic anhydride was determined using live cell fluorescent Ca2+ imaging and patch-clamp electrophysiology. Using RNA interference, immunoblotting, and Oil red O staining, we found that the TRPV3 agonists prevented adipogenesis by inhibiting the phosphorylation of insulin receptor substrate 1, the downstream phosphoinositide 3-kinase/Akt/forkhead box protein O1 axis, and the expression of the adipogenic genes peroxisome proliferator–activated receptor γ and CCAAT/enhancer-binding protein α. TRPV3 overexpression hindered adipogenesis in the 3T3-L1 cells. In vivo studies showed that chronic treatment with the TRPV3 activators prevented adipogenesis and weight gain in the mice fed on high-fat diets. Moreover, TRPV3 expression was reduced in the visceral adipose tissue from mice fed on high-fat diets and obese (ob/ob) and diabetic (db/m+) mice. In conclusion, our study illustrates the antiadipogenic role of TRPV3 in the adipocytes.

scholarly journals Regulation of the epithelial Ca2+ channel TRPV5 by reversible histidine phosphorylation mediated by NDPK-B and PHPT1

2014 ◽  
Vol 25 (8) ◽  
pp. 1244-1250 ◽  
Author(s):  
Xinjiang Cai ◽  
Shekhar Srivastava ◽  
Sheena Surindran ◽  
Zhai Li ◽  
Edward Y. Skolnik
Keyword(s):  
Transient Receptor Potential ◽  
Nucleoside Diphosphate Kinase ◽  
Receptor Potential ◽  
Whole Body ◽  
Transient Receptor Potential Vanilloid ◽  
Channel Activity ◽  
Transient Receptor ◽  
Histidine Phosphorylation ◽  
Carboxy Terminal

The kidney, together with bone and intestine, plays a crucial role in maintaining whole-body calcium (Ca2+) homoeostasis, which is primarily mediated by altering the reabsorption of Ca2+ filtered by the glomerulus. The transient receptor potential-vanilloid-5 (TRPV5) channel protein forms a six- transmembrane Ca2+-permeable channel that regulates urinary Ca2+ excretion by mediating active Ca2+ reabsorption in the distal convoluted tubule of the kidney. Here we show that the histidine kinase, nucleoside diphosphate kinase B (NDPK-B), activates TRPV5 channel activity and Ca2+ flux, and this activation requires histidine 711 in the carboxy-terminal tail of TRPV5. In addition, the histidine phosphatase, protein histidine phosphatase 1, inhibits NDPK-B–activated TRPV5 in inside/out patch experiments. This is physiologically relevant to Ca2+ reabsorption in vivo, as short hairpin RNA knockdown of NDPK-B leads to decreased TRPV5 channel activity, and urinary Ca2+ excretion is increased in NDPK-B−/− mice fed a high-Ca2+ diet. Thus these findings identify a novel mechanism by which TRPV5 and Ca2+ reabsorption is regulated by the kidney and support the idea that histidine phosphorylation plays other, yet-uncovered roles in mammalian biology.

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