TRPV4: A trigger of pathological RhoA activation in neurological disease

Bagnell, Anna M.; Sumner, Charlotte J.; McCray, Brett A.

doi:10.1002/bies.202100288

Cited by 15 publications

(19 citation statements)

References 116 publications

(166 reference statements)

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“…45 As a cell surface-localized ion channel, TRPV4 has been increasingly implicated in the regulation of cellular morphology that is associated with the cytoskeletal remodeling small GTPase RhoA. 46 Our data showed that mechanosensitive TRPV4 channels on the SMC membrane regulated the contraction of SMCs that is closely associated with actin cytoskeleton stress fibers and RhoA phosphorylation, suggesting that it senses intracellular traction force.…”

Section: Original Articlementioning

confidence: 63%

Vascular Smooth Muscle TRPV4 (Transient Receptor Potential Vanilloid Family Member 4) Channels Regulate Vasoconstriction and Blood Pressure in Obesity

et al. 2023

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Background: Vascular endothelium and smooth muscle work together to keep the balance of vasomotor tone and jointly maintain vascular homeostasis. Ca 2+ -permeable ion channel TRPV4 (transient receptor potential vanilloid family member 4) in endothelial cells regulates endothelium-dependent vasodilation and contraction in various states. However, how vascular smooth muscle cell TRPV4 (TRPV4 SMC ) contributes to vascular function and blood pressure regulation in physiological and pathologically obese condition has not been fully studied. Methods: We generated smooth muscle TRPV4-deficient mice and developed diet-induced obese mice model and analyzed the role of TRPV4 SMC in intracellular Ca 2+ ([Ca 2+ ] i ) regulation and vasoconstriction. Vasomotor changes of mouse mesenteric artery were measured by wire, and pressure myography. [Ca 2+ ] i were measured by fluo-4 staining. Blood pressure was recorded by telemetric device. Results: Vascular TRPV4 SMC played different roles in regulating vasomotor tone than endothelial TRPV4 due to their different features of [Ca 2+ ] i regulation. Loss of TRPV4 SMC attenuated U46619- and phenylephrine-induced contraction, suggesting its involvement in regulating vascular contractility. Mesenteric arteries from obese mice showed SMC hyperplasia, suggesting an increased level of TRPV4 SMC . Loss of TRPV4 SMC did not influence the development of obesity but protected mice from obesity-induced vasoconstriction and hypertension. In arteries deficient in SMC TRPV4, SMCs F-actin polymerization and RhoA dephosphorylation were attenuated under contractile stimuli. Moreover, SMC-dependent vasoconstriction was inhibited in human resistance arteries with TRPV4 inhibitor application. Conclusions: Our data identify TRPV4 SMC as a regulator of vascular contraction in both physiological states and pathologically obese mice. TRPV4 SMC contributes to the ontogeny of vasoconstriction and hypertension induced by TRPV4 SMC over-expression in obese mice mesenteric artery.

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Section: Original Articlementioning

confidence: 63%

Vascular Smooth Muscle TRPV4 (Transient Receptor Potential Vanilloid Family Member 4) Channels Regulate Vasoconstriction and Blood Pressure in Obesity

et al. 2023

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“…Although our current studies focus on the effect of RhoA on TRPV4 function, conversely, TRPV4 activity can modulate RhoA unbinding and release 22 . Once TRPV4 is activated, the membrane-bound RhoA is released to regulate cytoskeleton dynamics upon activation by TRPV4-mediated calcium influx 41 .…”

Section: Discussionmentioning

confidence: 99%

Structural insights into TRPV4-Rho GTPase signaling complex function and disease

Kwon

Zhang

McCray

et al. 2023

Preprint

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Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease. Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the apo, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that the interaction strength between TRPV4 and RhoA tunes TRPV4-mediated calcium homeostasis and actin remodeling, and that disruption of TRPV4-RhoA interactions leads to TRPV4-related neuromuscular disease, findings that will guide TRPV4 therapeutics development.

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“…The influx of Ca 2+ is induced by some ion channels such as Piezo-1, transient receptor potential vanilloid 4 (TRPV4) and N -methyl- D -aspartate (NMDA) receptor. Interestingly, Piezo-1 and TRPV4 are activated by mechanical forces such as shear stress and the tension of the plasma membrane; Piezo-1 acts as an upstream regulator for TRPV4 and induces a transient Ca 2+ influx while TRPV4 induces a sustained Ca 2+ influx and activates associated RhoA [ 114 , 115 ]. Activation of TRPV4 is inhibited by phosphatidylinositol 4,5-bisphosphate (PIP 2 ) but the activation of Gα q/11 subunits convert PIP 2 to inositol trisphosphate (IP 3 ) [ 116 , 117 ].…”

Section: The Regulatory Mechanisms Of Cldn-5 By Junctional Proteins A...mentioning

confidence: 99%

The CLDN5 gene at the blood-brain barrier in health and disease

Hashimoto

Münnich

Campbell

2023

Fluids Barriers CNS

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The CLDN5 gene encodes claudin-5 (CLDN-5) that is expressed in endothelial cells and forms tight junctions which limit the passive diffusions of ions and solutes. The blood–brain barrier (BBB), composed of brain microvascular endothelial cells and associated pericytes and end-feet of astrocytes, is a physical and biological barrier to maintain the brain microenvironment. The expression of CLDN-5 is tightly regulated in the BBB by other junctional proteins in endothelial cells and by supports from pericytes and astrocytes. The most recent literature clearly shows a compromised BBB with a decline in CLDN-5 expression increasing the risks of developing neuropsychiatric disorders, epilepsy, brain calcification and dementia. The purpose of this review is to summarize the known diseases associated with CLDN-5 expression and function. In the first part of this review, we highlight the recent understanding of how other junctional proteins as well as pericytes and astrocytes maintain CLDN-5 expression in brain endothelial cells. We detail some drugs that can enhance these supports and are being developed or currently in use to treat diseases associated with CLDN-5 decline. We then summarise mutagenesis-based studies which have facilitated a better understanding of the physiological role of the CLDN-5 protein at the BBB and have demonstrated the functional consequences of a recently identified pathogenic CLDN-5 missense mutation from patients with alternating hemiplegia of childhood. This mutation is the first gain-of-function mutation identified in the CLDN gene family with all others representing loss-of-function mutations resulting in mis-localization of CLDN protein and/or attenuated barrier function. Finally, we summarize recent reports about the dosage-dependent effect of CLDN-5 expression on the development of neurological diseases in mice and discuss what cellular supports for CLDN-5 regulation are compromised in the BBB in human diseases.

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TRPV4: A trigger of pathological RhoA activation in neurological disease

Cited by 15 publications

References 116 publications

Vascular Smooth Muscle TRPV4 (Transient Receptor Potential Vanilloid Family Member 4) Channels Regulate Vasoconstriction and Blood Pressure in Obesity

Vascular Smooth Muscle TRPV4 (Transient Receptor Potential Vanilloid Family Member 4) Channels Regulate Vasoconstriction and Blood Pressure in Obesity

Structural insights into TRPV4-Rho GTPase signaling complex function and disease

The CLDN5 gene at the blood-brain barrier in health and disease

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