scholarly journals TRPV4 is activated by mechanical stimulation to induce prostaglandins release in trabecular meshwork, lowering intraocular pressure

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258911
Author(s):  
Takatoshi Uchida ◽  
Shota Shimizu ◽  
Reiko Yamagishi ◽  
Suzumi M. Tokuoka ◽  
Yoshihiro Kita ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Intraocular Pressure ◽  
Mechanical Stimulation ◽  
Trabecular Meshwork ◽  
Cellular Response ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mechanical Stretch ◽  
Therapeutic Benefits ◽  
Aqueous Outflow

Trabecular meshwork constitutes the conventional outflow pathway and controls intraocular pressure by regulating aqueous outflow. Mechanical stimulation has been studied as one of the triggers to regulate aqueous outflow in trabecular meshwork, but it is not well understood. We investigated that how transient receptor potential cation channel subfamily V member 4 (TRPV4) functions in human trabecular meshwork cells (HTMC) and affects intraocular pressure (IOP). HTMC were treated with TRPV4 siRNA, followed by incubation for 24 hours. We confirmed the suppression of TRPV4 mRNA expression and the reduction of Ca2+ influx by the TRPV4 agonist GSK1016790A in TRPV4 siRNA-treated HTMC. TRPV4 siRNA-treated HTMC exhibited a significant reduction in Ca2+ influx and production of arachidonic acid and prostaglandin (PG) E2 induced by mechanical stretch, and direct activation of TRPV4 by GSK1016790A increased production of arachidonic acid, PGE2, and PGD2 and inhibited gel contraction. Furthermore, TRPV4-deficient mice had higher IOP than wild-type mice, and GSK1016790A administration lowered IOP. These results suggest that TRPV4 mediates the cellular response induced by trabecular meshwork stretch, leading to IOP reduction through the production of prostaglandins and inhibition of cell contraction. Targeting TRPV4 may have therapeutic benefits that lead to lowering IOP in glaucoma patients.

scholarly journals Mechanical stretch induces Ca2+ influx and extracellular release of PGE2 through Piezo1 activation in trabecular meshwork cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takatoshi Uchida ◽  
Shota Shimizu ◽  
Reiko Yamagishi ◽  
Suzumi M. Tokuoka ◽  
Yoshihiro Kita ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Intraocular Pressure ◽  
Trabecular Meshwork ◽  
Pressure Fluctuations ◽  
Mechanical Stretch ◽  
Cell Contraction ◽  
Trabecular Meshwork Cells ◽  
Extracellular Release ◽  
Main Pathway ◽  
Outflow Pathway

AbstractThe trabecular meshwork (TM) constitutes the main pathway for aqueous humor drainage and is exposed to complex intraocular pressure fluctuations. The mechanism of homeostasis in which TM senses changes in intraocular pressure and leads to normal levels of outflow resistance is not yet well understood. Previous reports have shown that Piezo1, a mechanically-activated cation channel, is expressed in TM and isolated TM cells. Therefore, we tested hypothesis that Piezo1 may function in response to membrane tension and stretch in TM. In human trabecular meshwork (hTM) cells, PIEZO1 was showed to be abundantly expressed, and Piezo1 agonist Yoda1 and mechanical stretch caused a Piezo1-dependent Ca2+ influx and release of arachidonic acid and PGE2. Treatment with Yoda1 or PGE2 significantly inhibited hTM cell contraction. These results suggest that mechanical stretch stimuli in TM activates Piezo1 and subsequently regulates TM cell contraction by triggering Ca2+ influx and release of arachidonic acid and PGE2. Thus, Piezo1 could acts as a regulator of intraocular pressure (IOP) within the conventional outflow pathway and could be a novel therapeutic strategy to modulate IOP in glaucoma patients.

scholarly journals Morphological changes in the trabecular meshwork and Schlemm’s canal after treatment with topical intraocular pressure-lowering agents

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ji-Hye Park ◽  
Hyun Woo Chung ◽  
Eun Gyu Yoon ◽  
Min Jung Ji ◽  
Chungkwon Yoo ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Trabecular Meshwork ◽  
Morphological Changes ◽  
Open Angle Glaucoma ◽  
Anterior Segment ◽  
Schlemm’S Canal ◽  
Schlemm's Canal ◽  
Before And After ◽  
Treatment Naïve ◽  
Aqueous Outflow

AbstractGlaucoma treatment is usually initiated with topical medication that lowers the intraocular pressure (IOP) by reducing the aqueous production, enhancing the aqueous outflow, or both. However, the effect of topical IOP-lowering medications on the microstructures of the aqueous outflow pathway are relatively unknown. In this retrospective, observational study, 56 treatment-naïve patients with primary open-angle glaucoma were enrolled. Images of the nasal and temporal corneoscleral limbus were obtained using anterior segment optical coherence tomography (AS-OCT). The conjunctival vessels and iris anatomy were used as landmarks to select the same limbal area scan, and the trabecular meshwork (TM) width, TM thickness, and Schlemm’s canal (SC) area were measured before and after using the IOP-lowering agents for 3 months. Among the 56 patients enrolled, 33 patients used prostaglandin (PG) analogues, and 23 patients used dorzolamide/timolol fixed combination (DTFC). After 3 months of DTFC usage, the TM width, TM thickness, and SC area did not show significant changes in either the nasal or temporal sectors. Conversely, after prostaglandin analog usage, the TM thickness significantly increased, and the SC area significantly decreased (all P < 0.01). These findings warrant a deeper investigation into their relationship to aqueous outflow through the conventional and unconventional outflow pathways after treatment with PG analogues.

scholarly journals Anatomical and functional characterization of a duodeno-pancreatic neural reflex that can induce acute pancreatitis

2013 ◽  
Vol 304 (5) ◽  
pp. G490-G500 ◽  
Author(s):  
Cuiping Li ◽  
Yaohui Zhu ◽  
Mohan Shenoy ◽  
Reetesh Pai ◽  
Liansheng Liu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Cross Talk ◽  
Mechanical Stimulation ◽  
Transient Receptor Potential ◽  
Functional Characterization ◽  
Receptor Potential ◽  
Splanchnic Nerve ◽  
Mustard Oil ◽  
Myeloperoxidase Activity ◽  
Stimulation Of

Neural cross talk between visceral organs may play a role in mediating inflammation and pain remote from the site of the insult. We hypothesized such a cross talk exists between the duodenum and pancreas, and further it induces pancreatitis in response to intraduodenal toxins. A dichotomous spinal innervation serving both the duodenum and pancreas was examined, and splanchnic nerve responses to mechanical stimulation of these organs were detected. This pathway was then excited on the duodenal side by exposure to ethanol followed by luminal mustard oil to activate transient receptor potential subfamily A, member 1 (TRPA1). Ninety minutes later, pancreatic inflammation was examined. Ablation of duodenal afferents by resiniferatoxin (RTX) or blocking TRPA1 by Chembridge (CHEM)-5861528 was used to further investigate the duodeno-pancreatic neural reflex via TRPA1. ∼40% of dorsal root ganglia (DRG) from the spinal cord originated from both duodenum and pancreas via dichotomous peripheral branches; ∼50% splanchnic nerve single units responded to mechanical stimulation of both organs. Ethanol sensitized TRPA1 currents in cultured DRG neurons. Pancreatic edema and myeloperoxidase activity significantly increased after intraduodenal ethanol followed by mustard oil (but not capsaicin) but significantly decreased after ablation of duodenal afferents by using RTX or blocking TRPA1 by CHEM-5861528. We found the existence of a neural cross talk between the duodenum and pancreas that can promote acute pancreatitis in response to intraduodenal chemicals. It also proves a previously unexamined mechanism by which alcohol can induce pancreatitis, which is novel both in terms of the site (duodenum), process (neurogenic), and receptor (TRPA1).

Abstract 044: Transient Receptor Potential Channel 6 (TRPC6) Is An Important Mediator Of Mechanical Stretch Responses In The Atrial Endocardial Endothelium.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Vesna Nikolova-Krstevski ◽  
Soeren Wagner ◽  
Oliver Friedrich ◽  
Diane Fatkin
Keyword(s):  
Mechanical Stress ◽  
Transient Receptor Potential ◽  
Volume Overload ◽  
Receptor Potential ◽  
Mechanical Stretch ◽  
Transient Receptor Potential Channel ◽  
Cyclic Stretch ◽  
Mechanical Stimuli ◽  
Important Mediator ◽  
Endocardial Endothelium

Atrial fibrillation (AF) is the most common heart arrhythmia and a major risk factor for thromboembolic stroke and hearth failure. Atrial pressure and/or volume overload that cause increased mechanical stretch in the atrium are the common features of the diseases that cause AF. The latter suggests that mechanical stress has a major role in the pathogenesis of AF. The atrial endocardial endothelium (AE) is the interface between the myocardium and the circulating blood but its role in the mechanotransduction in the atrium is unknown. Endothelial cells (EC) are very sensitive and responsive to external mechanical stimuli and AE dysfunction has been reported in individuals with AF. We therefore hypothesized that the AE is an important mediator of stretch responses in the atrium and that stretch-induced AE dysfunction may be critical for initiation and/or maintenance of AF. We investigated the AE responses to increased mechanical stress by subjecting novel primary AE cells to mechanical stretch. The mechanical stretch conditions included cyclic stretch of 30 cycles/min at 10 percent displacement. The AE cells were stretched for 1-10 min, and 1, 4, 8, and 24h. Changes in the cell shape with elongation, hypertrophy and re-alignment of the cells and their stress fibres in a direction perpendicular to the lines of stretch were first observed after 1h of stretch. TRPC6 is a stretch sensitive ion channel and important regulator of Ca2+-signalling in the EC cells. Immunostaining and Western blot analysis showed redistribution and changed levels of expression of TRPC6 in the stretched AE cells, respectively. The latter suggested changed TRPC6 activity which was evaluated by measuring extracellular Ca2+ influx through the TRPC6 channels in the AE cells under baseline and stretch conditions. We found that short-stretch (1-10min) increased TRPC6 activity, while the long stretch (1-24h) silenced it. Based on these findings it could be concluded that TRPC6 is an important mediator of the mechanical stretch responses in the AE; the functional consequences of the altered channel activity are predetermined by the duration of the stretch-stimulus; and TRPC6 changes in the stretched AE may cause AE dysfunction through altered Ca2+ signalling that contributes to AF development.

scholarly journals TREK-1 channels regulate pressure sensitivity and calcium signaling in trabecular meshwork cells

2018 ◽  
Vol 150 (12) ◽  
pp. 1660-1675 ◽  
Author(s):  
Oleg Yarishkin ◽  
Tam T.T. Phuong ◽  
Colin A. Bretz ◽  
Kenneth W. Olsen ◽  
Jackson M. Baumann ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Trabecular Meshwork ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Gene Profiling ◽  
Resting Membrane Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Pressure Sensitivity ◽  
Trabecular Meshwork Cells ◽  
Transient Receptor

Mechanotransduction by the trabecular meshwork (TM) is an essential component of intraocular pressure regulation in the vertebrate eye. This process is compromised in glaucoma but is poorly understood. In this study, we identify transient receptor potential vanilloid isoform 4 (TRPV4) and TWIK-related potassium channel-1 (TREK-1) as key molecular determinants of TM membrane potential, pressure sensitivity, calcium homeostasis, and transcellular permeability. We show that resting membrane potential in human TM cells is unaffected by “classical” inhibitors of voltage-activated, calcium-activated, and inwardly rectifying potassium channels but is depolarized by blockers of tandem-pore K+ channels. Using gene profiling, we reveal the presence of TREK-1, TASK-1, TWIK-2, and THIK transcripts in TM cells. Pressure stimuli, arachidonic acid, and TREK-1 activators hyperpolarize these cells, effects that are antagonized by quinine, amlodipine, spadin, and short-hairpin RNA–mediated knockdown of TREK-1 but not TASK-1. Activation and inhibition of TREK-1 modulates [Ca2+]TM and lowers the impedance of cell monolayers. Together, these results suggest that tensile homeostasis in the TM may be regulated by balanced, pressure-dependent activation of TRPV4 and TREK-1 mechanotransducers.

scholarly journals Impact of heating on passive and active biomechanics of suspended cells

2014 ◽  
Vol 4 (2) ◽  
pp. 20130069 ◽  
Author(s):  
C. J. Chan ◽  
G. Whyte ◽  
L. Boyde ◽  
G. Salbreux ◽  
J. Guck
Keyword(s):  
Mechanical Properties ◽  
Cell Mechanics ◽  
Cellular Response ◽  
Transient Receptor Potential ◽  
Prolonged Exposure ◽  
Calcium Influx ◽  
Polymer Networks ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Temperature Sensitive

A cell is a complex material whose mechanical properties are essential for its normal functions. Heating can have a dramatic effect on these mechanical properties, similar to its impact on the dynamics of artificial polymer networks. We investigated such mechanical changes by the use of a microfluidic optical stretcher, which allowed us to probe cell mechanics when the cells were subjected to different heating conditions at different time scales. We find that HL60/S4 myeloid precursor cells become mechanically more compliant and fluid-like when subjected to either a sudden laser-induced temperature increase or prolonged exposure to higher ambient temperature. Above a critical temperature of 52 ± 1°C, we observed active cell contraction, which was strongly correlated with calcium influx through temperature-sensitive transient receptor potential vanilloid 2 (TRPV2) ion channels, followed by a subsequent expansion in cell volume. The change from passive to active cellular response can be effectively described by a mechanical model incorporating both active stress and viscoelastic components. Our work highlights the role of TRPV2 in regulating the thermomechanical response of cells. It also offers insights into how cortical tension and osmotic pressure govern cell mechanics and regulate cell-shape changes in response to heat and mechanical stress.

scholarly journals Endocannabinoids in the gastrointestinal tract

2016 ◽  
Vol 311 (4) ◽  
pp. G655-G666 ◽  
Author(s):  
Yunna Lee ◽  
Jeongbin Jo ◽  
Hae Young Chung ◽  
Charalabos Pothoulakis ◽  
Eunok Im
Keyword(s):  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Receptor Potential ◽  
Gastrointestinal Diseases ◽  
Transient Receptor Potential Channels ◽  
Therapeutic Benefits ◽  
Potential Channels ◽  
Transient Receptor

The endocannabinoid system mainly consists of endogenously produced cannabinoids (endocannabinoids) and two G protein-coupled receptors (GPCRs), cannabinoid receptors 1 and 2 (CB1 and CB2). This system also includes enzymes responsible for the synthesis and degradation of endocannabinoids and molecules required for the uptake and transport of endocannabinoids. In addition, endocannabinoid-related lipid mediators and other putative endocannabinoid receptors, such as transient receptor potential channels and other GPCRs, have been identified. Accumulating evidence indicates that the endocannabinoid system is a key modulator of gastrointestinal physiology, influencing satiety, emesis, immune function, mucosal integrity, motility, secretion, and visceral sensation. In light of therapeutic benefits of herbal and synthetic cannabinoids, the vast potential of the endocannabinoid system for the treatment of gastrointestinal diseases has been demonstrated. This review focuses on the role of the endocannabinoid system in gut homeostasis and in the pathogenesis of intestinal disorders associated with intestinal motility, inflammation, and cancer. Finally, links between gut microorganisms and the endocannabinoid system are briefly discussed.

scholarly journals Structural and Biological Basis for Proprioception

2021 ◽  
Author(s):  
José A. Vega ◽  
Juan Cobo
Keyword(s):  
Transient Receptor Potential ◽  
Neurological Diseases ◽  
Receptor Potential ◽  
Mechanical Stretch ◽  
Future Research ◽  
Small Subset ◽  
Transient Receptor Potential Vanilloid ◽  
Golgi Tendon Organs ◽  
Tendon Organs ◽  
Transient Receptor

The proprioception is the sense of positioning and movement. It is mediate by proprioceptors, a small subset of mechanosensory neurons localized in the dorsal root ganglia that convey information about the stretch and tension of muscles, tendons, and joints. These neurons supply of afferent innervation to specialized sensory organs in muscles (muscle spindles) and tendons (Golgi tendon organs). Thereafter, the information originated in the proprioceptors travels throughout two main nerve pathways reaching the central nervous system at the level of the spinal cord and the cerebellum (unconscious) and the cerebral cortex (conscious) for processing. On the other hand, since the stimuli for proprioceptors are mechanical (stretch, tension) proprioception can be regarded as a modality of mechanosensitivity and the putative mechanotransducers proprioceptors begins to be known now. The mechanogated ion channels acid-sensing ion channel 2 (ASIC2), transient receptor potential vanilloid 4 (TRPV4) and PIEZO2 are among candidates. Impairment or poor proprioception is proper of aging and some neurological diseases. Future research should focus on treating these defects. This chapter intends provide a comprehensive update an overview of the anatomical, structural and molecular basis of proprioception as well as of the main causes of proprioception impairment, including aging, and possible treatments.

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