International Journal of Molecular Sciences

Research

Jump to: Review

19 pages, 2208 KiB

Open AccessArticle

The Contribution of TRPA1 to Corneal Thermosensitivity and Blink Regulation in Young and Aged Mice

by Laura Frutos-Rincón, Carolina Luna, Fernando Aleixandre-Carrera, Enrique Velasco, Ariadna Diaz-Tahoces, Víctor Meseguer, Juana Gallar and M. Carmen Acosta

Int. J. Mol. Sci. 2023, 24(16), 12620; https://doi.org/10.3390/ijms241612620 - 9 Aug 2023

Viewed by 1246

Abstract

The role of TRPA1 in the thermosensitivity of the corneal cold thermoreceptor nerve endings was studied in young and aged mice. The contribution of the TRPA1-dependent activity to basal tearing and thermally-evoked blink was also explored. The corneal cold thermoreceptors’ activity was recorded [...] Read more.

The role of TRPA1 in the thermosensitivity of the corneal cold thermoreceptor nerve endings was studied in young and aged mice. The contribution of the TRPA1-dependent activity to basal tearing and thermally-evoked blink was also explored. The corneal cold thermoreceptors’ activity was recorded extracellularly in young (5-month-old) and aged (18-month-old) C57BL/6WT (WT) and TRPA1^−/− knockout (TRPA1-KO) mice at basal temperature (34 °C) and during cooling (15 °C) and heating (45 °C) ramps. The blink response to cold and heat stimulation of the ocular surface and the basal tearing rate were also measured in young animals using orbicularis oculi muscle electromyography (OOemg) and phenol red threads, respectively. The background activity at 34 °C and the cooling- and heating-evoked responses of the cold thermoreceptors were similar in WT and TRPA1-KO animals, no matter the age. Similar to the aged WT mice, in the young and aged TRPA1-KO mice, most of the cold thermoreceptors presented low frequency background activity, a low cooling threshold, and a sluggish response to heating. The amplitude and duration of the OOemg signals correlated with the magnitude of the induced thermal change in the WT but not in the TRPA1-KO mice. The basal tearing was similar in the TRPA1-KO and WT mice. The electrophysiological data suggest that the TRPA1-dependent nerve activity, which declines with age, contributes to detecting the warming of the ocular surface and also to integrating the thermally-evoked reflex blink. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

15 pages, 4171 KiB

Open AccessArticle

L-Carnitine Suppresses Transient Receptor Potential Vanilloid Type 1 Activation in Human Corneal Epithelial Cells

by Alexander Lucius, Sirjan Chhatwal, Monika Valtink, Peter S. Reinach, Aruna Li, Uwe Pleyer and Stefan Mergler

Int. J. Mol. Sci. 2023, 24(14), 11815; https://doi.org/10.3390/ijms241411815 - 23 Jul 2023

Cited by 7 | Viewed by 1830

Abstract

Tear film hyperosmolarity induces dry eye syndrome (DES) through transient receptor potential vanilloid type 1 (TRPV1) activation. L-carnitine is a viable therapeutic agent since it protects against this hypertonicity-induced response. Here, we investigated whether L-carnitine inhibits TRPV1 activation by blocking heat- or capsaicin-induced [...] Read more.

Tear film hyperosmolarity induces dry eye syndrome (DES) through transient receptor potential vanilloid type 1 (TRPV1) activation. L-carnitine is a viable therapeutic agent since it protects against this hypertonicity-induced response. Here, we investigated whether L-carnitine inhibits TRPV1 activation by blocking heat- or capsaicin-induced increases in Ca²⁺ influx or hyperosmotic stress-induced cell volume shrinkage in a human corneal epithelial cell line (HCE-T). Single-cell fluorescence imaging of calcein/AM-loaded cells or fura-2/AM-labeled cells was used to evaluate cell volume changes and intracellular calcium levels, respectively. Planar patch-clamp technique was used to measure whole-cell currents. TRPV1 activation via either capsaicin (20 µmol/L), hyperosmolarity (≈450 mosmol/L) or an increase in ambient bath temperature to 43 °C induced intracellular calcium transients and augmented whole-cell currents, whereas hypertonicity induced cell volume shrinkage. In contrast, either capsazepine (10 µmol/L) or L-carnitine (1–3 mmol/L) reduced all these responses. Taken together, L-carnitine and capsazepine suppress hypertonicity-induced TRPV1 activation by blocking cell volume shrinkage. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

11 pages, 30613 KiB

Open AccessCommunication

Immunohistochemistry Reveals TRPC Channels in the Human Hearing Organ—A Novel CT-Guided Approach to the Cochlea

by Colya N. Englisch, Jakob Steinhäuser, Silke Wemmert, Martin Jung, Joshua Gawlitza, Gentiana Wenzel, Bernhard Schick and Thomas Tschernig

Int. J. Mol. Sci. 2023, 24(11), 9290; https://doi.org/10.3390/ijms24119290 - 26 May 2023

Cited by 5 | Viewed by 3309

Abstract

TRPC channels are critical players in cochlear hair cells and sensory neurons, as demonstrated in animal experiments. However, evidence for TRPC expression in the human cochlea is still lacking. This reflects the logistic and practical difficulties in obtaining human cochleae. The purpose of [...] Read more.

TRPC channels are critical players in cochlear hair cells and sensory neurons, as demonstrated in animal experiments. However, evidence for TRPC expression in the human cochlea is still lacking. This reflects the logistic and practical difficulties in obtaining human cochleae. The purpose of this study was to detect TRPC6, TRPC5 and TRPC3 in the human cochlea. Temporal bone pairs were excised from ten body donors, and the inner ear was first assessed based on computed tomography scans. Decalcification was then performed using 20% EDTA solutions. Immunohistochemistry with knockout-tested antibodies followed. The organ of Corti, the stria vascularis, the spiral lamina, spiral ganglion neurons and cochlear nerves were specifically stained. This unique report of TRPC channels in the human cochlea supports the hypothesis of the potentially critical role of TRPC channels in human cochlear health and disease which has been suggested in previous rodent experiments. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

16 pages, 15115 KiB

Open AccessArticle

Diacylglycerol Activates the Drosophila Light Sensitive Channel TRPL Expressed in HEK Cells

by Elisheva Rhodes-Mordov, Tal Brandwine-Shemmer, Rachel Zaguri, Rita Gutorov, Maximilian Peters and Baruch Minke

Int. J. Mol. Sci. 2023, 24(7), 6289; https://doi.org/10.3390/ijms24076289 - 27 Mar 2023

Cited by 2 | Viewed by 1676

Abstract

Physiological activation by light of the Drosophila TRP and TRP-like (TRPL) channels requires the activation of phospholipase Cβ (PLC). The hydrolysis of phosphatidylinositol 4,5, bisphosphate (PIP₂) by PLC is a crucial step in the still-unclear light activation, while the generation of [...] Read more.

Physiological activation by light of the Drosophila TRP and TRP-like (TRPL) channels requires the activation of phospholipase Cβ (PLC). The hydrolysis of phosphatidylinositol 4,5, bisphosphate (PIP₂) by PLC is a crucial step in the still-unclear light activation, while the generation of Diacylglycerol (DAG) by PLC seems to be involved. In this study, we re-examined the ability of a DAG analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG) to activate the TRPL channels expressed in HEK cells. Unlike previous studies, we added OAG into the cytosol via a patch-clamp pipette and observed robust activation of the expressed TRPL channels. However, TRPL channel activation was much slower than the physiologically activated TRPL by light. Therefore, we used a picosecond-fast optically activated DAG analogue, OptoDArG. Inactive OptoDArG was added into the intracellular solution with the patch-clamp pipette, and it slowly accumulated on the surface membrane of the recorded HEK cell in the dark. A fast application of intense UV light to the recorded cell resulted in a robust and relatively fast TRPL-dependent current that was greatly accelerated by the constitutively active TRPL^F557I pore-region mutation. However, this current of the mutant channel was still considerably slower than the native light-induced TRPL current, suggesting that DAG alone is not sufficient for TRPL channel activation under physiological conditions. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

18 pages, 2196 KiB

Open AccessArticle

Involvement of TRPM7 in Alcohol-Induced Damage of the Blood–Brain Barrier in the Presence of HIV Viral Proteins

by Michelle L. Mack, Wenfei Huang and Sulie L. Chang

Int. J. Mol. Sci. 2023, 24(3), 1910; https://doi.org/10.3390/ijms24031910 - 18 Jan 2023

Cited by 2 | Viewed by 1726

Abstract

Ethanol (EtOH) exerts its effects through various protein targets, including transient receptor potential melastatin 7 (TRPM7) channels, which play an essential role in cellular homeostasis. We demonstrated that TRPM7 is expressed in rat brain microvascular endothelial cells (rBMVECs), the major cellular component of [...] Read more.

Ethanol (EtOH) exerts its effects through various protein targets, including transient receptor potential melastatin 7 (TRPM7) channels, which play an essential role in cellular homeostasis. We demonstrated that TRPM7 is expressed in rat brain microvascular endothelial cells (rBMVECs), the major cellular component of the blood–brain barrier (BBB). Heavy alcohol drinking is often associated with HIV infection, however mechanisms underlying alcohol-induced BBB damage and HIV proteins, are not fully understood. We utilized the HIV-1 transgenic (HIV-1Tg) rat to mimic HIV-1 patients on combination anti-retroviral therapy (cART) and demonstrated TRPM7 expression in rBMVECs wass lower in adolescent HIV-1Tg rats compared to control animals, however control and HIV-1Tg rats expressed similar levels at 9 weeks, indicating persistent presence of HIV-1 proteins delayed TRPM7 expression. Binge exposure to EtOH (binge EtOH) decreased TRPM7 expression in control rBMVECs in a concentration-dependent manner, and abolished TRPM7 expression in HIV-1Tg rats. In human BMVECs (hBMVECs), TRPM7 expression was downregulated after treatment with EtOH, HIV-1 proteins, and in combination. Next, we constructed in vitro BBB models using BMVECs and found TRPM7 antagonists enhanced EtOH-mediated BBB integrity changes. Our study demonstrated alcohol decreased TRPM7 expression, whereby TRPM7 could be involved in the mechanisms underlying BBB alcohol-induced damage in HIV-1 patients on cART. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

13 pages, 3126 KiB

Open AccessArticle

Mechanical Stretch Activates TRPV4 and Hemichannel Responses in the Nonpigmented Ciliary Epithelium

by Mohammad Shahidullah and Nicholas A. Delamere

Int. J. Mol. Sci. 2023, 24(2), 1673; https://doi.org/10.3390/ijms24021673 - 14 Jan 2023

Cited by 4 | Viewed by 1661

Abstract

Previously, we reported a mechanosensitive ion channel, TRPV4, along with functional connexin hemichannels on the basolateral surface of the ocular nonpigmented ciliary epithelium (NPE). In the lens, TRPV4-mediated hemichannel opening is part of a feedback loop that senses and respond to swelling. The [...] Read more.

Previously, we reported a mechanosensitive ion channel, TRPV4, along with functional connexin hemichannels on the basolateral surface of the ocular nonpigmented ciliary epithelium (NPE). In the lens, TRPV4-mediated hemichannel opening is part of a feedback loop that senses and respond to swelling. The present study was undertaken to test the hypothesis that TRPV4 and hemichannels in the NPE respond to a mechanical stimulus. Porcine NPE cells were cultured on flexible membranes to study effects of cyclic stretch and ATP release was determined by a luciferase assay. The uptake of propidium iodide (PI) was measured as an indicator of hemichannel opening. NPE cells subjected to cyclic stretch for 1–10 min (10%, 0.5 Hz) displayed a significant increase in ATP release into the bathing medium. In studies where PI was added to the bathing medium, the same stretch stimulus increased cell PI uptake. The ATP release and PI uptake responses to stretch both were prevented by a TRPV4 antagonist, HC067047 (10 µM), and a connexin mimetic peptide, Gap 27 (200µm). In the absence of a stretch stimulus, qualitatively similar ATP release and PI uptake responses were observed in cells exposed to the TRPV4 agonist GSK1016790A (10 nM), and Gap 27 prevented the responses. Cells subjected to an osmotic swelling stimulus (hypoosmotic medium: 200 mOsm) also displayed a significant increase in ATP release and PI uptake and the responses were abolished by TRPV4 inhibition. The findings point to TRPV4-dependent connexin hemichannel opening in response to mechanical stimulus. The TRPV4-hemichannel mechanism may act as a mechanosensor that facilitates the release of ATP and possibly other autocrine or paracrine signaling molecules that influence fluid (aqueous humor) secretion by the NPE. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

16 pages, 4654 KiB

Open AccessArticle

Anti-Inflammatory Effects of Cannabigerol in Rheumatoid Arthritis Synovial Fibroblasts and Peripheral Blood Mononuclear Cell Cultures Are Partly Mediated by TRPA1

by Torsten Lowin, Marianne Sofia Tigges-Perez, Eva Constant and Georg Pongratz

Int. J. Mol. Sci. 2023, 24(1), 855; https://doi.org/10.3390/ijms24010855 - 3 Jan 2023

Cited by 5 | Viewed by 7421

Abstract

Since its medical legalization, cannabis preparations containing the major phytocannabinoids (cannabidiol (CBD) and δ⁹-tetrahydrocannabinol (THC)) have been used by patients with rheumatoid arthritis (RA) to alleviate pain and inflammation. However, minor cannabinoids such as cannabigerol (CBG) also demonstrated anti-inflammatory properties, but [...] Read more.

Since its medical legalization, cannabis preparations containing the major phytocannabinoids (cannabidiol (CBD) and δ⁹-tetrahydrocannabinol (THC)) have been used by patients with rheumatoid arthritis (RA) to alleviate pain and inflammation. However, minor cannabinoids such as cannabigerol (CBG) also demonstrated anti-inflammatory properties, but due to the lack of studies, they are not widely used. CBG binds several cellular target proteins such as cannabinoid and α2-adrenergic receptors, but it also ligates several members of the transient potential receptor (TRP) family with TRPA1 being the main target. TRPA1 is not only involved in nnociception, but it also protects cells from apoptosis under oxidative stress conditions. Therefore, modulation of TRPA1 signaling by CBG might be used to modulate disease activity in RA as this autoimmune disease is accompanied by oxidative stress and subsequent activation of pro-inflammatory pathways. Rheumatoid synovial fibroblasts (RASF) were stimulated or not with tumor necrosis factor (TNF) for 72 h to induce TRPA1 protein. CBG increased intracellular calcium levels in TNF-stimulated RASF but not unstimulated RASF in a TRPA1-dependent manner. In addition, PoPo3 uptake, a surrogate marker for drug uptake, was enhanced by CBG. RASF cell viability, IL-6 and IL-8 production were decreased by CBG. In peripheral blood mononuclear cell cultures (PBMC) alone or together with RASF, CBG-modulated interleukin (IL)-6, IL-10, TNF and immunoglobulin M and G production which was dependent on activation stimulus (T cell-dependent or independent). However, effects on PBMCs were only partially mediated by TRPA1 as the antagonist A967079 did inhibit some but not all effects of CBG on cytokine production. In contrast, TRPA1 antagonism even enhanced the inhibitory effects of CBG on immunoglobulin production. CBG showed broad anti-inflammatory effects in isolated RASF, PBMC and PBMC/RASF co-cultures. As CBG is non-psychotropic, it might be used as add-on therapy in RA to reduce IL-6 and autoantibody levels. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

21 pages, 4236 KiB

Open AccessArticle

Modulation of Glia Activation by TRPA1 Antagonism in Preclinical Models of Migraine

by Chiara Demartini, Rosaria Greco, Giulia Magni, Anna Maria Zanaboni, Benedetta Riboldi, Miriam Francavilla, Cristina Nativi, Stefania Ceruti and Cristina Tassorelli

Int. J. Mol. Sci. 2022, 23(22), 14085; https://doi.org/10.3390/ijms232214085 - 15 Nov 2022

Cited by 11 | Viewed by 2309

Abstract

Preclinical data point to the contribution of transient receptor potential ankyrin 1 (TRPA1) channels to the complex mechanisms underlying migraine pain. TRPA1 channels are expressed in primary sensory neurons, as well as in glial cells, and they can be activated/sensitized by inflammatory mediators. [...] Read more.

Preclinical data point to the contribution of transient receptor potential ankyrin 1 (TRPA1) channels to the complex mechanisms underlying migraine pain. TRPA1 channels are expressed in primary sensory neurons, as well as in glial cells, and they can be activated/sensitized by inflammatory mediators. The aim of this study was to investigate the relationship between TRPA1 channels and glial activation in the modulation of trigeminal hyperalgesia in preclinical models of migraine based on acute and chronic nitroglycerin challenges. Rats were treated with ADM_12 (TRPA1 antagonist) and then underwent an orofacial formalin test to assess trigeminal hyperalgesia. mRNA levels of pro- and anti-inflammatory cytokines, calcitonin gene-related peptide (CGRP) and glia cell activation were evaluated in the Medulla oblongata and in the trigeminal ganglia. In the nitroglycerin-treated rats, ADM_12 showed an antihyperalgesic effect in both acute and chronic models, and it counteracted the changes in CGRP and cytokine gene expression. In the acute nitroglycerin model, ADM_12 reduced nitroglycerin-induced increase in microglial and astroglial activation in trigeminal nucleus caudalis area. In the chronic model, we detected a nitroglycerin-induced activation of satellite glial cells in the trigeminal ganglia that was inhibited by ADM_12. These findings show that TRPA1 antagonism reverts experimentally induced hyperalgesia in acute and chronic models of migraine and prevents multiple changes in inflammatory pathways by modulating glial activation. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Graphical abstract

19 pages, 2644 KiB

Open AccessArticle

A Comparative Study on the Effect of Acute Pharyngeal Stimulation with TRP Agonists on the Biomechanics and Neurophysiology of Swallow Response in Patients with Oropharyngeal Dysphagia

by Noemí Tomsen, Omar Ortega, Daniel Alvarez-Berdugo, Laia Rofes and Pere Clavé

Int. J. Mol. Sci. 2022, 23(18), 10773; https://doi.org/10.3390/ijms231810773 - 15 Sep 2022

Cited by 5 | Viewed by 2207

Abstract

Fluid thickening is the main compensatory strategy for patients with oropharyngeal dysphagia (OD) associated with aging or neurological diseases, and there is still no pharmacological treatment. We aimed to compare the effects of increasing bolus viscosity with that of acute stimulation with TRPV1, [...] Read more.

Fluid thickening is the main compensatory strategy for patients with oropharyngeal dysphagia (OD) associated with aging or neurological diseases, and there is still no pharmacological treatment. We aimed to compare the effects of increasing bolus viscosity with that of acute stimulation with TRPV1, TRPA1 or TRPM8 agonists on the biomechanics and neurophysiology of swallow response in patients with OD. We retrospectively analyzed seven studies from our laboratory on 329 patients with OD. The effect of increasing shear viscosity up to 3682 mPa·s was compared by videofluoroscopy and pharyngeal sensory evoked potentials (pSEP) with that of adding to the bolus: capsaicin (TRPV1, 150 μM/10 μM), piperine (TRPA1/V1, 1 mM/150 μM), menthol (TRPM8, 1 mM/10 mM), cinnamaldehyde-zinc (TRPA1, 100 ppm–70 mM), citral (TRPA1, 250 ppm) or citral-isopulegol (TRPA1-TRPM8, 250 ppm–200 ppm). Fluid thickening improved the safety of swallow by 80% (p < 0.0001) by delaying bolus velocity by 20.7 ± 7.0% and time to laryngeal vestibule closure (LVC) by 23.1 ± 3.7%. Capsaicin 150μM or piperine 1 mM significantly improved safety of swallow by 50% (p < 0.01) and 57.1% (p < 0.01) by speeding time to LVC by 27.6% (p < 0.001) and 19.5% (p < 0.01) and bolus velocity by 24.8% (p < 0.01) and 16.9% (p < 0.05), respectively. Cinnamaldehyde-zinc shortened the P2 latency of pSEPs by 11.0% (p < 0.01) and reduced N2-P2 amplitude by 35% (p < 0.01). In conclusion, TRPV1 and TRPV1/A1 agonists are optimal candidates to develop new pharmacological strategies to promote the recovery of brain and swallow function in patients with chronic OD. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

17 pages, 13518 KiB

Open AccessArticle

Regulation of the Membrane Trafficking of the Mechanosensitive Ion Channels TRPV1 and TRPV4 by Zonular Tension, Osmotic Stress and Activators in the Mouse Lens

by Yosuke Nakazawa, Rosica S. Petrova, Yuki Sugiyama, Noriaki Nagai, Hiroomi Tamura and Paul J. Donaldson

Int. J. Mol. Sci. 2021, 22(23), 12658; https://doi.org/10.3390/ijms222312658 - 23 Nov 2021

Cited by 8 | Viewed by 2638

Abstract

Lens water transport generates a hydrostatic pressure gradient that is regulated by a dual-feedback system that utilizes the mechanosensitive transient receptor potential vanilloid (TRPV) channels, TRPV1 and TRPV4, to sense changes in mechanical tension and extracellular osmolarity. Here, we investigate whether the modulation [...] Read more.

Lens water transport generates a hydrostatic pressure gradient that is regulated by a dual-feedback system that utilizes the mechanosensitive transient receptor potential vanilloid (TRPV) channels, TRPV1 and TRPV4, to sense changes in mechanical tension and extracellular osmolarity. Here, we investigate whether the modulation of TRPV1 or TRPV4 activity dynamically affects their membrane trafficking. Mouse lenses were incubated in either pilocarpine or tropicamide to alter zonular tension, exposed to osmotic stress, or the TRPV1 and TRPV4 activators capsaicin andGSK1016790A (GSK101), and the effect on the TRPV1 and TRPV4 membrane trafficking in peripheral fiber cells visualized using confocal microscopy. Decreases in zonular tension caused the removal of TRPV4 from the membrane of peripheral fiber cells. Hypotonic challenge had no effect on TRPV1, but increased the membrane localization of TRPV4. Hypertonic challenge caused the insertion of TRPV1 and the removal of TRPV4 from the membranes of peripheral fiber cells. Capsaicin caused an increase in TRPV4 membrane localization, but had no effect on TRPV1; while GSK101 decreased the membrane localization of TRPV4 and increased the membrane localization of TRPV1. These reciprocal changes in TRPV1/4 membrane localization are consistent with the channels acting as mechanosensitive transducers of a dual-feedback pathway that regulates lens water transport. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

Review

Jump to: Research

17 pages, 1020 KiB

Open AccessReview

Pathophysiological Roles of Transient Receptor Potential (Trp) Channels and Zinc Toxicity in Brain Disease

by Dae Ki Hong, A Ra Kho, Song Hee Lee, Beom Seok Kang, Min Kyu Park, Bo Young Choi and Sang Won Suh

Int. J. Mol. Sci. 2023, 24(7), 6665; https://doi.org/10.3390/ijms24076665 - 3 Apr 2023

Cited by 4 | Viewed by 2373

Abstract

Maintaining the correct ionic gradient from extracellular to intracellular space via several membrane-bound transporters is critical for maintaining overall cellular homeostasis. One of these transporters is the transient receptor potential (TRP) channel family that consists of six putative transmembrane segments systemically expressed in [...] Read more.

Maintaining the correct ionic gradient from extracellular to intracellular space via several membrane-bound transporters is critical for maintaining overall cellular homeostasis. One of these transporters is the transient receptor potential (TRP) channel family that consists of six putative transmembrane segments systemically expressed in mammalian tissues. Upon the activation of TRP channels by brain disease, several cations are translocated through TRP channels. Brain disease, especially ischemic stroke, epilepsy, and traumatic brain injury, triggers the dysregulation of ionic gradients and promotes the excessive release of neuro-transmitters and zinc. The divalent metal cation zinc is highly distributed in the brain and is specifically located in the pre-synaptic vesicles as free ions, usually existing in cytoplasm bound with metallothionein. Although adequate zinc is essential for regulating diverse physiological functions, the brain-disease-induced excessive release and translocation of zinc causes cell damage, including oxidative stress, apoptotic cascades, and disturbances in energy metabolism. Therefore, the regulation of zinc homeostasis following brain disease is critical for the prevention of brain damage. In this review, we summarize recent experimental research findings regarding how TRP channels (mainly TRPC and TRPM) and zinc are regulated in animal brain-disease models of global cerebral ischemia, epilepsy, and traumatic brain injury. The blockade of zinc translocation via the inhibition of TRPC and TRPM channels using known channel antagonists, was shown to be neuroprotective in brain disease. The regulation of both zinc and TRP channels may serve as targets for treating and preventing neuronal death. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

17 pages, 1539 KiB

Open AccessReview

New Frontiers on ER Stress Modulation: Are TRP Channels the Leading Actors?

by Vincenzo Vestuto, Veronica Di Sarno, Simona Musella, Giorgio Di Dona, Ornella Moltedo, Isabel Maria Gomez-Monterrey, Alessia Bertamino, Carmine Ostacolo, Pietro Campiglia and Tania Ciaglia

Int. J. Mol. Sci. 2023, 24(1), 185; https://doi.org/10.3390/ijms24010185 - 22 Dec 2022

Cited by 8 | Viewed by 2640

Abstract

The endoplasmic reticulum (ER) is a dynamic structure, playing multiple roles including calcium storage, protein synthesis and lipid metabolism. During cellular stress, variations in ER homeostasis and its functioning occur. This condition is referred as ER stress and generates a cascade of signaling [...] Read more.

The endoplasmic reticulum (ER) is a dynamic structure, playing multiple roles including calcium storage, protein synthesis and lipid metabolism. During cellular stress, variations in ER homeostasis and its functioning occur. This condition is referred as ER stress and generates a cascade of signaling events termed unfolded protein response (UPR), activated as adaptative response to mitigate the ER stress condition. In this regard, calcium levels play a pivotal role in ER homeostasis and therefore in cell fate regulation since calcium signaling is implicated in a plethora of physiological processes, but also in disease conditions such as neurodegeneration, cancer and metabolic disorders. A large body of emerging evidence highlighted the functional role of TRP channels and their ability to promote cell survival or death depending on endoplasmic reticulum stress resolution, making them an attractive target. Thus, in this review we focused on the TRP channels’ correlation to UPR-mediated ER stress in disease pathogenesis, providing an overview of their implication in the activation of this cellular response. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

18 pages, 29944 KiB

Open AccessReview

TRPC Channels in the Physiology and Pathophysiology of the Renal Tubular System: What Do We Know?

by Colya N. Englisch, Friedrich Paulsen and Thomas Tschernig

Int. J. Mol. Sci. 2023, 24(1), 181; https://doi.org/10.3390/ijms24010181 - 22 Dec 2022

Cited by 13 | Viewed by 2849

Abstract

The study of transient receptor potential (TRP) channels has dramatically increased during the past few years. TRP channels function as sensors and effectors in the cellular adaptation to environmental changes. Here, we review literature investigating the physiological and pathophysiological roles of TRPC channels [...] Read more.

The study of transient receptor potential (TRP) channels has dramatically increased during the past few years. TRP channels function as sensors and effectors in the cellular adaptation to environmental changes. Here, we review literature investigating the physiological and pathophysiological roles of TRPC channels in the renal tubular system with a focus on TRPC3 and TRPC6. TRPC3 plays a key role in Ca²⁺ homeostasis and is involved in transcellular Ca²⁺ reabsorption in the proximal tubule and the collecting duct. TRPC3 also conveys the osmosensitivity of principal cells of the collecting duct and is implicated in vasopressin-induced membrane translocation of AQP-2. Autosomal dominant polycystic kidney disease (ADPKD) can often be attributed to mutations of the PKD2 gene. TRPC3 is supposed to have a detrimental role in ADPKD-like conditions. The tubule-specific physiological functions of TRPC6 have not yet been entirely elucidated. Its pathophysiological role in ischemia-reperfusion injuries is a subject of debate. However, TRPC6 seems to be involved in tumorigenesis of renal cell carcinoma. In summary, TRPC channels are relevant in multiples conditions of the renal tubular system. There is a need to further elucidate their pathophysiology to better understand certain renal disorders and ultimately create new therapeutic targets to improve patient care. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

► Show Figures

Figure 1

Journal Menu

Journal Browser

TRP Channels in Physiology and Pathophysiology

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issues

Published Papers (13 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI