scholarly journals TRPM4 is required for calcium oscillations downstream from the stretch-activated TRPV4 channel

2021 ◽  
Author(s):  
Oleg Yarishkin ◽  
Tam T. Phuong ◽  
Felix Vazquez-Chona ◽  
Jacques A Bertrand ◽  
Sarah Redmon ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Membrane Surface ◽  
Receptor Potential ◽  
Calcium Oscillations ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Insight Into

Transduction of mechanical information is influenced by physical, chemical and thermal cues but the molecular mechanisms through which transducer activation shapes temporal signaling remain underexplored. In the present study, electrophysiology, histochemistry and functional imaging were combined with gene silencing and heterologous expression to gain insight into calcium signaling downstream from TRPV4 (Transient Receptor Potential Vanilloid 4), a stretch-activated nonselective cation channel. We show that trabecular meshwork (TM) cells, which employ mechanotransduction to actively regulate intraocular pressure, respond to the TRPV4 agonist GSK1016790A with fluctuations in intracellular Ca2+ concentration ([Ca2+]i) and an increase in [Na+]i. [Ca2+]i oscillations coincided with a monovalent cation current that was suppressed by BAPTA, Ruthenium Red and 9-phenanthrol, an inhibitor of TRPM4 (Transient Receptor Potential Melastatin 4) channels. Accordingly, TM cells expressed TRPM4 mRNA, protein at the expected 130-150 kDa and showed punctate TRPM4 immunoreactivity at the membrane surface. Genetic silencing of TRPM4 antagonized TRPV4-evoked oscillatory signaling whereas TRPV4 and TRPM4 co-expression in HEK-293 cells reconstituted the oscillations. Membrane potential recordings indicated that TRPM4-dependent oscillations required release of Ca2+ from internal stores. 9-phenanthrol did not affect the outflow facility in mouse eyes. Collectively, our results show that TRPV4 activity initiates dynamic calcium signaling in TM cells by stimulating TRPM4 channels and intracellular Ca2+ release. These findings provide insight into the complexity of membrane-cytosolic interactions during TRPV4 signaling and may foster strategies to promote homeostatic regulation and counter pathological remodeling within the conventional outflow pathway of the mammalian eye.

scholarly journals Eugenol Inhibits Sodium Currents in Dental Afferent Neurons

2006 ◽  
Vol 85 (10) ◽  
pp. 900-904 ◽  
Author(s):  
C.-K. Park ◽  
H.Y. Li ◽  
K.-Y. Yeon ◽  
S.J. Jung ◽  
S.-Y. Choi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Inhibitory Effect ◽  
Transient Receptor Potential Vanilloid ◽  
Afferent Neurons ◽  
Patch Clamp Technique ◽  
Independent Manner ◽  
Pre Treatment ◽  
Transient Receptor

Although eugenol is widely used in dentistry, little is known about the molecular mechanisms responsible for its anesthetic properties. In addition to calcium channels, recently demonstrated by our group, there could be another molecular target for eugenol. Using a whole-cell patch-clamp technique, we investigated the effect of eugenol on voltage-gated sodium channel currents ( I Na) in rat dental primary afferent neurons identified by retrograde labeling with a fluorescent dye in maxillary molars. Eugenol inhibited action potentials and I Na in both capsaicin-sensitive and capsaicin-insensitive neurons. The pre-treatment with capsazepine, a competitive antagonist of transient receptor potential vanilloid 1 (TRPV1), failed to block the inhibitory effect of eugenol on I Na, suggesting no involvement of TRPV1. Two types of I Na, tetrodotoxin (TTX)-resistant and TTX-sensitive I Na, were inhibited by eugenol. Our results demonstrated that eugenol inhibits I Na in a TRPV1-independent manner. We suggest that I Na inhibition by eugenol contributes to its analgesic effect.

scholarly journals Structural insight into TRPV5 channel function and modulation

2019 ◽  
Vol 116 (18) ◽  
pp. 8869-8878 ◽  
Author(s):  
Shangyu Dang ◽  
Mark K. van Goor ◽  
Daniel Asarnow ◽  
YongQiang Wang ◽  
David Julius ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Calcium Dependent ◽  
Resolution Electron ◽  
Trpv Channels ◽  
Transient Receptor ◽  
Lipid Nanodiscs ◽  
Insight Into

TRPV5 (transient receptor potential vanilloid 5) is a unique calcium-selective TRP channel essential for calcium homeostasis. Unlike other TRPV channels, TRPV5 and its close homolog, TRPV6, do not exhibit thermosensitivity or ligand-dependent activation but are constitutively open at physiological membrane potentials and modulated by calmodulin (CaM) in a calcium-dependent manner. Here we report high-resolution electron cryomicroscopy structures of truncated and full-length TRPV5 in lipid nanodiscs, as well as of a TRPV5 W583A mutant and TRPV5 in complex with CaM. These structures highlight the mechanism of calcium regulation and reveal a flexible stoichiometry of CaM binding to TRPV5.

scholarly journals Relationship between low magnesium status and TRPM6 expression in the kidney and large intestine

2008 ◽  
Vol 294 (6) ◽  
pp. R2001-R2007 ◽  
Author(s):  
Lusliany J. Rondón ◽  
Wouter M. Tiel Groenestege ◽  
Yves Rayssiguier ◽  
Andrzej Mazur
Keyword(s):  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
The Body ◽  
Deficient Diet ◽  
Adequate Diet ◽  
Low Magnesium ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
The Relationship

The body maintains Mg2+ homeostasis by renal and intestinal (re)absorption. However, the molecular mechanisms that mediate transepithelial Mg2+ transport are largely unknown. Transient receptor potential melastatin 6 (TRPM6) was recently identified and shown to function in active epithelial Mg2+ transport in intestine and kidney. To define the relationship between Mg2+ status and TRPM6 expression, we used two models of hypomagnesemia: 1) C57BL/6J mice fed a mildly or severely Mg2+-deficient diet, and 2) mice selected for either low (MgL) or high (MgH) erythrocyte and plasma Mg2+ status. In addition, the mice were subjected to a severely Mg2+-deficient diet. Our results show that C57BL/6J mice fed a severely Mg2+-deficient diet developed hypomagnesemia and hypomagnesuria and showed increased TRPM6 expression in kidney and intestine. When fed a Mg2+-adequate diet, MgL mice presented hypomagnesemia and hypermagnesuria, and lower kidney and intestinal TRPM6 expression, compared with MgH mice. A severely Mg2+-deficient diet led to hypomagnesemia and hypomagnesuria in both strains. Furthermore, this diet induced kidney TRPM6 expression in MgL mice, but not in MgH mice. In conclusion, as shown in C57BL/6J mice, dietary Mg2+-restriction results in increased Mg2+ (re)absorption, which is correlated with increased TRPM6 expression. In MgL and MgH mice, the inherited Mg2+ status is linked to different TRPM6 expression. The MgL and MgH mice respond differently to a low-Mg2+ diet with regard to TRPM6 expression in the kidney, consistent with genetic factors contributing to the regulation of cellular Mg2+ levels. Further studies of these mice strains could improve our understanding of the genetics of Mg2+ homeostasis.

scholarly journals Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation

2020 ◽  
Author(s):  
Mathieu Botte ◽  
Alexander K. C. Ulrich ◽  
Ricardo Adaixo ◽  
David Gnutt ◽  
Andreas Brockmann ◽  
...  
Keyword(s):  
Ion Channel ◽  
Binding Site ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Structural Information ◽  
Critical Role ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Open Conformation ◽  
Transient Receptor

ABSTRACTThe human transient receptor potential vanilloid 4 (hTRPV4) ion channel plays a critical role in a variety of biological processes. Whilst the activation of hTRPV4 gating properties has been reported for a broad spectrum of stimuli, including synthetic 4α-phorbols, the molecular basis of the activation is poorly understood. Here we report the novel cryo-EM structure of the hTRPV4 determined in the presence of the archetypical phorbol acid agonist, 4α-PDD. Complementary mutagenesis experiments support the EM-identified binding site as well as allowing rationalization of disruptive mutants located outside of the 4α-PDD binding site. This work represents the first structural information of hTRPV4 in a ligand-induced open conformation. Together, our data reveal the underlying molecular mechanisms resulting in the opening of the central pore and ion-channel activation and provide a structural template for designing inhibitors targeting the open-state conformation of hTRPV4.

Heartburn Sensation in Non-Erosive Reflux Disease: Pattern of Superficial Sensory Nerves Expressing TRPV1 and Epithelial Cells Expressing ASIC3 Receptors

2021 ◽  
Author(s):  
Ahsen Ustaoglu ◽  
Akinari Sawada ◽  
Chung Lee ◽  
Wei-Yi Lei ◽  
Chien-Lin Chen ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Reflux Disease ◽  
Transient Receptor Potential ◽  
Sensory Nerve ◽  
Receptor Potential ◽  
Sensory Nerves ◽  
Transient Receptor Potential Vanilloid ◽  
Esophageal Mucosa ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

The underlying causes of heartburn, characteristic symptom of gastro-esophageal reflux disease(GERD), remain incompletely understood. Superficial afferent innervation of the esophageal mucosa in nonerosive reflux disease(NERD) may drive nociceptive reflux perception, but its acid-sensing role has not yet been established. Transient receptor potential vanilloid subfamily member-1(TRPV1), transient receptor potential Melastatin 8(TRPM8), and acid sensing ion channel 3(ASIC3) are regulators of sensory nerve activity and could be important reflux-sensing receptors within the esophageal mucosa. We characterised TRPV1, TRPM8, and ASIC3 expression in esophageal mucosa of GERD patients. We studied 10 NERD, 10 erosive reflux disease(ERD), 7 functional heartburn(FH), and 8 Barrett's esophagus(BE) patients. Biopsies obtained from the distal esophageal mucosa were co-stained with TRPV1, TRPM8, or ASIC3, and CGRP, CD45, or E-cadherin. RNA expression of TRPV1, TRPM8, and ASIC3 was assessed using qPCR. NERD patients had significantly increased expression of TRPV1 on superficial sensory nerves compared to ERD (p=0.028) or BE (p=0.017). Deep intrapapillary nerve endings did not express TRPV1 in all phenotypes studied. ASIC3 was exclusively expressed on epithelial cells most significantly in NERD and ERD patients (p=<0.0001). TRPM8 was expressed on submucosal CD45+ leukocytes. Superficial localisation of TRPV1-immunoreactive nerves in NERD, and increased ASIC3 co-expression on epithelial cells in NERD and ERD suggests a mechanism for heartburn sensation. Esophageal epithelial cells may play a sensory role in acid reflux perception and act interdependently with TRPV1-expressing mucosal nerves to augment hypersensitivity in NERD patients, raising the enticing possibility of topical antagonists for these ion channels as a therapeutic option.

scholarly journals Crosstalk Between Vascular Redox and Calcium Signaling in Hypertension Involves TRPM2 (Transient Receptor Potential Melastatin 2) Cation Channel

Hypertension ◽  
2020 ◽  
Vol 75 (1) ◽  
pp. 139-149 ◽  
Author(s):  
Rhéure Alves-Lopes ◽  
Karla B. Neves ◽  
Aikaterini Anagnostopoulou ◽  
Francisco J. Rios ◽  
Silvia Lacchini ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channel ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor
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