scholarly journals Regulation of calcium reabsorption along the rat nephron: a modeling study

2015 ◽  
Vol 308 (6) ◽  
pp. F553-F566 ◽  
Author(s):  
Aurélie Edwards
Keyword(s):  
Transient Receptor Potential ◽  
Stone Formation ◽  
Collecting Duct ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Transepithelial Transport ◽  
Thick Ascending Limb ◽  
Calcium Sensing ◽  
The Impact

We expanded a mathematical model of transepithelial transport along the rat nephron to include the transport of Ca2+ and probe the impact of calcium-sensing mechanisms on Ca2+ reabsorption. The model nephron extends from the medullary thick ascending limb (mTAL) to the inner medullary collecting duct (IMCD). Our model reproduces several experimental findings, such as measurements of luminal Ca2+ concentrations in cortical tubules, and the effects of furosemide or deletion of the transient receptor potential channel vanilloid subtype 5 (TRPV5) on urinary Ca2+ excretion. In vitro microperfusion of rat TAL has demonstrated that activation of the calcium-sensing receptor CaSR lowers the TAL permeability to Ca2+, PCaTAL (Loupy A, Ramakrishnan SK, Wootla B, Chambrey R, de la Faille R, Bourgeois S, Bruneval P, Mandet C, Christensen EI, Faure H, Cheval L, Laghmani K, Collet C, Eladari D, Dodd RH, Ruat M, Houillier P. J Clin Invest 122: 3355, 2012). Our results suggest that this regulatory mechanism significantly impacts renal Ca2+ handling: when plasma Ca2+ concentration ([Ca2+]) is raised by 10%, the CaSR-mediated reduction in PCaTAL per se is predicted to enhance urinary Ca2+ excretion by ∼30%. If high [Ca2+] also induces renal outer medullary potassium (ROMK) inhibition, urinary Ca2+ excretion is further raised. In vitro, increases in luminal [Ca2+] have been shown to activate H+-ATPase pumps in the outer medullary CD and to lower the water permeability of IMCD. Our model suggests that if these responses exhibit the sigmoidal dependence on luminal [Ca2+] that is characteristic of CaSR, then the impact of elevated Ca2+ levels in the CD on urinary volume and pH remains limited. Finally, our model suggests that CaSR inhibitors could significantly reduce urinary Ca2+ excretion in hypoparathyroidism, thereby reducing the risk of calcium stone formation.

scholarly journals Design, Synthesis and In Vitro Experimental Validation of Novel TRPV4 Antagonists Inspired by Labdane Diterpenes

Marine Drugs ◽  
2020 ◽  
Vol 18 (10) ◽  
pp. 519
Author(s):  
Sarah Mazzotta ◽  
Gabriele Carullo ◽  
Aniello Schiano Moriello ◽  
Pietro Amodeo ◽  
Vincenzo Di Marzo ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Biological Activities ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Design Synthesis ◽  
Cellular Assays ◽  
Transient Receptor ◽  
Trpv4 Channel

Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents “natural libraries” of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound 6 was the most active with an IC50 of 5.3 μM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators.

scholarly journals Dissecting independent channel and scaffolding roles of the Drosophila transient receptor potential channel

2005 ◽  
Vol 171 (4) ◽  
pp. 685-694 ◽  
Author(s):  
Tao Wang ◽  
Yuchen Jiao ◽  
Craig Montell
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Loss Of Function ◽  
Visual Transduction ◽  
Channel Function ◽  
Transient Receptor ◽  
The Impact

Drosophila transient receptor potential (TRP) serves dual roles as a cation channel and as a molecular anchor for the PDZ protein, INAD (inactivation no afterpotential D). Null mutations in trp cause impairment of visual transduction, mislocalization of INAD, and retinal degeneration. However, the impact of specifically altering TRP channel function is not known because existing loss-of-function alleles greatly reduce protein expression. In the current study we describe the isolation of a set of new trp alleles, including trp14 with an amino acid substitution juxtaposed to the TRP domain. The trp14 flies stably express TRP and display normal molecular anchoring, but defective channel function. Elimination of the anchoring function alone in trpΔ1272, had minor effects on retinal morphology whereas disruption of channel function caused profound light-induced cell death. This retinal degeneration was greatly suppressed by elimination of the Na+/Ca2+ exchanger, CalX, indicating that the cell death was due primarily to deficient Ca2+ entry rather than disruption of the TRP-anchoring function.

scholarly journals Role of TRPC3 channels in ATP-induced Ca2+ signaling in principal cells of the inner medullary collecting duct

2010 ◽  
Vol 299 (1) ◽  
pp. F225-F233 ◽  
Author(s):  
Monu Goel ◽  
William P. Schilling
Keyword(s):  
Transient Receptor Potential ◽  
Apical Membrane ◽  
Collecting Duct ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Dominant Negative ◽  
Principal Cells ◽  
Basolateral Side ◽  
Influx Pathways

The transient receptor potential channel TRPC3 is exclusively expressed in the apical membrane of principal cells of the collecting duct (CD) both in vivo and in the mouse CD cell line IMCD-3. Previous studies revealed that ATP-induced apical-to-basolateral transepithelial Ca2+ flux across IMCD-3 monolayers is increased by overexpression of TRPC3 and attenuated by a dominant negative TRPC3 construct, suggesting that Ca2+ entry across the apical membrane occurs via TRPC3 channels. To test this hypothesis, we selectively measured the Ca2+ permeability of the apical membrane of fura-2-loaded IMCD-3 cells using the Mn2+ quench technique. Mn2+ influx across the apical membrane was increased 12- to 16-fold by apical ATP and was blocked by the pyrazole derivative BTP2, a known inhibitor of TRPC3 channels, with an IC50 value <100 nM. In contrast, Mn2+ influx was only increased ∼2-fold by basolateral ATP. Mn2+ influx was also activated by apical, but not basolateral, 1-stearoyl-2-acetyl- sn-glycerol (SAG), a known activator of TRPC3 channels. Apical ATP- and SAG-induced Mn2+ influx was increased by overexpression of TRPC3 and completely blocked by expression of the dominant negative TRPC3 construct. Mn2+ influx was also stimulated ∼2-fold by thapsigargin applied to either the apical or basolateral side. Thapsigargin-induced flux was blocked by BTP2 but was unaffected by overexpression of TRPC3 or by dominant negative TRPC3. Apical ATP, but not basolateral ATP, increased transepithelial 45Ca2+ flux. These results demonstrate that the apical membrane of IMCD-3 cells has two distinct Ca2+ influx pathways: 1) a store-operated channel activated by thapsigargin and basolateral ATP and 2) TRPC3 channels activated by apical ATP. Only activation of TRPC3 leads to net transepithelial apical-to-basolateral Ca2+ flux. Furthermore, these results demonstrate that native TRPC3 is not a store-operated channel in IMCD-3 cells.

Caveolae-associated signalling in smooth muscle

2004 ◽  
Vol 82 (5) ◽  
pp. 289-299 ◽  
Author(s):  
Andreas Bergdahl ◽  
Karl Swärd
Keyword(s):  
Smooth Muscle ◽  
Transient Receptor Potential ◽  
Muscle Tone ◽  
Receptor Potential ◽  
Transgenic Animals ◽  
Transient Receptor Potential Channel ◽  
Structural Protein ◽  
Outward Currents ◽  
Transient Receptor

Caveolae are flask-shaped invaginations in the membrane that depend on the contents of cholesterol and on the structural protein caveolin. The organisation of caveolae in parallel strands between dense bands in smooth muscle is arguably unique. It is increasingly recognised, bolstered in large part by recent studies in caveolae deficient animals, that caveolae sequester and regulate a variety of signalling intermediaries. The role of caveolae in smooth muscle signal transduction, as inferred from studies on transgenic animals and in vitro approaches, is the topic of the current review. Both G-protein coupled receptors and tyrosine kinase receptors are believed to cluster in caveolae, and the exciting possibility that caveolae provide a platform for interactions between the sarcoplasmic reticulum and plasmalemmal ion channels is emerging. Moreover, messengers involved in Ca2+ sensitization of myosin phosphorylation and contraction may depend on caveolae or caveolin. Caveolae thus appear to constitute an important signalling domain that plays a role not only in regulation of smooth muscle tone, but also in proliferation, such as seen in neointima formation and atherosclerosis.Key words: caveolin, RhoA, transient receptor potential channel, endothelin, spontaneous transient outward currents.

scholarly journals Modulating the Mechanical Activation of TRPV4 at the Cell-Substrate Interface

2021 ◽  
Vol 8 ◽  
Author(s):  
Setareh Sianati ◽  
Lioba Schroeter ◽  
Jessica Richardson ◽  
Andy Tay ◽  
Shireen R. Lamandé ◽  
...  
Keyword(s):  
Mechanical Activation ◽  
Mammalian Cells ◽  
Transient Receptor Potential ◽  
Point Mutations ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Force Sensor ◽  
Substrate Interface ◽  
Cell Substrate ◽  
The Impact

Ion channels activated by mechanical inputs are important force sensing molecules in a wide array of mammalian cells and tissues. The transient receptor potential channel, TRPV4, is a polymodal, nonselective cation channel that can be activated by mechanical inputs but only if stimuli are applied directly at the interface between cells and their substrate, making this molecule a context-dependent force sensor. However, it remains unclear how TRPV4 is activated by mechanical inputs at the cell-substrate interface, which cell intrinsic and cell extrinsic parameters might modulate the mechanical activation of the channel and how mechanical activation differs from TRPV4 gating in response to other stimuli. Here we investigated the impact of substrate mechanics and cytoskeletal components on mechanically evoked TRPV4 currents and addressed how point mutations associated with TRPV4 phosphorylation and arthropathy influence mechanical activation of the channel. Our findings reveal distinct regulatory modulation of TRPV4 from the mechanically activated ion channel PIEZO1, suggesting the mechanosensitivity of these two channels is tuned in response to different parameters. Moreover, our data demonstrate that the effect of point mutations in TRPV4 on channel activation are profoundly dependent on the gating stimulus.

scholarly journals Generators of Pressure-Evoked Currents in Vertebrate Outer Retinal Neurons

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1288
Author(s):  
Ji-Jie Pang ◽  
Fan Gao ◽  
Samuel M. Wu
Keyword(s):  
Transient Receptor Potential ◽  
Peripheral Vision ◽  
Plexiform Layer ◽  
Outward Current ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Ruthenium Red ◽  
K Channel ◽  
Photoreceptor Outer Segment ◽  
The Impact

(1) Background: High-tension glaucoma damages the peripheral vision dominated by rods. How mechanosensitive channels (MSCs) in the outer retina mediate pressure responses is unclear. (2) Methods: Immunocytochemistry, patch clamp, and channel fluorescence were used to study MSCs in salamander photoreceptors. (3) Results: Immunoreactivity of transient receptor potential channel vanilloid 4 (TRPV4) was revealed in the outer plexiform layer, K+ channel TRAAK in the photoreceptor outer segment (OS), and TRPV2 in some rod OS disks. Pressure on the rod inner segment evoked sustained currents of three components: A) the inward current at <−50 mV (Ipi), sensitive to Co2+; B) leak outward current at ³−80 mV (Ipo), sensitive to intracellular Cs+ and ruthenium red; and C) cation current reversed at ~10 mV (Ipc). Hypotonicity induced slow currents like Ipc. Environmental pressure and light increased the FM 1-43-identified open MSCs in the OS membrane, while pressure on the OS with internal Cs+ closed a Ca2+-dependent current reversed at ~0 mV. Rod photocurrents were thermosensitive and affected by MSC blockers. (4) Conclusions: Rods possess depolarizing (TRPV) and hyperpolarizing (K+) MSCs, which mediate mutually compensating currents between −50 mV and 10 mV, serve as an electrical cushion to minimize the impact of ocular mechanical stress.

scholarly journals trpm7 Regulation of in Vivo Cation Homeostasis and Kidney Function Involves Stanniocalcin 1 and fgf23

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5700-5709 ◽  
Author(s):  
Michael R. Elizondo ◽  
Erine H. Budi ◽  
David M. Parichy
Keyword(s):  
Kidney Function ◽  
Transient Receptor Potential ◽  
Stone Formation ◽  
Fibroblast Growth Factor 23 ◽  
Receptor Potential ◽  
Larval Stages ◽  
Transient Receptor Potential Melastatin ◽  
Cation Homeostasis

The transient receptor potential melastatin 7 (trpm7) channel kinase is a primary regulator of magnesium homeostasis in vitro. Here we show that trpm7 is an important regulator of cation homeostasis as well as kidney function in vivo. Using zebrafish trpm7 mutants, we show that early larvae exhibit reduced levels of both total magnesium and total calcium. Accompanying these deficits, we show that trpm7 mutants express higher levels of stanniocalcin 1 (stc1), a potent regulator of calcium homeostasis. Using transgenic overexpression and morpholino oligonucleotide knockdown, we demonstrate that stc1 modulates both calcium and magnesium levels in trpm7 mutants and in the wild type and that levels of these cations are restored to normal in trpm7 mutants when stc1 activity is blocked. Consistent with defects in both calcium and phosphate homeostasis, we further show that trpm7 mutants develop kidney stones by early larval stages and exhibit increased levels of the anti-hyperphosphatemic factor, fibroblast growth factor 23 (fgf23). Finally, we demonstrate that elevated fgf23 expression contributes to kidney stone formation by morpholino knockdown of fgf23 in trpm7 mutants. Together, these analyses reveal roles for trpm7 in regulating cation homeostasis and kidney function in vivo and implicate both stc1 and fgf23 in these processes.

scholarly journals Transient Receptor Potential Channel, Vanilloid 5, Induces Chondrocyte Apoptosis in a Rat Osteoarthritis Model Through the Mediation of Ca2+ Influx

2018 ◽  
Vol 46 (2) ◽  
pp. 687-698 ◽  
Author(s):  
Yingliang Wei ◽  
Dianbin Zheng ◽  
Xiaocheng Guo ◽  
Min Zhao ◽  
Linlin Gao ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Western Blotting ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Chondrocyte Apoptosis ◽  
Caspase 8 ◽  
Pathological Feature ◽  
Transient Receptor

Background/Aims: Chondrocyte apoptosis is the most common pathological feature in cartilage in osteoarthritis (OA). Transient receptor potential channel vanilloid 5 (TRPV5) is important in regulating calcium ion (Ca2+) influx. Accumulating evidences suggest that Ca2+ is a major intracellular second messenger that can trigger cell apoptosis. Therefore, we investigate the potential role of TRPV5 in mediating Ca2+ influx to promote chondrocyte apoptosis in OA. Methods: The monoiodoacetic acid (MIA)-induced rat OA model was assessed by macroscopic and radiographic analyses. Calmodulin protein immunolocalization was detected by immunohistochemistry. The mRNA and protein level of TRPV5, calmodulin and cleaved caspase-8 in articular cartilage were assessed by real time polymerase chain reaction and western blotting. Primary chondrocytes were isolated and cultured in vitro. TRPV5 small interfering RNA was used to silence TRPV5 in chondrocytes. Then, calmodulin and cleaved caspase-8 were immunolocalized by immunofluorescence in chondrocyte. Fluo-4AM staining was used to assess intracellular Ca2+ to reflect TRPV5 function of mediation Ca2+ influx. Annexin V-fluorescein isothiocyanatepropidium iodide flow cytometric analysis was performed to determine chondrocytes apoptosis. Western blotting techniques were used to measure the apoptosis-related proteins in chondrocyte level. Results: Here, we reported TRPV5 was up-regulated in MIA-induced OA articular cartilage. Ruthenium red (a TRPV5 inhibitor) can relieve progression of joint destruction in vivo which promoted us to demonstrate the effect of TRPV5 in OA. We found that TRPV5 had a specific role in mediating extracellular Ca2+ influx leading to chondrocytes apoptosis in vitro. The apoptotic effect was inhibited even reversed by silencing TRPV5. Furthermore, we found that the increase Ca2+ influx triggered apoptosis by up-regulating the protein of death-associated protein, FAS-associated death domain, cleaved caspase-8, cleaved caspase-3, cleaved caspase-6, and cleaved caspase-7, and the up-regulated proteins were abolished by silencing TRPV5 or 1, 2-bis-(o-Aminophenoxy)-ethane-N,N,N’,N’-tetraacetic acid, tetraacetoxymethyl ester (a Ca2+ chelating agent). Conclusion: The up-regulated TRPV5 could used be as an initiating factor that induces extrinsic chondrocyte apoptosis via the mediation of Ca2+ influx. These findings suggested TRPV5 could be an intriguing mediator for drug target in OA.

scholarly journals Severely blunted allergen-induced pulmonary Th2 cell response and lung hyperresponsiveness in type 1 transient receptor potential channel-deficient mice

2012 ◽  
Vol 303 (6) ◽  
pp. L539-L549 ◽  
Author(s):  
Eda Yildirim ◽  
Michelle A. Carey ◽  
Jeffrey W. Card ◽  
Alexander Dietrich ◽  
Gordon P. Flake ◽  
...  
Keyword(s):  
Cell Response ◽  
Transient Receptor Potential ◽  
Cell Function ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Transient Receptor Potential Channels ◽  
Airway Hyperreactivity ◽  
Th2 Cell ◽  
Transient Receptor

Transient receptor potential channels (TRPCs) are widely expressed and regulate Ca2+entry in the cells that participate in the pathophysiology of airway hyperreactivity, inflammation, and remodeling. In vitro studies point to a role for TRPC1-mediated Ca2+signaling in several of these cell types; however, physiological evidence is lacking. Here we identify TRPC1 signaling as proinflammatory and a regulator of lung hyperresponsiveness during allergen-induced pulmonary response. TRPC1-deficient ( Trpc1−/−) mice are hyposensitive to methacholine challenge and have significantly reduced allergen-induced pulmonary leukocyte infiltration coupled with an attenuated T helper type 2 (Th2) cell response. Upon in vitro allergen exposure, Trpc1−/−splenocytes show impaired proliferation and T cell receptor-induced IL-2 production. A high number of germinal centers in spleens of Trpc1−/−mice and elevated levels of immunoglobulins in their serum are indicative of dysregulated B cell function and homeostasis. Thus we propose that TRPC1 signaling is necessary in lymphocyte biology and in regulation of allergen-induced lung hyperresponsiveness, making TRPC1 a potential target for treatment of immune diseases and asthma.

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