scholarly journals Phosphodiesterase 5 inhibition ameliorates angiontensin II-induced podocyte dysmotility via the protein kinase G-mediated downregulation of TRPC6 activity

2014 ◽  
Vol 306 (12) ◽  
pp. F1442-F1450 ◽  
Author(s):  
Gentzon Hall ◽  
Janelle Rowell ◽  
Federica Farinelli ◽  
Rasheed A. Gbadegesin ◽  
Peter Lavin ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Soluble Guanylate Cyclase ◽  
Pde5 Inhibitor ◽  
Receptor Potential ◽  
Nitric Oxide Donor ◽  
Ang Ii ◽  
Calcineurin Phosphatase ◽  
Phosphodiesterase 5

The emerging role of the transient receptor potential cation channel isotype 6 (TRPC6) as a central contributor to various pathological processes affecting podocytes has generated interest in the development of therapeutics to modulate its function. Recent insights into the regulation of TRPC6 have revealed PKG as a potent negative modulator of TRPC6 conductance and associated signaling via its phosphorylation at two highly conserved amino acid residues: Thr69/Thr70 (Thr69 in mice and Thr70 in humans) and Ser321/Ser322 (Ser321 in mice and Ser322 in humans). Here, we tested the role of PKG in modulating TRPC6-dependent responses in primary and conditionally immortalized mouse podocytes. TRPC6 was phosphorylated at Thr69 in nonstimulated podocytes, but this declined upon ANG II stimulation or overexpression of constitutively active calcineurin phosphatase. ANG II induced podocyte motility in an in vitro wound assay, and this was reduced 30–60% in cells overexpressing a phosphomimetic mutant TRPC6 (TRPC6T70E/S322E) or activated PKG ( P < 0.05). Pretreatment of podocytes with the PKG agonists S-nitroso- N-acetyl-dl-penicillamine (nitric oxide donor), 8-bromo-cGMP, Bay 41–2772 (soluble guanylate cyclase activator), or phosphodiesterase 5 (PDE5) inhibitor 4-{[3′,4′-(methylenedioxy)benzyl]amino}[7]-6-methoxyquinazoline attenuated ANG II-induced Thr69 dephosphorylation and also inhibited TRPC6-dependent podocyte motility by 30–60%. These data reveal that PKG activation strategies, including PDE5 inhibition, ameliorate ANG II-induced podocyte dysmotility by targeting TRPC6 in podocytes, highlighting the potential therapeutic utility of these approaches to treat hyperactive TRPC6-dependent glomerular disease.

SEARCH FOR POTENTIAL LIGANDS FOR TRPM8 WITH THE HELP OF COMPUTER DESIGN

2020 ◽  
Author(s):  
Evgeniy Borodin
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Computer Design ◽  
Critical Residue ◽  
The Family ◽  
Transient Receptor ◽  
Selection Of

A search was carried out for potential ligands to TRPM8 - a representative of the family of cationic channels with a transient receptor potential involved in the development of bronchial hypersensitivity and the occurrence of bronchospasm in response to low temperatures. We used a structural design and molecular docking using the autodock software package (http://autodock.scripps.edu/), which allows automated testing of many potential ligands for TRPM8. Docking was carried out with tyrosine 745 (Y745) amino acid residue as a critical residue for channel sensitivity to menthol, a classic TRPM8 agonist. The selection of potential candidates for the role of drugs intended for the treatment of bronchial cold hyperreactivity using in silico methods can be supplemented by testing their biological activity in vitro experiments with cell and tissue cultures and in vivo with experimental animals.

scholarly journals Transient Receptor Potential (TRP) Channels in Haematological Malignancies: An Update

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 765
Author(s):  
Federica Maggi ◽  
Maria Beatrice Morelli ◽  
Massimo Nabissi ◽  
Oliviero Marinelli ◽  
Laura Zeppa ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Haematological Malignancy ◽  
Receptor Potential ◽  
Progression Free Survival ◽  
Free Survival ◽  
Channel Expression ◽  
Transient Receptor

Transient receptor potential (TRP) channels are improving their importance in different cancers, becoming suitable as promising candidates for precision medicine. Their important contribution in calcium trafficking inside and outside cells is coming to light from many papers published so far. Encouraging results on the correlation between TRP and overall survival (OS) and progression-free survival (PFS) in cancer patients are available, and there are as many promising data from in vitro studies. For what concerns haematological malignancy, the role of TRPs is still not elucidated, and data regarding TRP channel expression have demonstrated great variability throughout blood cancer so far. Thus, the aim of this review is to highlight the most recent findings on TRP channels in leukaemia and lymphoma, demonstrating their important contribution in the perspective of personalised therapies.

Angiotensin II-stimulated Ca2+ entry mechanisms in afferent arterioles: role of transient receptor potential canonical channels and reverse Na+/Ca2+ exchange

2008 ◽  
Vol 294 (1) ◽  
pp. F212-F219 ◽  
Author(s):  
Susan K. Fellner ◽  
William J. Arendshorst
Keyword(s):  
Angiotensin Ii ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Flufenamic Acid ◽  
Polystyrene Bead ◽  
Ang Ii ◽  
Transient Receptor Potential Canonical ◽  
Afferent Arterioles ◽  
Transient Receptor

In afferent arterioles, the signaling events that lead to an increase in cytosolic Ca2+ concentration ([Ca2+]i) and initiation of vascular contraction are increasingly being delineated. We have recently studied angiotensin II (ANG II)-mediated effects on sarcoplasmic reticulum (SR) mobilization of Ca2+ and the role of superoxide and cyclic adenosine diphosphoribose in these processes. In the current study we investigated the participation of transient receptor potential canonical channels (TRPC) and a Na+/Ca2+ exchanger (NCX) in Ca2+ entry mechanisms. Afferent arterioles, isolated with the magnetized polystyrene bead method, were loaded with fura-2 to measure [Ca2+]i ratiometrically. We observed that the Ca2+-dependent chloride channel blocker niflumic acid (10 and 50 μ M) affects neither the peak nor plateau [Ca2+]i response to ANG II. Arterioles were pretreated with ryanodine (100 μM) and TMB-8 to block SR mobilization via the ryanodine receptor and inositol trisphosphate receptor, respectively. The peak [Ca2+]i response to ANG II was reduced by 40%. Addition of 2-aminoethoxydiphenyl borane to block TRPC-mediated Ca2+ entry inhibited the peak [Ca2+]i ANG II response by 80% and the plateau by 74%. Flufenamic acid (FFA; 50 μM), which stimulates TRPC6, caused a sustained increase of [Ca2+]i of 146 nM. This response was unaffected by diltiazem or nifedipine. KB-R7943 (at the low concentration of 10 μM) inhibits reverse (but not forward) mode NCX. KB-R7943 decreased the peak [Ca2+]i response to ANG II by 48% and to FFA by 38%. We conclude that TRPC6 and reverse-mode NCX may be important Ca2+ entry pathways in afferent arterioles.

scholarly journals The Transient Receptor Potential Vanilloid Type-2 (TRPV2) Ion Channels in Neurogenesis and Gliomagenesis: Cross-Talk between Transcription Factors and Signaling Molecules

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 322 ◽  
Author(s):  
Giorgio Santoni ◽  
Consuelo Amantini
Keyword(s):  
Ion Channels ◽  
Neural Progenitor Cells ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
New Therapeutic Approaches ◽  
Transient Receptor

Recently, the finding of cancer stem cells in brain tumors has increased the possibilitiesfor advancing new therapeutic approaches with the aim to overcome the limits of current availabletreatments. In addition, a role for ion channels, particularly of TRP channels, in developing neuronsas well as in brain cancer development and progression have been demonstrated. Herein, we focuson the latest advancements in understanding the role of TRPV2, a Ca2+ permeable channel belongingto the TRPV subfamily in neurogenesis and gliomagenesis. TRPV2 has been found to be expressedin both neural progenitor cells and glioblastoma stem/progenitor-like cells (GSCs). In developingneurons, post-translational modifications of TRPV2 (e.g., phosphorylation by ERK2) are required tostimulate Ca2+ signaling and nerve growth factor-mediated neurite outgrowth. TRPV2overexpression also promotes GSC differentiation and reduces gliomagenesis in vitro and in vivo.In glioblastoma, TRPV2 inhibits survival and proliferation, and induces Fas/CD95-dependentapoptosis. Furthermore, by proteomic analysis, the identification of a TRPV2 interactome-basedsignature and its relation to glioblastoma progression/recurrence, high or low overall survival anddrug resistance strongly suggest an important role of the TRPV2 channel as a potential biomarkerin glioblastoma prognosis and therapy.

scholarly journals Emerging Roles for Ion Channels in Ovarian Cancer: Pathomechanisms and Pharmacological Treatment

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 668
Author(s):  
Concetta Altamura ◽  
Maria Raffaella Greco ◽  
Maria Rosaria Carratù ◽  
Rosa Angela Cardone ◽  
Jean-François Desaphy
Keyword(s):  
Ovarian Cancer ◽  
Ion Channels ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Gynecologic Cancer ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Platinum Resistance

Ovarian cancer (OC) is the deadliest gynecologic cancer, due to late diagnosis, development of platinum resistance, and inadequate alternative therapy. It has been demonstrated that membrane ion channels play important roles in cancer processes, including cell proliferation, apoptosis, motility, and invasion. Here, we review the contribution of ion channels in the development and progression of OC, evaluating their potential in clinical management. Increased expression of voltage-gated and epithelial sodium channels has been detected in OC cells and tissues and shown to be involved in cancer proliferation and invasion. Potassium and calcium channels have been found to play a critical role in the control of cell cycle and in the resistance to apoptosis, promoting tumor growth and recurrence. Overexpression of chloride and transient receptor potential channels was found both in vitro and in vivo, supporting their contribution to OC. Furthermore, ion channels have been shown to influence the sensitivity of OC cells to neoplastic drugs, suggesting a critical role in chemotherapy resistance. The study of ion channels expression and function in OC can improve our understanding of pathophysiology and pave the way for identifying ion channels as potential targets for tumor diagnosis and treatment.

scholarly journals Linalool odor‐induced analgesia is triggered by TRPA1-independent pathway in mice

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Hideki Kashiwadani ◽  
Yurina Higa ◽  
Mitsutaka Sugimura ◽  
Tomoyuki Kuwaki
Keyword(s):  
Pain Threshold ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Analgesic Effects ◽  
Neuronal Mechanisms ◽  
Odor Exposure ◽  
Noxious Mechanical Stimulation ◽  
Transient Receptor ◽  
Deficient Mice

AbstractWe had recently reported that linalool odor exposure induced significant analgesic effects in mice and that the effects were disappeared in olfactory-deprived mice in which the olfactory epithelium was damaged, thus indicating that the effects were triggered by chemical senses evoked by linalool odor exposure. However, the peripheral neuronal mechanisms, including linalool receptors that contribute toward triggering the linalool odor-induced analgesia, still remain unexplored. In vitro studies have shown that the transient receptor potential ankyrin 1 (TRPA1) responded to linalool, thus raising the possibility that TRPA1 expressed on the trigeminal nerve terminal detects linalool odor inhaled into the nostril and triggers the analgesic effects. To address this hypothesis, we measured the behavioral pain threshold for noxious mechanical stimulation in TRPA1-deficient mice. In contrast to our expectation, we found a significant increase in the threshold after linalool odor exposure in TRPA1-deficient mice, indicating the analgesic effects of linalool odor even in TRPA1-deficient mice. Furthermore, intranasal application of TRPA1 selective antagonist did not alter the analgesic effect of linalool odor. These results showed that the linalool odor-induced analgesia was triggered by a TRPA1-independent pathway in mice.

scholarly journals Interactions between Chemesthesis and Taste: Role of TRPA1 and TRPV1

2021 ◽  
Vol 22 (7) ◽  
pp. 3360
Author(s):  
Mee-Ra Rhyu ◽  
Yiseul Kim ◽  
Vijay Lyall
Keyword(s):  
Transient Receptor Potential ◽  
Taste Receptor ◽  
Sensory Nerve ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channels ◽  
Trigeminal Neurons ◽  
Calcitonin Gene ◽  
Transient Receptor

In addition to the sense of taste and olfaction, chemesthesis, the sensation of irritation, pungency, cooling, warmth, or burning elicited by spices and herbs, plays a central role in food consumption. Many plant-derived molecules demonstrate their chemesthetic properties via the opening of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) channels. TRPA1 and TRPV1 are structurally related thermosensitive cation channels and are often co-expressed in sensory nerve endings. TRPA1 and TRPV1 can also indirectly influence some, but not all, primary taste qualities via the release of substance P and calcitonin gene-related peptide (CGRP) from trigeminal neurons and their subsequent effects on CGRP receptor expressed in Type III taste receptor cells. Here, we will review the effect of some chemesthetic agonists of TRPA1 and TRPV1 and their influence on bitter, sour, and salt taste qualities.

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