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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (1 December 2021) | Viewed by 37360

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Special Issue Editors

Dr. Balazs Istvan Toth

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Guest Editor

Laboratory of Molecular and Cellular Physiology, Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Interests: TRPM channels

Prof. Dr. Thomas Voets

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Laboratory of Ion Channel Research (VIB-KU Leuven Center for Brain & Disease Research) Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
Interests: TRPM channels

Special Issue Information

Dear Colleagues,

The Melastatin (TRPM) subfamily of the fascinating Transient Receptor Potential (TRP) ion channels forms a structurally and functionally diverse group of eight close relatives of cation channels. They are characterized by diverse gating stimuli, including changes in environmental temperature, osmolarity, ADP-ribose or intra- and extracellular ions. They function as thermosensors, gatekeepers of cellular ion homeostasis, or regulators of secretory functions, inflammatory processes and redox signaling. Some of them possess a unique double identity, simultaneously functioning as ion channels and enzymes (“chanzymes”).

TRPM channels are widely studied in the sensory system, in various immune cells, as well as in epithelial barriers, but they are virtually expressed by every cell-types of the human body. Intense research of the past two decades advanced a lot in their understanding and in the last years we gained a deeper insight into their molecular structure. However, in spite of our rapidly growing knowledge, there are still several mysteries in this intriguing group of ion channels. This Special Issue provides a forum for summarizing our current knowledge and presenting selected chapters of actual research targeting any aspect of these exciting members of TRP channels.

Dr. Balazs Istvan Toth
Prof. Dr. Thomas Voets
Guest Editors

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Keywords

TRP ion channels
TRPM channels
molecular structure
ion channels

Published Papers (14 papers)

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17 pages, 4103 KiB

Open AccessArticle

In Vitro and In Vivo Pharmacological Characterization of a Novel TRPM8 Inhibitor Chemotype Identified by Small-Scale Preclinical Screening

by Nunzio Iraci, Carmine Ostacolo, Alicia Medina-Peris, Tania Ciaglia, Anton M. Novoselov, Andrea Altieri, David Cabañero, Asia Fernandez-Carvajal, Pietro Campiglia, Isabel Gomez-Monterrey, Alessia Bertamino and Alexander V. Kurkin

Int. J. Mol. Sci. 2022, 23(4), 2070; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042070 - 13 Feb 2022

Viewed by 2083

Abstract

Transient receptor potential melastatin type 8 (TRPM8) is a target for the treatment of different physio-pathological processes. While TRPM8 antagonists are reported as potential drugs for pain, cancer, and inflammation, to date only a limited number of chemotypes have been investigated and thus a limited number of compounds have reached clinical trials. Hence there is high value in searching for new TRPM8 antagonistic to broaden clues to structure-activity relationships, improve pharmacological properties and explore underlying molecular mechanisms. To address this, the EDASA Scientific in-house molecular library has been screened in silico, leading to identifying twenty-one potentially antagonist compounds of TRPM8. Calcium fluorometric assays were used to validate the in-silico hypothesis and assess compound selectivity. Four compounds were identified as selective TRPM8 antagonists, of which two were dual-acting TRPM8/TRPV1 modulators. The most potent TRPM8 antagonists (BB 0322703 and BB 0322720) underwent molecular modelling studies to highlight key structural features responsible for drug–protein interaction. The two compounds were also investigated by patch-clamp assays, confirming low micromolar potencies. The most potent compound (BB 0322703, IC₅₀ 1.25 ± 0.26 μM) was then profiled in vivo in a cold allodinya model, showing pharmacological efficacy at 30 μM dose. The new chemotypes identified showed remarkable pharmacological properties paving the way to further investigations for drug discovery and pharmacological purposes. Full article

(This article belongs to the Special Issue TRPM Channels)

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13 pages, 7310 KiB

Open AccessArticle

A Central Role for TRPM4 in Ca²⁺-Signal Amplification and Vasoconstriction

by Tamás Csípő, Ágnes Czikora, Gábor Á. Fülöp, Hajnalka Gulyás, Ibolya Rutkai, Enikő Pásztorné Tóth, Róbert Pórszász, Andrea Szalai, Kata Bölcskei, Zsuzsanna Helyes, Erika Pintér, Zoltán Papp, Zoltán Ungvári and Attila Tóth

Int. J. Mol. Sci. 2022, 23(3), 1465; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031465 - 27 Jan 2022

Cited by 3 | Viewed by 2196

Abstract

Transient receptor potential melastatin-4 (TRPM4) is activated by an increase in intracellular Ca²⁺ concentration and is expressed on smooth muscle cells (SMCs). It is implicated in the myogenic constriction of cerebral arteries. We hypothesized that TRPM4 has a general role in intracellular Ca²⁺ signal amplification in a wide range of blood vessels. TRPM4 function was tested with the TRPM4 antagonist 9-phenanthrol and the TRPM4 activator A23187 on the cardiovascular responses of the rat, in vivo and in isolated basilar, mesenteric, and skeletal muscle arteries. TRPM4 inhibition by 9-phenanthrol resulted in hypotension and a decreased heart rate in the rat. TRPM4 inhibition completely antagonized myogenic tone development and norepinephrine-evoked vasoconstriction, and depolarization (high extracellular KCl concentration) evoked vasoconstriction in a wide range of peripheral arteries. Vasorelaxation caused by TRPM4 inhibition was accompanied by a significant decrease in intracellular Ca²⁺ concentration, suggesting an inhibition of Ca²⁺ signal amplification. Immunohistochemistry confirmed TRPM4 expression in the smooth muscle cells of the peripheral arteries. Finally, TRPM4 activation by the Ca²⁺ ionophore A23187 was competitively inhibited by 9-phenanthrol. In summary, TRPM4 was identified as an essential Ca²⁺-amplifying channel in peripheral arteries, contributing to both myogenic tone and agonist responses. These results suggest an important role for TRPM4 in the circulation. The modulation of TRPM4 activity may be a therapeutic target for hypertension. Furthermore, the Ca²⁺ ionophore A23187 was identified as the first high-affinity (nanomolar) direct activator of TRPM4, acting on the 9-phenanthrol binding site. Full article

(This article belongs to the Special Issue TRPM Channels)

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13 pages, 3006 KiB

Open AccessArticle

TRPM3 Is Expressed in Afferent Bladder Neurons and Is Upregulated during Bladder Inflammation

by Matthias Vanneste, Marie Mulier, Ana Cristina Nogueira Freitas, Nele Van Ranst, Axelle Kerstens, Thomas Voets and Wouter Everaerts

Int. J. Mol. Sci. 2022, 23(1), 107; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010107 - 22 Dec 2021

Cited by 11 | Viewed by 3151

Abstract

The cation channel TRPM3 is activated by heat and the neurosteroid pregnenolone sulfate. TRPM3 is expressed on sensory neurons innervating the skin, where together with TRPV1 and TRPA1, it functions as one of three redundant sensors of acute heat. Moreover, functional upregulation of TRPM3 during inflammation contributes to heat hyperalgesia. The role of TRPM3 in sensory neurons innervating internal organs such as the bladder is currently unclear. Here, using retrograde labeling and single-molecule fluorescent RNA in situ hybridization, we demonstrate expression of mRNA encoding TRPM3 in a large subset of dorsal root ganglion (DRG) neurons innervating the mouse bladder, and confirm TRPM3 channel functionality in these neurons using Fura-2-based calcium imaging. After induction of cystitis by injection of cyclophosphamide, we observed a robust increase of the functional responses to agonists of TRPM3, TRPV1, and TRPA1 in bladder-innervating DRG neurons. Cystometry and voided spot analysis in control and cyclophosphamide-treated animals did not reveal differences between wild type and TRPM3-deficient mice, indicating that TRPM3 is not critical for normal voiding. We conclude that TRPM3 is functionally expressed in a large proportion of sensory bladder afferent, but its role in bladder sensation remains to be established. Full article

(This article belongs to the Special Issue TRPM Channels)

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17 pages, 3293 KiB

Open AccessArticle

Partial Agonistic Actions of Sex Hormone Steroids on TRPM3 Function

by Eleonora Persoons, Sara Kerselaers, Thomas Voets, Joris Vriens and Katharina Held

Int. J. Mol. Sci. 2021, 22(24), 13652; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413652 - 20 Dec 2021

Cited by 5 | Viewed by 1968

Abstract

Sex hormone steroidal drugs were reported to have modulating actions on the ion channel TRPM3. Pregnenolone sulphate (PS) presents the most potent known endogenous chemical agonist of TRPM3 and affects several gating modes of the channel. These includes a synergistic action of PS and high temperatures on channel opening and the PS-induced opening of a noncanonical pore in the presence of other TRPM3 modulators. Moreover, human TRPM3 variants associated with neurodevelopmental disease exhibit an increased sensitivity for PS. However, other steroidal sex hormones were reported to influence TRPM3 functions with activating or inhibiting capacity. Here, we aimed to answer how DHEAS, estradiol, progesterone and testosterone act on the various modes of TRPM3 function in the wild-type channel and two-channel variants associated with human disease. By means of calcium imaging and whole-cell patch clamp experiments, we revealed that all four drugs are weak TRPM3 agonists that share a common steroidal interaction site. Furthermore, they exhibit increased activity on TRPM3 at physiological temperatures and in channels that carry disease-associated mutations. Finally, all steroids are able to open the noncanonical pore in wild-type and DHEAS also in mutant TRPM3. Collectively, our data provide new valuable insights in TRPM3 gating, structure-function relationships and ligand sensitivity. Full article

(This article belongs to the Special Issue TRPM Channels)

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14 pages, 2704 KiB

Open AccessArticle

Control of TRPM3 Ion Channels by Protein Kinase CK2-Mediated Phosphorylation in Pancreatic β-Cells of the Line INS-1

by Alexander Becker, Claudia Götz, Mathias Montenarh and Stephan E. Philipp

Int. J. Mol. Sci. 2021, 22(23), 13133; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313133 - 04 Dec 2021

Cited by 8 | Viewed by 1780

Abstract

In pancreatic β-cells of the line INS-1, glucose uptake and metabolism induce the openings of Ca²⁺-permeable TRPM3 channels that contribute to the elevation of the intracellular Ca²⁺ concentration and the fusion of insulin granules with the plasma membrane. Conversely, glucose-induced Ca²⁺ signals and insulin release are reduced by the activity of the serine/threonine kinase CK2. Therefore, we hypothesized that TRPM3 channels might be regulated by CK2 phosphorylation. We used recombinant TRPM3α2 proteins, native TRPM3 proteins from INS-1 β-cells, and TRPM3-derived oligopeptides to analyze and localize CK2-dependent phosphorylation of TRPM3 channels. The functional consequences of CK2 phosphorylation upon TRPM3-mediated Ca²⁺ entry were investigated in Fura-2 Ca²⁺-imaging experiments. Recombinant TRPM3α2 channels expressed in HEK293 cells displayed enhanced Ca²⁺ entry in the presence of the CK2 inhibitor CX-4945 and their activity was strongly reduced after CK2 overexpression. TRPM3α2 channels were phosphorylated by CK2 in vitro at serine residue 1172. Accordingly, a TRPM3α2 S₁₁₇₂A mutant displayed enhanced Ca²⁺ entry. The TRPM3-mediated Ca²⁺ entry in INS-1 β-cells was also strongly increased in the presence of CX-4945 and reduced after overexpression of CK2. Our study shows that CK2-mediated phosphorylation controls TRPM3 channel activity in INS-1 β-cells. Full article

(This article belongs to the Special Issue TRPM Channels)

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22 pages, 4017 KiB

Open AccessArticle

Electrophysiological Effects of the Transient Receptor Potential Melastatin 4 Channel Inhibitor (4-Chloro-2-(2-chlorophenoxy)acetamido) Benzoic Acid (CBA) in Canine Left Ventricular Cardiomyocytes

by Csaba Dienes, Tamás Hézső, Dénes Zsolt Kiss, Dóra Baranyai, Zsigmond Máté Kovács, László Szabó, János Magyar, Tamás Bányász, Péter P. Nánási, Balázs Horváth, Mónika Gönczi and Norbert Szentandrássy

Int. J. Mol. Sci. 2021, 22(17), 9499; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179499 - 31 Aug 2021

Cited by 7 | Viewed by 2090

Abstract

Transient receptor potential melastatin 4 (TRPM4) plays an important role in many tissues, including pacemaker and conductive tissues of the heart, but much less is known about its electrophysiological role in ventricular myocytes. Our earlier results showed the lack of selectivity of 9-phenanthrol, so CBA ((4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) was chosen as a new, potentially selective inhibitor. Goal: Our aim was to elucidate the effect and selectivity of CBA in canine left ventricular cardiomyocytes and to study the expression of TRPM4 in the canine heart. Experiments were carried out in enzymatically isolated canine left ventricular cardiomyocytes. Ionic currents were recorded with an action potential (AP) voltage-clamp technique in whole-cell configuration at 37 °C. An amount of 10 mM BAPTA was used in the pipette solution to exclude the potential activation of TRPM4 channels. AP was recorded with conventional sharp microelectrodes. CBA was used in 10 µM concentrations. Expression of TRPM4 protein in the heart was studied by Western blot. TRPM4 protein was expressed in the wall of all four chambers of the canine heart as well as in samples prepared from isolated left ventricular cells. CBA induced an approximately 9% reduction in AP duration measured at 75% and 90% of repolarization and decreased the short-term variability of APD₉₀. Moreover, AP amplitude was increased and the maximal rates of phase 0 and 1 were reduced by the drug. In AP clamp measurements, CBA-sensitive current contained a short, early outward and mainly a long, inward current. Transient outward potassium current (I_to) and late sodium current (I_Na,L) were reduced by approximately 20% and 47%, respectively, in the presence of CBA, while L-type calcium and inward rectifier potassium currents were not affected. These effects of CBA were largely reversible upon washout. Based on our results, the CBA induced reduction of phase-1 slope and the slight increase of AP amplitude could have been due to the inhibition of I_to. The tendency for AP shortening can be explained by the inhibition of inward currents seen in AP-clamp recordings during the plateau phase. This inward current reduced by CBA is possibly I_Na,L, therefore, CBA is not entirely selective for TRPM4 channels. As a consequence, similarly to 9-phenanthrol, it cannot be used to test the contribution of TRPM4 channels to cardiac electrophysiology in ventricular cells, or at least caution must be applied. Full article

(This article belongs to the Special Issue TRPM Channels)

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15 pages, 2905 KiB

Open AccessArticle

Modulation of the Cardiac Myocyte Action Potential by the Magnesium-Sensitive TRPM6 and TRPM7-like Current

by Asfree Gwanyanya, Inga Andriulė, Bogdan M. Istrate, Farjana Easmin, Kanigula Mubagwa and Regina Mačianskienė

Int. J. Mol. Sci. 2021, 22(16), 8744; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168744 - 14 Aug 2021

Cited by 4 | Viewed by 2387

Abstract

The cardiac Mg²⁺-sensitive, TRPM6, and TRPM7-like channels remain undefined, especially with the uncertainty regarding TRPM6 expression in cardiomyocytes. Additionally, their contribution to the cardiac action potential (AP) profile is unclear. Immunofluorescence assays showed the expression of the TRPM6 and TRPM7 proteins in isolated pig atrial and ventricular cardiomyocytes, of which the expression was modulated by incubation in extracellular divalent cation-free conditions. In patch clamp studies of cells dialyzed with solutions containing zero intracellular Mg²⁺ concentration ([Mg²⁺]_i) to activate the Mg²⁺-sensitive channels, raising extracellular [Mg²⁺] ([Mg²⁺]_o) from the 0.9-mM baseline to 7.2 mM prolonged the AP duration (APD). In contrast, no such effect was observed in cells dialyzed with physiological [Mg²⁺]_i. Under voltage clamp, in cells dialyzed with zero [Mg²⁺]_i, depolarizing ramps induced an outward-rectifying current, which was suppressed by raising [Mg²⁺]_o and was absent in cells dialyzed with physiological [Mg²⁺]_i. In cells dialyzed with physiological [Mg²⁺]_i, raising [Mg²⁺]_o decreased the L-type Ca²⁺ current and the total delayed-rectifier current but had no effect on the APD. These results suggest a co-expression of the TRPM6 and TRPM7 proteins in cardiomyocytes, which are therefore the molecular candidates for the native cardiac Mg²⁺-sensitive channels, and also suggest that the cardiac Mg²⁺-sensitive current shortens the APD, with potential implications in arrhythmogenesis. Full article

(This article belongs to the Special Issue TRPM Channels)

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14 pages, 3113 KiB

Open AccessArticle

Theoretical Investigation of the Mechanism by which A Gain-of-Function Mutation of the TRPM4 Channel Causes Conduction Block

by Yaopeng Hu, Qin Li, Yanghua Shen, Takayuki Fujita, Xin Zhu and Ryuji Inoue

Int. J. Mol. Sci. 2021, 22(16), 8513; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168513 - 07 Aug 2021

Cited by 4 | Viewed by 1802

Abstract

In the heart, TRPM4 is most abundantly distributed in the conduction system. Previously, a single mutation, ‘E7K’, was identified in its distal N-terminus to cause conduction disorder because of enhanced cell-surface expression. It remains, however, unclear how this expression increase leads to conduction failure rather than abnormally enhanced cardiac excitability. To address this issue theoretically, we mathematically formulated the gating kinetics of the E7K-mutant TRPM4 channel by a combined use of voltage jump analysis and ionomycin-perforated cell-attached recording technique and incorporated the resultant rate constants of opening and closing into a human Purkinje fiber single-cell action potential (AP) model (Trovato model) to perform 1D-cable simulations. The results from TRPM4 expressing HEK293 cells showed that as compared with the wild-type, the open state is much preferred in the E7K mutant with increased voltage-and Ca²⁺-sensitivities. These theoretical predictions were confirmed by power spectrum and single channel analyses of expressed wild-type and E7K-mutant TRPM4 channels. In our modified Trovato model, the facilitated opening of the E7K mutant channel markedly prolonged AP duration with concomitant depolarizing shifts of the resting membrane potential in a manner dependent on the channel density (or maximal activity). This was, however, little evident in the wild-type TRPM4 channel. Moreover, 1D-cable simulations with the modified Trovato model revealed that increasing the density of E7K (but not of wild-type) TRPM4 channels progressively reduced AP conduction velocity eventually culminating in complete conduction block. These results clearly suggest the brady-arrhythmogenicity of the E7K mutant channel which likely results from its pathologically enhanced activity. Full article

(This article belongs to the Special Issue TRPM Channels)

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11 pages, 69590 KiB

Open AccessArticle

Expression Profiles of ASIC1/2 and TRPV1/4 in Common Skin Tumors

by Kirsten Ackermann, Susanne Wallner, Christoph Brochhausen and Stephan Schreml

Int. J. Mol. Sci. 2021, 22(11), 6024; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116024 - 02 Jun 2021

Cited by 7 | Viewed by 2979

Abstract

The acid-sensing ion channels ASIC1 and ASIC2, as well as the transient receptor potential vanilloid channels TRPV1 and TRPV4, are proton-gated cation channels that can be activated by low extracellular pH (pH_e), which is a hallmark of the tumor microenvironment in solid tumors. However, the role of these channels in the development of skin tumors is still unclear. In this study, we investigated the expression profiles of ASIC1, ASIC2, TRPV1 and TRPV4 in malignant melanoma (MM), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and in nevus cell nevi (NCN). We conducted immunohistochemistry using paraffin-embedded tissue samples from patients and found that most skin tumors express ASIC1/2 and TRPV1/4. Striking results were that BCCs are often negative for ASIC2, while nearly all SCCs express this marker. Epidermal MM sometimes seem to lack ASIC1 in contrast to NCN. Dermal portions of MM show strong expression of TRPV1 more frequently than dermal NCN portions. Some NCN show a decreasing ASIC1/2 expression in deeper dermal tumor tissue, while MM seem to not lose ASIC1/2 in deeper dermal portions. ASIC1, ASIC2, TRPV1 and TRPV4 in skin tumors might be involved in tumor progression, thus being potential diagnostic and therapeutic targets. Full article

(This article belongs to the Special Issue TRPM Channels)

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16 pages, 2335 KiB

Open AccessArticle

Oxaliplatin Causes Transient Changes in TRPM8 Channel Activity

by Vittoria Rimola, Tabea Osthues, Vanessa Königs, Gerd Geißlinger and Marco Sisignano

Int. J. Mol. Sci. 2021, 22(9), 4962; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094962 - 07 May 2021

Cited by 9 | Viewed by 3064

Abstract

Oxaliplatin is a third-generation platinum-based anticancer drug that is widely used as first-line treatment for colorectal carcinoma. Patients treated with oxaliplatin develop an acute peripheral pain several hours after treatment, mostly characterized by cold allodynia as well as a long-term chronic neuropathy. These two phenomena seem to be causally connected. However, the underlying mechanisms that trigger the acute peripheral pain are still poorly understood. Here we show that the activity of the transient receptor potential melastatin 8 (TRPM8) channel but not the activity of any other member of the TRP channel family is transiently increased 1 h after oxaliplatin treatment and decreased 24 h after oxaliplatin treatment. Mechanistically, this is connected with activation of the phospholipase C (PLC) pathway and depletion of phosphatidylinositol 4,5-bisphosphate (PIP₂) after oxaliplatin treatment. Inhibition of the PLC pathway can reverse the decreased TRPM8 activity as well as the decreased PIP₂-concentrations after oxaliplatin treatment. In summary, these results point out transient changes in TRPM8 activity early after oxaliplatin treatment and a later occurring TRPM8 channel desensitization in primary sensory neurons. These mechanisms may explain the transient cold allodynia after oxaliplatin treatment and highlight an important role of TRPM8 in oxaliplatin-induced acute and neuropathic pain. Full article

(This article belongs to the Special Issue TRPM Channels)

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15 pages, 5526 KiB

Open AccessArticle

Species-Specific Regulation of TRPM2 by PI(4,5)P₂ via the Membrane Interfacial Cavity

by Daniel Barth, Andreas Lückhoff and Frank J. P. Kühn

Int. J. Mol. Sci. 2021, 22(9), 4637; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094637 - 28 Apr 2021

Cited by 8 | Viewed by 1657

Abstract

The human apoptosis channel TRPM2 is stimulated by intracellular ADR-ribose and calcium. Recent studies show pronounced species-specific activation mechanisms. Our aim was to analyse the functional effect of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂), commonly referred to as PIP₂, on different TRPM2 orthologues. Moreover, we wished to identify the interaction site between TRPM2 and PIP₂. We demonstrate a crucial role of PIP₂, in the activation of TRPM2 orthologues of man, zebrafish, and sea anemone. Utilizing inside-out patch clamp recordings of HEK-293 cells transfected with TRPM2, differential effects of PIP₂ that were dependent on the species variant became apparent. While depletion of PIP₂ via polylysine uniformly caused complete inactivation of TRPM2, restoration of channel activity by artificial PIP₂ differed widely. Human TRPM2 was the least sensitive species variant, making it the most susceptible one for regulation by changes in intramembranous PIP₂ content. Furthermore, mutations of highly conserved positively charged amino acid residues in the membrane interfacial cavity reduced the PIP₂ sensitivity in all three TRPM2 orthologues to varying degrees. We conclude that the membrane interfacial cavity acts as a uniform PIP₂ binding site of TRPM2, facilitating channel activation in the presence of ADPR and Ca²⁺ in a species-specific manner. Full article

(This article belongs to the Special Issue TRPM Channels)

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14 pages, 1862 KiB

Open AccessArticle

TRPM7-Mediated Calcium Transport in HAT-7 Ameloblasts

by Kristóf Kádár, Viktória Juhász, Anna Földes, Róbert Rácz, Yan Zhang, Heike Löchli, Erzsébet Kató, László Köles, Martin C. Steward, Pamela DenBesten, Gábor Varga and Ákos Zsembery

Int. J. Mol. Sci. 2021, 22(8), 3992; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083992 - 13 Apr 2021

Cited by 7 | Viewed by 2275

Abstract

TRPM7 plays an important role in cellular Ca²⁺, Zn²⁺ and Mg²⁺ homeostasis. TRPM7 channels are abundantly expressed in ameloblasts and, in the absence of TRPM7, dental enamel is hypomineralized. The potential role of TRPM7 channels in Ca²⁺ transport during amelogenesis was investigated in the HAT-7 rat ameloblast cell line. The cells showed strong TRPM7 mRNA and protein expression. Characteristic TRPM7 transmembrane currents were observed, which increased in the absence of intracellular Mg²⁺ ([Mg²⁺]_i), were reduced by elevated [Mg²⁺]_i, and were inhibited by the TRPM7 inhibitors NS8593 and FTY720. Mibefradil evoked similar currents, which were suppressed by elevated [Mg²⁺]_i, reducing extracellular pH stimulated transmembrane currents, which were inhibited by FTY720. Naltriben and mibefradil both evoked Ca²⁺ influx, which was further enhanced by the acidic intracellular conditions. The SOCE inhibitor BTP2 blocked Ca²⁺ entry induced by naltriben but not by mibefradil. Thus, in HAT-7 cells, TRPM7 may serves both as a potential modulator of Orai-dependent Ca²⁺ uptake and as an independent Ca²⁺ entry pathway sensitive to pH. Therefore, TRPM7 may contribute directly to transepithelial Ca²⁺ transport in amelogenesis. Full article

(This article belongs to the Special Issue TRPM Channels)

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Review

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32 pages, 8175 KiB

Open AccessReview

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

by Carolina Izquierdo, Mercedes Martín-Martínez, Isabel Gómez-Monterrey and Rosario González-Muñiz

Int. J. Mol. Sci. 2021, 22(16), 8502; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168502 - 07 Aug 2021

Cited by 23 | Viewed by 5919

Abstract

The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field. Full article

(This article belongs to the Special Issue TRPM Channels)

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16 pages, 992 KiB

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Transient Receptor Potential Channels in the Epithelial-to-Mesenchymal Transition

by Charlotte Van den Eynde, Katrien De Clercq and Joris Vriens

Int. J. Mol. Sci. 2021, 22(15), 8188; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158188 - 30 Jul 2021

Cited by 14 | Viewed by 2299

Abstract

The epithelial-to-mesenchymal transition (EMT) is a strictly regulated process that is indispensable for normal development, but it can result in fibrosis and cancer progression. It encompasses a complete alteration of the cellular transcriptomic profile, promoting the expression of genes involved in cellular migration, invasion and proliferation. Extracellular signaling factors driving the EMT process require secondary messengers to convey their effects to their targets. Due to its remarkable properties, calcium represents an ideal candidate to translate molecular messages from receptor to effector. Therefore, calcium-permeable ion channels that facilitate the influx of extracellular calcium into the cytosol can exert major influences on cellular phenotype. Transient receptor potential (TRP) channels represent a superfamily of non-selective cation channels that decode physical and chemical stimuli into cellular behavior. Their role as cellular sensors renders them interesting proteins to study in the context of phenotypic transitions, such as EMT. In this review, we elaborate on the current knowledge regarding TRP channel expression and activity in cellular phenotype and EMT. Full article

(This article belongs to the Special Issue TRPM Channels)

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