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Pharmaceuticals
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Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets
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Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 20 July 2024 | Viewed by 7982

Special Issue Editor

Dr. Dana Cucu

E-Mail Website
Guest Editor
Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania
Interests: TRP channels; signalling pathways; tumoral process

Special Issue Information

Dear Colleagues,

The discovery of a transient receptor potential (TRP) channel in 1969 as a sensor for phototransduction in Drosophila melanogaster began an era of intensive research, leading to the identification of the TRP superfamily comprising 28 cation-permeable channels. The work culminated with the 2021 Nobel Prize in Physiology that was received by Dr. David Julius and Dr. Ardem Patapoutian for the discovery of the roles of these channels (TRP and Piezo) in temperature and touch sensation. The expression of these proteins was found in tissues as diverse as their function. Some of the family members (e.g., TRPV1 and TRPM8) were studied with electrophysiological and imaging methods in sensory neurons, where they were found to transduce thermal stimuli, neuropathic pain or taste. Others (e.g., TRPM8, TRPM7 and TRPV6) were analysed in cancer cells via molecular methods, and were found to participate in migration, apoptosis or proliferation, while others (e.g., TRPV1, TRPA1 and TRMP2) were determined to be sensors for reactive oxygen species and Ph variations.

Altogether, these knowledge and technical developments have brought us to the point where we can identify TRP channels as chemical and cellular sensors. It may be the moment that we propose some ways to use these poly-modal channels, as well as their agonists and antagonists, for therapy. However, before our knowledge in the field breaks the barrier from bench to bedside, we still need to answer some questions.  We do not know, for instance, the signalling pathways in which TRP channels stimulate or inhibit cell migration, cell proliferation or other tumoral processes. Is this related only to the transport of Ca2+, as we are tempted to believe? Or are there other features independent of the channel conductance? How come TRPM8 are stimulators of migration in some tumoral cells and inhibitors in others? Which are the protein actors involved in the fine tuning all these functions? For these and many other questions, we want to search for answers in this Special Issue, "Transient Receptor Potential Channels as Novel Therapeutic Targets". Therefore, this is an invitation to all participants in this fascinating field to propose their models based on precise scientific methods, to decipher signalling pathways and to explain the dual role of these proteins in various tissues.

Dr. Dana Cucu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • TRP channels
  • signalling pathways
  • tumoral process
  • pain
  • migration
  • apoptosis
  • inflammation
  • oxidative stress

Published Papers (8 papers)

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Research

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16 pages, 8817 KiB  
Article
Transient Receptor Potential Ankyrin 1 (TRPA1) Modulation by 4-Hydroxynonenal (4-HNE) in Pancreatic Adenocarcinoma Cell Lines: Putative Roles for Therapies
by Florentina Piciu, Dan Domocos, Gabriela Chiritoiu, Marioara Chiritoiu-Butnaru, Maria Mernea, Cezar Gabriel Popescu, Dragos Paul Mihai, Bianca Galateanu, Ariana Hudita, Alexandru Babes and Dana Cucu
Pharmaceuticals 2024, 17(3), 344; https://doi.org/10.3390/ph17030344 - 06 Mar 2024
Viewed by 765
Abstract
Background: Transient receptor potential channels (TRP) are overexpressed in some pancreatic adenocarcinoma (PDAC) patients and cell lines, settling them as putative therapeutic targets in this disease. Reactive oxygen species (ROS), with levels increased in PDAC, modulate some members of the TRP family renamed [...] Read more.
Background: Transient receptor potential channels (TRP) are overexpressed in some pancreatic adenocarcinoma (PDAC) patients and cell lines, settling them as putative therapeutic targets in this disease. Reactive oxygen species (ROS), with levels increased in PDAC, modulate some members of the TRP family renamed “redox channels”. Here, we investigate the direct effects of 4-hydroxinonenal (4-HNE) on TRPA1, natively expressed in PDAC cell lines and in association with cell migration and cell cycle progression. Methods: We performed microfluorimetry experiments, while the activation of resident membrane channels was investigated using confocal microscopy. We applied a prospective molecular docking of 4-HNE using Autodock and AutoDock Tools4. Also, we simulated the diffusion of 4-HNE through the membrane from the extracellular space with the Permeability of Molecules across Membranes (PerMM) web server. The analysis of cell migration was performed using the wound healing assay, and cell cycle progression was acquired using a Beckman Coulter CytoFlex flow cytometer. Results: Our results show, for the first time in PDAC, that 4-HNE diffuses through the cell membrane and rapidly activates Ca2+ uptake in PDAC cells. This process depends on TRPA1 activation, as 4-HNE forms a covalent binding with a pocket-like region within the intracellular N-terminal of the channel, shaped by the cysteine residues 621, 641, and 665. The activation of TRPA1 by 4-HNE inhibits cell migration and induces cell cycle arrest in the G2/M phase. Conclusions: Our study brings new insights into the effects of 4-HNE, highlighting the activation of the TRPA1 channel, a druggable, putative target for PDAC-expressing tumors. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets)
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23 pages, 3619 KiB  
Article
TRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca2+ and Na+ Influx
by Luis M. Montaño, Abril Carbajal-García, María F. Casas-Hernández, David Arredondo-Zamarripa and Jorge Reyes-García
Pharmaceuticals 2024, 17(3), 293; https://doi.org/10.3390/ph17030293 - 24 Feb 2024
Viewed by 702
Abstract
Airway smooth muscle (ASM) contraction is determined by the increase in intracellular Ca2+ concentration ([Ca2+]i) caused by its release from the sarcoplasmic reticulum (SR) or by extracellular Ca2+ influx. Major channels involved in Ca2+ influx in [...] Read more.
Airway smooth muscle (ASM) contraction is determined by the increase in intracellular Ca2+ concentration ([Ca2+]i) caused by its release from the sarcoplasmic reticulum (SR) or by extracellular Ca2+ influx. Major channels involved in Ca2+ influx in ASM cells are L-type voltage-dependent Ca2+ channels (L-VDCCs) and nonselective cation channels (NSCCs). Transient receptor potential vanilloid 4 (TRPV4) is an NSCC recently studied in ASM. Mechanical stimuli, such as contraction, can activate TRPV4. We investigated the possible activation of TRPV4 by histamine (His)- or carbachol (CCh)-induced contraction in guinea pig ASM. In single myocytes, the TRPV4 agonist (GSK101) evoked an increase in [Ca2+]i, characterized by a slow onset and a plateau phase. The TRPV4 antagonist (GSK219) decreased channel activity by 94%, whereas the Ca2+-free medium abolished the Ca2+ response induced by GSK101. Moreover, GSK101 caused Na+ influx in tracheal myocytes. GSK219 reduced the Ca2+ peak and the Ca2+ plateau triggered by His or CCh. TRPV4 blockade shifted the concentration–response curve relating to His and CCh to the right in tracheal rings and reduced the maximal contraction. Finally, the activation of TRPV4 in single myocytes increased the Ca2+ refilling of the SR. We conclude that contraction of ASM cells after stimulation with His or CCh promotes TRPV4 activation, the subsequent influx of Ca2+ and Na+, and the opening of L-VDCCs. The entry of Ca2+ into ASM cells via TRPV4 and L-VDCCs contributes to optimal smooth muscle contraction. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets)
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14 pages, 4892 KiB  
Article
Functional Analysis of TRPA1, TRPM3, and TRPV1 Channels in Human Dermal Arteries and Their Role in Vascular Modulation
by Eduardo Rivera-Mancilla, Linda Al-Hassany, Heleen Marynissen, Dorien Bamps, Ingrid M. Garrelds, Jérôme Cornette, A. H. Jan Danser, Carlos M. Villalón, Jan N. de Hoon and Antoinette MaassenVanDenBrink
Pharmaceuticals 2024, 17(2), 156; https://doi.org/10.3390/ph17020156 - 25 Jan 2024
Viewed by 850
Abstract
Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces “local” changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels’ contributions and the pharmacological [...] Read more.
Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces “local” changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels’ contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries. Ex vivo studies assessed the vascular function of artery segments and analyzed the effects of different compounds. Concentration–response curves to cinnamaldehyde, pregnenolone sulfate (PregS, TRPM3 agonist), and capsaicin were constructed to evaluate the effect of the antagonists HC030031 (TRPA1); isosakuranetin (TRPM3); and capsazepine (TRPV1). Additionally, the antagonists/inhibitors olcegepant (CGRP receptor); L-NAME (nitric oxide synthase); indomethacin (cyclooxygenase); TRAM-34 plus apamin (K+ channels); and MK-801 (NMDA receptors, only for PregS) were used. Moreover, CGRP release was assessed in the organ bath fluid post-agonist-exposure. In dermal arteries, cinnamaldehyde- and capsaicin-induced relaxation remained unchanged after the aforementioned antagonists, while PregS-induced relaxation was significantly inhibited by isosakuranetin, L-NAME and MK-801. Furthermore, there was a significant increase in CGRP levels post-agonist-exposure. In our experimental model, TRPA1 and TRPV1 channels seem not to be involved in cinnamaldehyde- or capsaicin-induced relaxation, respectively, whereas TRPM3 channels contribute to PregS-induced relaxation, possibly via CGRP-independent mechanisms. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets)
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11 pages, 2352 KiB  
Article
Pharmacological Differences between Native Homomeric Transient Receptor Potential Canonical Type 4 Channels and Heteromeric Transient Receptor Potential Canonical Type 1/4 Channels in Lateral Septal Neurons
by Kevin D. Phelan, U Thaung Shwe and Fang Zheng
Pharmaceuticals 2023, 16(9), 1291; https://doi.org/10.3390/ph16091291 - 13 Sep 2023
Cited by 2 | Viewed by 625
Abstract
Given the unique expression patterns and revelations of its critical involvement in a host of neurological disorders, the TRPC1/4/5 subgroup has become an intense target of drug development, and some compounds are now in clinical trials. However, little is known about the exact [...] Read more.
Given the unique expression patterns and revelations of its critical involvement in a host of neurological disorders, the TRPC1/4/5 subgroup has become an intense target of drug development, and some compounds are now in clinical trials. However, little is known about the exact subunit composition of this subfamily of TRPC channels in various native tissues, and whether it has functional and pharmacological implications. In this study, we investigated the effects of two TRPC4 modulators located in the lateral septum, in which a metabotropic glutamate receptor (mGluR) agonist-induced plateau potential is mediated by TRPC channels composed of TRPC1 and TRPC4. Lateral septal neurons were recorded intracellularly in brain slices using sharp electrodes. Drugs were applied via bath superfusion. We showed that the plateau potential in mice lacking TRPC1 is modulated by ML204 and La3+ in a manner that is like homomeric TRPC4 channels in artificial expression systems. However, the plateau potential that is primarily mediated by heteromeric TRPC1/4 channels in lateral septal neurons in wildtype mice was modulated differently by ML204 and La3+. Our data suggest that native homomeric TRPC4 channels and heteromeric TRPC1/4 channels are pharmacologically distinct, and the current drug development strategy regarding TRPC1/4/5 may need to be reevaluated. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets)
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16 pages, 4670 KiB  
Article
Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis
by Marisa Jadna Silva Frederico, Andreza Cipriani, Jocelyn Brice Alexandre Heim, Ana Karla Bittencourt Mendes, Marcela Aragón, Joana Margarida Gaspar, Nylane Maria Nunes De Alencar and Fátima Regina Mena Barreto Silva
Pharmaceuticals 2023, 16(8), 1167; https://doi.org/10.3390/ph16081167 - 16 Aug 2023
Cited by 1 | Viewed by 758
Abstract
This pre-clinical study investigated the transient receptor potential ankyrin-1 (TRPA1) channels on modulating targets for glucose homeostasis using agonists: the electrophilic agonists, cinnamaldehyde (CIN) and allyl isothiocyanate (AITC), and the non-electrophilic agonist, carvacrol (CRV). A glucose tolerance test was performed on rats. CIN [...] Read more.
This pre-clinical study investigated the transient receptor potential ankyrin-1 (TRPA1) channels on modulating targets for glucose homeostasis using agonists: the electrophilic agonists, cinnamaldehyde (CIN) and allyl isothiocyanate (AITC), and the non-electrophilic agonist, carvacrol (CRV). A glucose tolerance test was performed on rats. CIN and AITC (5, 10 and 20 mg/kg) or CRV (25, 100, 300, and 600 mg/kg) were administered intraperitoneally (i.p.), and glycemia was measured. In the intestine, Glucagon-like peptide-1 (GLP-1) and disaccharidase activity were evaluated (in vivo and in vitro, respectively). Furthermore, in vivo and in vitro insulin secretion was determined. Islets were used to measure insulin secretion and calcium influx. CIN and AITC improved glucose tolerance and increased insulin secretion in vivo and in vitro. CRV was unable to reduce glycemia. Electrophilic agonists, CIN and AITC, inhibited disaccharidases and acted as secretagogues in the intestine by inducing GLP-1 release in vivo and in vitro and contributed to insulin secretion and glycemia. The effect of CIN on calcium influx in pancreatic islets (insulin secretion) involves voltage-dependent calcium channels and calcium from stores. TRPA1 triggers calcium influx and potentiates intracellular calcium release to induce insulin secretion, suggesting that electrophilic agonists mediate this signaling transduction for the control of glycemia. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets)
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13 pages, 3018 KiB  
Article
Analysis of the Effect of the TRPC4/TRPC5 Blocker, ML204, in Sucrose-Induced Metabolic Imbalance
by Mizael C. Araújo, Suzany H. S. Soczek, Jaqueline P. Pontes, Bruno A. S. Pinto, Lucas M. França, Bruna da Silva Soley, Gabriela S. Santos, Warlison F. de Silva Saminez, Fernanda K. M. Fernandes, João L. do Carmo Lima, Daniele Maria-Ferreira, João F. S. Rodrigues, Nara L. M. Quintão, Valério Monteiro-Neto, Antônio M. A. Paes and Elizabeth S. Fernandes
Pharmaceuticals 2023, 16(8), 1100; https://doi.org/10.3390/ph16081100 - 03 Aug 2023
Cited by 3 | Viewed by 925
Abstract
Sugar-induced metabolic imbalances are a major health problem since an excessive consumption of saccharides has been linked to greater obesity rates at a global level. Sucrose, a disaccharide composed of 50% glucose and 50% fructose, is commonly used in the food industry and [...] Read more.
Sugar-induced metabolic imbalances are a major health problem since an excessive consumption of saccharides has been linked to greater obesity rates at a global level. Sucrose, a disaccharide composed of 50% glucose and 50% fructose, is commonly used in the food industry and found in a range of fast, restaurant, and processed foods. Herein, we investigated the effects of a TRPC4/TRPC5 blocker, ML204, in the metabolic imbalances triggered by early exposure to sucrose-enriched diet in mice. TRPC4 and TRPC5 belong to the family of non-selective Ca+2 channels known as transient receptor potential channels. High-sucrose (HS)-fed animals with hyperglycaemia and dyslipidaemia, were accompanied by increased body mass index. mesenteric adipose tissue accumulation with larger diameter cells and hepatic steatosis in comparison to those fed normal diet. HS mice also exhibited enhanced adipose, liver, and pancreas TNFα and VEGF levels. ML204 exacerbated hyperglycaemia, dyslipidaemia, fat tissue deposition, hepatic steatosis, and adipose tissue and liver TNFα in HS-fed mice. Normal mice treated with the blocker had greater hepatic steatosis and adipose tissue cell numbers/diameter than those receiving vehicle, but showed no significant changes in tissue inflammation, glucose, and lipid levels. The results indicate that TRPC4/TRPC5 protect against the metabolic imbalances caused by HS ingestion. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets)
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Review

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18 pages, 1424 KiB  
Review
Targeting Transient Receptor Potential (TRP) Channels, Mas-Related G-Protein-Coupled Receptors (Mrgprs), and Protease-Activated Receptors (PARs) to Relieve Itch
by Merab G. Tsagareli, Taylor Follansbee, Mirela Iodi Carstens and Earl Carstens
Pharmaceuticals 2023, 16(12), 1707; https://doi.org/10.3390/ph16121707 - 08 Dec 2023
Viewed by 1344
Abstract
Itch (pruritus) is a sensation in the skin that provokes the desire to scratch. The sensation of itch is mediated through a subclass of primary afferent sensory neurons, termed pruriceptors, which express molecular receptors that are activated by itch-evoking ligands. Also expressed in [...] Read more.
Itch (pruritus) is a sensation in the skin that provokes the desire to scratch. The sensation of itch is mediated through a subclass of primary afferent sensory neurons, termed pruriceptors, which express molecular receptors that are activated by itch-evoking ligands. Also expressed in pruriceptors are several types of Transient Receptor Potential (TRP) channels. TRP channels are a diverse class of cation channels that are responsive to various somatosensory stimuli like touch, pain, itch, and temperature. In pruriceptors, TRP channels can be activated through intracellular signaling cascades initiated by pruritogen receptors and underly neuronal activation. In this review, we discuss the role of TRP channels TRPA1, TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPC3/4 in acute and chronic pruritus. Since these channels often mediate itch in association with pruritogen receptors, we also discuss Mas-related G-protein-coupled receptors (Mrgprs) and protease-activated receptors (PARs). Additionally, we cover the exciting therapeutic targets amongst the TRP family, as well as Mrgprs and PARs for the treatment of pruritus. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets)
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16 pages, 918 KiB  
Review
Role of Resolvins in Inflammatory and Neuropathic Pain
by Jaeik Park, Jueun Roh, Jingying Pan, Yong Ho Kim, Chul-Kyu Park and Youn Yi Jo
Pharmaceuticals 2023, 16(10), 1366; https://doi.org/10.3390/ph16101366 - 27 Sep 2023
Viewed by 1001
Abstract
Chronic pain is an unpleasant experience associated with actual or potential tissue damage. Inflammatory pain alerts the body to inflammation and promotes healing; however, unresolved inflammation can lead to chronic pain. Conversely, neuropathic pain, due to somatosensory damage, can be a disease in [...] Read more.
Chronic pain is an unpleasant experience associated with actual or potential tissue damage. Inflammatory pain alerts the body to inflammation and promotes healing; however, unresolved inflammation can lead to chronic pain. Conversely, neuropathic pain, due to somatosensory damage, can be a disease in itself. However, inflammation plays a considerable role in the progression of both types of pain. Resolvins, derived from omega-3 fatty acids, actively suppress pro-inflammatory mediators and aid in the resolution of inflammation. Resolvins alleviate various inflammatory and neuropathic pain models by reducing hypersensitivity and regulating inflammatory cytokines and glial activation in the spinal cord and dorsal root ganglia. Thus, resolvins are a promising alternative for pain management with the potential to reduce the side effects associated with conventional medications. Continued research is crucial to unlock the therapeutic potential of resolvins and integrate them into effective clinical pain management strategies. This review aimed to evaluate the literature surrounding the resolvins in inflammatory and neuropathic pain. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets)
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