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Voltage-Gated and TRP Ion Channels: Molecular Basis for their Function, Misfunction, and Therapeutic Applications

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

Deadline for manuscript submissions: closed (31 July 2019) | Viewed by 57360

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Prof. Dr. Pietro Campiglia

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Guest Editor

Department of Pharmacy, University of Salerno, Fisciano, Italy
Interests: voltage- and ligand-gated ion channels (particularly, TRP and Kv channels); nutraceuticals, medicinal chemistry
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Asia Fernandez Carvajal

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Co-Guest Editor

Institute of Molecular and Cell Biology, Miguel Hernandez University, Elche, Spain
Interests: high-throughput screening; discovery and development of anti-nociceptive drugs; structure–function studies on TRP ion channels; translational research in the field of sensory neurobiology; role of thermoTRP channels in the pathophysiology of migraine
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Carmine Ostacolo

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Co-Guest Editor

Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, I-80131 Napoli, Italy
Interests: drug design and synthesis; pharmacokinetics; food-derived bioactive molecules; voltage-gated potassium channels; TRPM8
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

The signal deriving from ion flux through membranes is responsible for a plethora of pivotal biological events, including hormone secretion, muscle contraction, sensation, brain information processing, and peripheral tissue control. In excitable cells, electrical signals also influence metabolism, signal transduction, gene expression, and protein synthesis, degradation, and targeting. These electrical signals are conducted by different members of the ion channel protein superfamily, composed of more than 140 structurally related pore-forming proteins. This is the reason why voltage-gated ion channels represent an intriguing pharmacological target for the treatment of different pathologies, including pain, cardiovascular diseases, neurological and neurodegenerative disorders, cancer, and metabolic syndromes, as widely reported in the literature. In addition, channellophaties, resulting from a congenital or acquired mutation of voltage-gated ion channels, are responsible for specific and, usually, rare diseases, such as episodic ataxia, epilepsy, hyperkalemic or hypokalemic periodic paralysis, Lambert–Eaton myasthenic syndrome, paramyotonia, Dravet syndrome, pain syndromes, and many others. Many efforts have been made in the last decade for the elucidation of the crystal structure of voltage-gated ion channels, their gating mechanisms, the molecular basis of their function or misfunction, their phatophysiological role, and their modulators. These are the main topics of interest of the present Special Issue that is aimed to highlight the latest advancements in this field, with a specific focus on transient receptor potential channels (TRP). Original research and review articles concerning this specific matter are invited.

Prof. Dr. Pietro Campiglia
Prof. Dr. Asia Fernandez Carvajal
Assist. Prof. Dr. Carmine Ostacolo
Guest Editors

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Keywords

Ion channels
Structure and gating mechanisms
Molecular basis of function and misfunction
Identification of modulators
Molecular pathways
Sensory signal transduction
Therapeutics
Pain
Inflammation
Cancer.

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Published Papers (9 papers)

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15 pages, 1602 KiB

Open AccessCommunication

Lipid Raft Destabilization Impairs Mouse TRPA1 Responses to Cold and Bacterial Lipopolysaccharides

by Justyna B. Startek and Karel Talavera

Int. J. Mol. Sci. 2020, 21(11), 3826; https://doi.org/10.3390/ijms21113826 - 28 May 2020

Cited by 19 | Viewed by 3569

Abstract

The Transient Receptor Potential ankyrin 1 cation channel (TRPA1) is expressed in nociceptive sensory neurons and epithelial cells, where it plays key roles in the detection of noxious stimuli. Recent reports showed that mouse TRPA1 (mTRPA1) localizes in lipid rafts and that its sensitivity to electrophilic and non-electrophilic agonists is reduced by cholesterol depletion from the plasma membrane. Since effects of manipulating membrane cholesterol levels on other TRP channels are known to vary across different stimuli we here tested whether the disruption of lipid rafts also affects mTRPA1 activation by cold or bacterial lipopolysaccharides (LPS). Cooling to 12 °C, E. coli LPS and allyl isothiocyanate (AITC) induced robust Ca²⁺ responses in CHO-K1 cells stably transfected with mTRPA1. The amplitudes of the responses to these stimuli were significantly lower in cells treated with the cholesterol scavenger methyl β-cyclodextrin (MCD) or with the sphingolipids hydrolyzer sphingomyelinase (SMase). This effect was more prominent with higher concentrations of the raft destabilizers. Our data also indicate that reduction of cholesterol does not alter the expression of mTRPA1 in the plasma membrane in the CHO-K1 stable expression system, and that the most salient effect is that on the channel gating. Our findings further indicate that the function of mTRPA1 is regulated by the local lipid environment and suggest that targeting lipid-TRPA1 interactions may be a strategy for the treatment of pain and neurogenic inflammation. Full article

(This article belongs to the Special Issue Voltage-Gated and TRP Ion Channels: Molecular Basis for their Function, Misfunction, and Therapeutic Applications)

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11 pages, 4011 KiB

Open AccessArticle

Ablation of Endothelial TRPV4 Channels Alters the Dynamic Ca²⁺ Signaling Profile in Mouse Carotid Arteries

by Stuart J. McFarland, David S. Weber, Chung-sik Choi, Mike T. Lin and Mark S. Taylor

Int. J. Mol. Sci. 2020, 21(6), 2179; https://doi.org/10.3390/ijms21062179 - 22 Mar 2020

Cited by 8 | Viewed by 3051

Abstract

Transient receptor potential vanilloid 4 channels (TRPV4) are pivotal regulators of vascular homeostasis. Altered TRPV4 signaling has recently been implicated in various cardiovascular diseases, including hypertension and atherosclerosis. These versatile nonselective cation channels increase endothelial Ca²⁺ influx in response to various stimuli including shear stress and G protein-coupled receptor (GPCR) activation. Recent findings suggest TRPV4 channels produce localized Ca²⁺ transients at the endothelial cell plasma membrane that may allow targeted effector recruitment and promote large-scale Ca²⁺ events via release from internal stores (endoplasmic reticulum). However, the specific impact of TRPV4 channels on Ca²⁺ signaling in the intact arterial intima remains unknown. In the current study, we employ an endothelium-specific TRPV4 knockout mouse model (ecTRPV4^−/−) to identify and characterize TRPV4-dependent endothelial Ca²⁺ dynamics. We find that carotid arteries from both ecTRPV4^−/− and WT mice exhibit a range of basal and acetylcholine (ACh)-induced Ca²⁺ dynamics, similar in net frequency. Analysis of discrete Ca²⁺ event parameters (amplitude, duration, and spread) and event composite values reveals that while ecTRPV4^−/− artery endothelium predominantly produces large Ca²⁺ events comparable to and in excess of those produced by WT endothelium, they are deficient in a particular population of small events, under both basal and ACh-stimulated conditions. These findings support the concept that TRPV4 channels are responsible for generating a distinct population of focal Ca²⁺ transients in the intact arterial endothelium, likely underlying their essential role in vascular homeostasis. Full article

(This article belongs to the Special Issue Voltage-Gated and TRP Ion Channels: Molecular Basis for their Function, Misfunction, and Therapeutic Applications)

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14 pages, 2257 KiB

Open AccessArticle

Characterization of New TRPM8 Modulators in Pain Perception

by Carmen De Caro, Claudia Cristiano, Carmen Avagliano, Alessia Bertamino, Carmine Ostacolo, Pietro Campiglia, Isabel Gomez-Monterrey, Giovanna La Rana, Oreste Gualillo, Antonio Calignano and Roberto Russo

Int. J. Mol. Sci. 2019, 20(22), 5544; https://doi.org/10.3390/ijms20225544 - 7 Nov 2019

Cited by 43 | Viewed by 5451

Abstract

Background: Transient Receptor Potential Melastatin-8 (TRPM8) is a non-selective cation channel activated by cold temperature and by cooling agents. Several studies have proved that this channel is involved in pain perception. Although some studies indicate that TRPM8 inhibition is necessary to reduce acute and chronic pain, it is also reported that TRPM8 activation produces analgesia. These conflicting results could be explained by extracellular Ca²⁺-dependent desensitization that is induced by an excessive activation. Likely, this effect is due to phosphatidylinositol 4,5-bisphosphate (PIP2) depletion that leads to modification of TRPM8 channel activity, shifting voltage dependence towards more positive potentials. This phenomenon needs further evaluation and confirmation that would allow us to understand better the role of this channel and to develop new therapeutic strategies for controlling pain. Experimental approach: To understand the role of TRPM8 in pain perception, we tested two specific TRPM8-modulating compounds, an antagonist (IGM-18) and an agonist (IGM-5), in either acute or chronic animal pain models using male Sprague-Dawley rats or CD1 mice, after systemic or topical routes of administration. Results: IGM-18 and IGM-5 were fully characterized in vivo. The wet-dog shake test and the body temperature measurements highlighted the antagonist activity of IGM-18 on TRPM8 channels. Moreover, IGM-18 exerted an analgesic effect on formalin-induced orofacial pain and chronic constriction injury-induced neuropathic pain, demonstrating the involvement of TRPM8 channels in these two pain models. Finally, the results were consistent with TRPM8 downregulation by agonist IGM-5, due to its excessive activation. Conclusions: TRPM8 channels are strongly involved in pain modulation, and their selective antagonist is able to reduce both acute and chronic pain. Full article

(This article belongs to the Special Issue Voltage-Gated and TRP Ion Channels: Molecular Basis for their Function, Misfunction, and Therapeutic Applications)

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14 pages, 1381 KiB

Open AccessArticle

Activation of Kv7 Potassium Channels Inhibits Intracellular Ca²⁺ Increases Triggered By TRPV1-Mediated Pain-Inducing Stimuli in F11 Immortalized Sensory Neurons

by Paolo Ambrosino, Maria Virginia Soldovieri, Erika Di Zazzo, Gianluca Paventi, Fabio Arturo Iannotti, Ilaria Mosca, Francesco Miceli, Cristina Franco, Lorella Maria Teresa Canzoniero and Maurizio Taglialatela

Int. J. Mol. Sci. 2019, 20(18), 4322; https://doi.org/10.3390/ijms20184322 - 4 Sep 2019

Cited by 9 | Viewed by 3883

Abstract

Kv7.2-Kv7.5 channels mediate the M-current (I_KM), a K⁺-selective current regulating neuronal excitability and representing an attractive target for pharmacological therapy against hyperexcitability diseases such as pain. Kv7 channels interact functionally with transient receptor potential vanilloid 1 (TRPV1) channels activated by endogenous and/or exogenous pain-inducing substances, such as bradykinin (BK) or capsaicin (CAP), respectively; however, whether Kv7 channels of specific molecular composition provide a dominant contribution in BK- or CAP-evoked responses is yet unknown. To this aim, Kv7 transcripts expression and function were assessed in F11 immortalized sensorial neurons, a cellular model widely used to assess nociceptive molecular mechanisms. In these cells, the effects of the pan-Kv7 activator retigabine were investigated, as well as the effects of ICA-27243 and (S)-1, two Kv7 activators acting preferentially on Kv7.2/Kv7.3 and Kv7.4/Kv7.5 channels, respectively, on BK- and CAP-induced changes in intracellular Ca²⁺ concentrations ([Ca²⁺]_i). The results obtained revealed the expression of transcripts of all Kv7 genes, leading to an I_KM-like current. Moreover, all tested Kv7 openers inhibited BK- and CAP-induced responses by a similar extent (~60%); at least for BK-induced Ca²⁺ responses, the potency of retigabine (IC₅₀~1 µM) was higher than that of ICA-27243 (IC₅₀~5 µM) and (S)-1 (IC₅₀~7 µM). Altogether, these results suggest that I_KM activation effectively counteracts the cellular processes triggered by TRPV1-mediated pain-inducing stimuli, and highlight a possible critical contribution of Kv7.4 subunits. Full article

(This article belongs to the Special Issue Voltage-Gated and TRP Ion Channels: Molecular Basis for their Function, Misfunction, and Therapeutic Applications)

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18 pages, 6553 KiB

Open AccessArticle

Cytoplasmic Inter-Subunit Interface Controls Use-Dependence of Thermal Activation of TRPV3 Channel

by Lucie Macikova, Lenka Vyklicka, Ivan Barvik, Alexander I. Sobolevsky and Viktorie Vlachova

Int. J. Mol. Sci. 2019, 20(16), 3990; https://doi.org/10.3390/ijms20163990 - 16 Aug 2019

Cited by 13 | Viewed by 4081

Abstract

The vanilloid transient receptor potential channel TRPV3 is a putative molecular thermosensor widely considered to be involved in cutaneous sensation, skin homeostasis, nociception, and pruritus. Repeated stimulation of TRPV3 by high temperatures above 50 °C progressively increases its responses and shifts the activation threshold to physiological temperatures. This use-dependence does not occur in the related heat-sensitive TRPV1 channel in which responses decrease, and the activation threshold is retained above 40 °C during activations. By combining structure-based mutagenesis, electrophysiology, and molecular modeling, we showed that chimeric replacement of the residues from the TRPV3 cytoplasmic inter-subunit interface (N251–E257) with the homologous residues of TRPV1 resulted in channels that, similarly to TRPV1, exhibited a lowered thermal threshold, were sensitized, and failed to close completely after intense stimulation. Crosslinking of this interface by the engineered disulfide bridge between substituted cysteines F259C and V385C (or, to a lesser extent, Y382C) locked the channel in an open state. On the other hand, mutation of a single residue within this region (E736) resulted in heat resistant channels. We propose that alterations in the cytoplasmic inter-subunit interface produce shifts in the channel gating equilibrium and that this domain is critical for the use-dependence of the heat sensitivity of TRPV3. Full article

(This article belongs to the Special Issue Voltage-Gated and TRP Ion Channels: Molecular Basis for their Function, Misfunction, and Therapeutic Applications)

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16 pages, 2745 KiB

Open AccessArticle

TRPM4 and TRPM5 Channels Share Crucial Amino Acid Residues for Ca²⁺ Sensitivity but Not Significance of PI(4,5)P₂

by Soichiro Yamaguchi, Akira Tanimoto, Shinsuke Iwasa and Ken-ichi Otsuguro

Int. J. Mol. Sci. 2019, 20(8), 2012; https://doi.org/10.3390/ijms20082012 - 24 Apr 2019

Cited by 14 | Viewed by 4499

Abstract

Transient receptor potential melastatin member 4 (TRPM4) and 5 (TRPM5) channels are Ca²⁺-activated nonselective cation channels. Intracellular Ca²⁺ is the most important regulator for them to open, though PI(4,5)P₂, a membrane phosphoinositide, has been reported to regulate their Ca²⁺-sensitivities. We previously reported that negatively-charged amino acid residues near and in the TRP domain are necessary for the normal Ca²⁺ sensitivity of TRPM4. More recently, a cryo-electron microscopy structure of Ca²⁺-bound (but closed) TRPM4 was reported, proposing a Ca²⁺-binding site within an intracellular cavity formed by S2 and S3. Here, we examined the functional effects of mutations of the amino acid residues related to the proposed Ca²⁺-binding site on TRPM4 and also TRPM5 using mutagenesis and patch clamp techniques. The mutations of the amino acid residues of TRPM4 and TRPM5 reduced their Ca²⁺-sensitivities in a similar way. On the other hand, intracellular applications of PI(4,5)P₂ recovered Ca²⁺-sensitivity of desensitized TRPM4, but its effect on TRPM5 was negligible. From these results, the Ca²⁺-binding sites of TRPM4 and TRPM5 were shown to be formed by the same amino acid residues by functional analyses, but the impact of PI(4,5)P₂ on the regulation of TRPM5 seemed to be smaller than that on the regulation of TRPM4. Full article

(This article belongs to the Special Issue Voltage-Gated and TRP Ion Channels: Molecular Basis for their Function, Misfunction, and Therapeutic Applications)

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Review

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36 pages, 651 KiB

Open AccessReview

Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders

by Arturo Andrade, Ashton Brennecke, Shayna Mallat, Julian Brown, Juan Gomez-Rivadeneira, Natalie Czepiel and Laura Londrigan

Int. J. Mol. Sci. 2019, 20(14), 3537; https://doi.org/10.3390/ijms20143537 - 19 Jul 2019

Cited by 84 | Viewed by 10822

Abstract

Psychiatric disorders are mental, behavioral or emotional disorders. These conditions are prevalent, one in four adults suffer from any type of psychiatric disorders world-wide. It has always been observed that psychiatric disorders have a genetic component, however, new methods to sequence full genomes of large cohorts have identified with high precision genetic risk loci for these conditions. Psychiatric disorders include, but are not limited to, bipolar disorder, schizophrenia, autism spectrum disorder, anxiety disorders, major depressive disorder, and attention-deficit and hyperactivity disorder. Several risk loci for psychiatric disorders fall within genes that encode for voltage-gated calcium channels (Ca_Vs). Calcium entering through Ca_Vs is crucial for multiple neuronal processes. In this review, we will summarize recent findings that link Ca_Vs and their auxiliary subunits to psychiatric disorders. First, we will provide a general overview of Ca_Vs structure, classification, function, expression and pharmacology. Next, we will summarize tools to study risk loci associated with psychiatric disorders. We will examine functional studies of risk variations in Ca_V genes when available. Finally, we will review pharmacological evidence of the use of Ca_V modulators to treat psychiatric disorders. Our review will be of interest for those studying pathophysiological aspects of Ca_Vs. Full article

(This article belongs to the Special Issue Voltage-Gated and TRP Ion Channels: Molecular Basis for their Function, Misfunction, and Therapeutic Applications)

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20 pages, 796 KiB

Open AccessReview

Is TRPA1 Burning Down TRPV1 as Druggable Target for the Treatment of Chronic Pain?

by Simona Giorgi, Magdalena Nikolaeva-Koleva, David Alarcón-Alarcón, Laura Butrón and Sara González-Rodríguez

Int. J. Mol. Sci. 2019, 20(12), 2906; https://doi.org/10.3390/ijms20122906 - 14 Jun 2019

Cited by 36 | Viewed by 10149

Abstract

Over the last decades, a great array of molecular mediators have been identified as potential targets for the treatment of chronic pain. Among these mediators, transient receptor potential (TRP) channel superfamily members have been thoroughly studied. Namely, the nonselective cationic channel, transient receptor potential ankyrin subtype 1 (TRPA1), has been described as a chemical nocisensor involved in noxious cold and mechanical sensation and as rivalling TRPV1, which traditionally has been considered as the most important TRP channel involved in nociceptive transduction. However, few TRPA1-related drugs have succeeded in clinical trials. In the present review, we attempt to discuss the latest data on the topic and future directions for pharmacological intervention. Full article

(This article belongs to the Special Issue Voltage-Gated and TRP Ion Channels: Molecular Basis for their Function, Misfunction, and Therapeutic Applications)

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22 pages, 1168 KiB

Open AccessReview

Recent Progress in TRPM8 Modulation: An Update

by Rosario González-Muñiz, M. Angeles Bonache, Cristina Martín-Escura and Isabel Gómez-Monterrey

Int. J. Mol. Sci. 2019, 20(11), 2618; https://doi.org/10.3390/ijms20112618 - 28 May 2019

Cited by 89 | Viewed by 10792

Abstract

The transient receptor potential melastatin subtype 8 (TRPM8) is a nonselective, multimodal ion channel, activated by low temperatures (<28 °C), pressure, and cooling compounds (menthol, icilin). Experimental evidences indicated a role of TRPM8 in cold thermal transduction, different life-threatening tumors, and other pathologies, including migraine, urinary tract dysfunction, dry eye disease, and obesity. Hence, the modulation of the TRPM8 channel could be essential in order to understand its implications in these pathologies and for therapeutic intervention. This short review will cover recent progress on the TRPM8 agonists and antagonists, describing newly reported chemotypes, and their application in the pharmacological characterization of TRPM8 in health and disease. The recently described structures of the TRPM8 channel alone or complexed with known agonists and PIP₂ are also discussed. Full article

(This article belongs to the Special Issue Voltage-Gated and TRP Ion Channels: Molecular Basis for their Function, Misfunction, and Therapeutic Applications)

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