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Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation (3rd Edition)

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: 20 August 2026 | Viewed by 3704

Special Issue Editor

Dr. Gabriella Guerrini

E-Mail Website
Guest Editor
Dipartimento Neurofarba, Università degli Studi di Firenze, Via U. Schiff, 6, Polo Scientifico, 50019 Sesto Fiorentino, Italy
Interests: heterocyclic nitrogen compounds; pyrazolo condensed compounds; synthesis; gabaa receptor subtype; human neutrophil elastase inhibitors; medicinal chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue “Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation”.

The targeting of ion channels represents a strategy for the treatment of several pathologies since they are responsible for ion fluxes across membranes and contribute to maintaining cellular functions in central and peripheral tissues. The ion channels include two principal types of membrane proteins:

  1. Ligand-gated ion channels (LGICs), opened by neurotransmitters or ligands that bind the orthosteric or allosteric sites involved in the overall fast synaptic transmission in the nervous system;
  2. Voltage-gated ion channels, opened or closed by a change in the electrical gradient across the membrane.

Ion channels are very intriguing targets, and the development of new techniques elucidating the structures of these channels (e.g., cryo-EM) contributes to the design of new potential therapeutic agents for the treatment of neurological and neurodegenerative diseases, cancer, metabolic syndrome, and pain.

This Special Issue, titled “Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation”, aims to collect contributions related to the drug design, molecular modeling, pharmacological investigation, and therapeutic applications of ion channel ligands.

Dr. Gabriella Guerrini
Guest Editor

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Keywords

  • LGIC
  • voltage-gated ion channel
  • other ion channels
  • biological studies
  • molecular modeling
  • drug design
  • synthesis

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Published Papers (3 papers)

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Research

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23 pages, 3209 KB  
Article
Resting Cytosolic and Nuclear Reactive Oxygen Species (ROS) Are Regulated by the Basal Activity of ET-1 Receptors in Human Vascular Smooth Muscle Cells
by Ghassan Bkaily, Rana Semaan and Danielle Jacques
Int. J. Mol. Sci. 2026, 27(6), 2524; https://doi.org/10.3390/ijms27062524 - 10 Mar 2026
Viewed by 297
Abstract
Endothelin-1 (ET-1) is a potent vasoconstrictor that exerts its numerous biological actions through two receptors, ETA and ETB. However, the implication and role of each receptor in ROS generation remain ambiguous. Previously, our group reported that blocking the basal activity [...] Read more.
Endothelin-1 (ET-1) is a potent vasoconstrictor that exerts its numerous biological actions through two receptors, ETA and ETB. However, the implication and role of each receptor in ROS generation remain ambiguous. Previously, our group reported that blocking the basal activity of ETA and ETB receptors with their respective peptidic antagonists increased basal intracellular calcium (Ca2+) levels, an effect inhibited by chelating extracellular Ca2+. Since a crosstalk between Ca2+ and reactive oxygen species (ROS) exists, the purpose of the present work was to investigate whether this increase in basal resting Ca2+ level induced by the blockade of ETA and ETB receptors is associated with an increase in resting ROS level. Our results showed that the basal activity of ETA and ETB receptors contributes negatively to the resting level of cytosolic and nuclear ROS, and that each receptor appears to act as the other’s physiological antagonist. Furthermore, our results showed that ET-1 receptor blockade increases ROS via a receptor insensitive to ETA and ETB receptor antagonists. This type of receptor could be the one reported by our group, ETC, or simply a heterodimeric ETA/ETB receptor. Moreover, blocking the heterodimerized ETA/ETB binding site is sufficient to unblock the physiological antagonism that each receptor exerts on the other. Furthermore, our results showed that blocking both ETA and ETB receptors, thereby preventing heterodimerization, prevented the increase in resting ROS, supporting the existence of a heterodimerized ET-1 receptor. Since human vascular smooth muscle cells (VSMCs) express only ETB receptors at the nuclear membrane, it is possible to suggest that nuclear ETB receptors are homodimers that regulate the resting nuclear ROS level. In conclusion, our results showed that the regulation of resting ROS levels by ET-1 and its receptors can be mediated by homodimerized and/or heterodimerized receptor activation; hence, the importance of developing drugs targeting this receptor type. Full article
(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation (3rd Edition))
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Review

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27 pages, 4582 KB  
Review
TRPV4-Mast Cell Interactions in Neurogenic Inflammation and Chronic Diseases: A Narrative Review
by Malak Fouani, Srishti Kumari, Anne Charles, Christopher Wickware, Ashley A. Moore, Calvin H. Cho, Soman N. Abraham and Carlene D. Moore
Int. J. Mol. Sci. 2026, 27(6), 2865; https://doi.org/10.3390/ijms27062865 - 21 Mar 2026
Viewed by 1346
Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a polymodal cation channel that is widely expressed in sensory neurons, immune cells, and structural tissues, where it integrates mechanical, osmotic, and chemical stimuli to regulate both physiological responses and disease-associated signaling. Mast cells (MCs), key [...] Read more.
Transient receptor potential vanilloid 4 (TRPV4) is a polymodal cation channel that is widely expressed in sensory neurons, immune cells, and structural tissues, where it integrates mechanical, osmotic, and chemical stimuli to regulate both physiological responses and disease-associated signaling. Mast cells (MCs), key immune effector cells capable of rapid mediator release through degranulation, also express TRPV4. Increasing evidence supports TRPV4-MC signaling as an important neuroimmune interface, linking mechanical and inflammatory stimuli to tissue hypersensitivity and pain. In this review, we synthesize current evidence supporting a role for TRPV4 in MC-associated neuroimmune signaling across multiple disease contexts while distinguishing settings in which TRPV4 directly regulates MC activation from those in which MC responses arise through multicellular tissue interactions. Direct TRPV4-dependent MC activation has been described in conditions such as LL-37–driven rosacea and mechanically induced inflammation, whereas in disorders including asthma, visceral hypersensitivity, bladder pain syndromes, and osteoarthritis, TRPV4 activity in epithelial, neuronal, or stromal compartments more often influences MC function indirectly through ATP–purinergic signaling, cytokine release, and neuropeptide-mediated crosstalk. Across systems, TRPV4 emerges not as a single pathogenic switch but as part of a context-dependent signaling network whose functional consequences depend on cell type, tissue microenvironment, and disease stage. Altogether, these findings identify TRPV4 as a therapeutically actionable node within neuroimmune signaling pathways and support the development of tissue-specific and combination strategies targeting both TRPV4 activity and MC-mediated signaling in chronic inflammatory and pain disorders. Full article
(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation (3rd Edition))
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20 pages, 1667 KB  
Review
The Two-Pore Channel 2 in Human Physiology and Diseases: Functional Characterisation and Pharmacology
by Laura Lagostena, Velia Minicozzi, Martina Meucci, Antonella Gradogna, Stefan Milenkovic, Fioretta Palombi, Matteo Ceccarelli, Antonio Filippini and Armando Carpaneto
Int. J. Mol. Sci. 2025, 26(19), 9708; https://doi.org/10.3390/ijms26199708 - 6 Oct 2025
Cited by 2 | Viewed by 1730
Abstract
Two-pore channel 2 (TPC2) is a member of the endolysosomal ion channel family, playing critical roles in intracellular calcium signaling and endomembrane dynamics. This review provides an in-depth analysis of TPC2, covering its structural and functional properties, physiological roles, and involvement in human [...] Read more.
Two-pore channel 2 (TPC2) is a member of the endolysosomal ion channel family, playing critical roles in intracellular calcium signaling and endomembrane dynamics. This review provides an in-depth analysis of TPC2, covering its structural and functional properties, physiological roles, and involvement in human diseases. We discuss current experimental approaches to studying TPC2, including heterologous expression in plant vacuoles and computational modeling strategies. Particular emphasis is placed on the structural determinants of ion permeation, with a focus on the selectivity filter and the central cavity’s influence on channel kinetics. Furthermore, we explore emerging roles of TPC2 in viral infections, particularly SARS-CoV-2, and in cancer, including melanoma progression and neoangiogenesis. The inhibitory potential of natural compounds, such as naringenin, is also examined. By offering a comprehensive overview of current knowledge and methodologies, this review underscores the potential of TPC2 as a promising pharmacological target in both infectious and neoplastic diseases. Full article
(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation (3rd Edition))
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