International Journal of Molecular Sciences

Research

Jump to: Review

15 pages, 7562 KiB

Open AccessArticle

Unnatural Amino Acid Photo-Crosslinking Sheds Light on Gating of the Mechanosensitive Ion Channel OSCA1.2

by Scarleth Duran-Morales, Rachel Reyes-Lizana, German Fernández, Macarena Loncon-Pavez, Yorley Duarte, Valeria Marquez-Miranda and Ignacio Diaz-Franulic

Int. J. Mol. Sci. 2025, 26(15), 7121; https://doi.org/10.3390/ijms26157121 - 23 Jul 2025

Viewed by 336

Abstract

Mechanosensitive ion channels such as OSCA1.2 enable cells to sense and respond to mechanical forces by translating membrane tension into ionic flux. While lipid rearrangement in the inter-subunit cleft has been proposed as a key activation mechanism, the contributions of other domains to [...] Read more.

Mechanosensitive ion channels such as OSCA1.2 enable cells to sense and respond to mechanical forces by translating membrane tension into ionic flux. While lipid rearrangement in the inter-subunit cleft has been proposed as a key activation mechanism, the contributions of other domains to OSCA gating remain unresolved. Here, we combined the genetic encoding of the photoactivatable crosslinker p-benzoyl-L-phenylalanine (BzF) with functional Ca²⁺ imaging and molecular dynamics simulations to dissect the roles of specific residues in OSCA1.2 gating. Targeted UV-induced crosslinking at positions F22, H236, and R343 locked the channel in a non-conducting state, indicating their functional relevance. Structural analysis revealed that these residues are strategically positioned: F22 interacts with lipids near the activation gate, H236 lines the lipid-filled cavity, and R343 forms cross-subunit contacts. Together, these results support a model in which mechanical gating involves a distributed network of residues across multiple channel regions, allosterically converging on the activation gate. This study expands our understanding of mechanotransduction by revealing how distant structural elements contribute to force sensing in OSCA channels. Full article

(This article belongs to the Special Issue Ion Channels as a Potential Target in Pharmaceutical Designs 2.0)

► Show Figures

Figure 1

13 pages, 1684 KiB

Open AccessCommunication

Comparison of Various Assays of Antioxidant Activity/Capacity: Limited Significance of Redox Potentials of Oxidants/Indicators

by Paulina Furdak, Kacper Kut, Grzegorz Bartosz and Izabela Sadowska-Bartosz

Int. J. Mol. Sci. 2025, 26(15), 7069; https://doi.org/10.3390/ijms26157069 - 23 Jul 2025

Viewed by 235

Abstract

Assays of total antioxidant capacity (TAC) of complex materials bring no information on the composition of antioxidants present in a sample. As the thermodynamic condition for a redox reaction is that redox potential of the oxidant must be higher than that of a [...] Read more.

Assays of total antioxidant capacity (TAC) of complex materials bring no information on the composition of antioxidants present in a sample. As the thermodynamic condition for a redox reaction is that redox potential of the oxidant must be higher than that of a reductant (antioxidants), it seemed to be of interest whether it is possible to estimate the content of antioxidants of various ranges of redox potentials using a set of assays employing oxidants/indicators of different values of redox potentials. Antioxidant activities of nine antioxidants and TAC of an aqueous garlic extract were estimated using nine assays of E_o′ of oxidants/indicators ranging from 0.11 to 1.15 V. The antioxidant activities were expressed in mol Trolox equivalents/mol compound. The thermodynamic conditions made some antioxidants unreactive with indicators of sufficiently low E_o′, but otherwise, no dependence between the antioxidant activities and redox potentials of oxidants/indicators and reactivities of antioxidants was observed. TAC of the garlic extract did not show any regular dependence on the redox potential of the oxidant/indicator, being the highest in the test of 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonate) radical (ABTS^•) decolorization. These results indicate that kinetic factors play a primary role in determining the antioxidant activities of antioxidants and TAC in various assays. Full article

(This article belongs to the Special Issue Ion Channels as a Potential Target in Pharmaceutical Designs 2.0)

► Show Figures

Figure 1

13 pages, 1498 KiB

Open AccessArticle

Evaluation of Ropivacaine and 3-OH-Ropivacaine Pharmacokinetics Following Interpectoral Nerve Block via LC-MS/MS—A Pilot Study

by Mihaela Butiulca, Lenard Farczadi, Silvia Imre, Camil Eugen Vari, Laurian Vlase, Leonard Azamfirei and Alexandra Elena Lazar

Int. J. Mol. Sci. 2025, 26(14), 6696; https://doi.org/10.3390/ijms26146696 - 12 Jul 2025

Viewed by 315

Abstract

Regional anesthesia techniques such as the ultrasound-guided PECS II (pectoral nerve block) block are increasingly employed to optimize perioperative analgesia while minimizing systemic anesthetic exposure. Ropivacaine is commonly used for its favorable pharmacological profile; however, clinical data on its pharmacokinetics and systemic metabolite [...] Read more.

Regional anesthesia techniques such as the ultrasound-guided PECS II (pectoral nerve block) block are increasingly employed to optimize perioperative analgesia while minimizing systemic anesthetic exposure. Ropivacaine is commonly used for its favorable pharmacological profile; however, clinical data on its pharmacokinetics and systemic metabolite behavior following interpectoral administration remain limited. This study aimed to characterize the plasma concentration–time profile of ropivacaine and its main active metabolite, 3-OH-ropivacaine, in patients undergoing interpectoral nerve block, using a validated LC-MS/MS (liquid chromatography coupled with mass spectrometry) method. Venous blood samples were collected from 18 patients at predefined time points (0, 1, 3, 6, and 24 h) following a PECS II block performed with a ropivacaine-lidocaine mixture. Plasma concentrations were quantified via a validated LC-MS/MS protocol in accordance with FDA (Food and Drug Administration) and EMA (European Medicines Agency) guidelines. Pharmacokinetic parameters were derived using non-compartmental analysis. Ropivacaine reached a mean peak plasma concentration (Cmax—maximum concentration) of 167.5 ± 28.3 ng/mL at 1.3 ± 0.2 h (Tmax—maximum time). The metabolite 3-OH-ropivacaine peaked at 124.1 ± 21.4 ng/mL at 2.3 ± 0.3 h. The terminal elimination half-life was 19.4 ± 2.8 h for ropivacaine and 29.2 ± 3.1 h for its metabolite. Plasma levels demonstrated prolonged systemic exposure with predictable pharmacokinetics. The PECS II block using ropivacaine results in sustained systemic levels of both the parent drug and its primary metabolite, supporting its role in prolonged perioperative analgesia. These data provide a pharmacokinetic foundation for personalized regional anesthesia protocols. This strategy facilitates the adaptation of anesthetic protocols to the individual characteristics of each patient, aligning with the principles of personalized medicine, particularly in patients with altered metabolic capacity. Full article

(This article belongs to the Special Issue Ion Channels as a Potential Target in Pharmaceutical Designs 2.0)

► Show Figures

Figure 1

17 pages, 8884 KiB

Open AccessArticle

Pharmacological Preconditioning with Diazoxide Upregulates HCN4 Channels in the Sinoatrial Node of Adult Rat Cardiomyocytes

by Wilibaldo Orea, Elba D. Carrillo, Ascención Hernández, Rubén Moreno, María C. García and Jorge A. Sánchez

Int. J. Mol. Sci. 2025, 26(13), 6062; https://doi.org/10.3390/ijms26136062 - 24 Jun 2025

Viewed by 391

Abstract

Cardioprotection against ischemia is achieved using openers of mitochondrial ATP-sensitive K⁺ (mitoKATP) channels such as diazoxide (DZX), leading to pharmacological preconditioning (PPC). We previously reported that PPC decreases the abundance of ventricular Cav1.2 channels, but PPC’s effects on other channels remain largely [...] Read more.

Cardioprotection against ischemia is achieved using openers of mitochondrial ATP-sensitive K⁺ (mitoKATP) channels such as diazoxide (DZX), leading to pharmacological preconditioning (PPC). We previously reported that PPC decreases the abundance of ventricular Cav1.2 channels, but PPC’s effects on other channels remain largely unexplored. In this study, we hypothesized that DZX regulates the expression of hyperpolarization-activated cyclic nucleotide potassium channel 4 (HCN4) channels in sinoatrial node cells (SANCs), the specialized cardiomyocytes that generate the heartbeat. DZX increased the heart rate in intact adult rats. Patch-clamp experiments revealed an increase in the magnitude of ionic currents through HCN4 channels, which was abolished by the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the selective mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD). Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot assays showed that DZX increased HCN4 channel expression at the mRNA and protein levels. Immunofluorescence analyses revealed that PPC increased HCN4 fluorescence, which was abolished by NAC. DZX increased nuclear translocation of c-Fos and decreased protein abundance of RE1 silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF), suggesting the involvement of these factors. Our results suggest that PPC increases the heart rate by upregulating HCN4 channel expression through a mechanism involving c-Fos, REST, and ROS. Full article

(This article belongs to the Special Issue Ion Channels as a Potential Target in Pharmaceutical Designs 2.0)

► Show Figures

Figure 1

Review

Jump to: Research

26 pages, 1203 KiB

Open AccessReview

Deciphering the Role of Functional Ion Channels in Cancer Stem Cells (CSCs) and Their Therapeutic Implications

by Krishna Samanta, Gali Sri Venkata Sai Rishma Reddy, Neeraj Kumar Sharma and Pulak Kar

Int. J. Mol. Sci. 2025, 26(15), 7595; https://doi.org/10.3390/ijms26157595 - 6 Aug 2025

Abstract

Despite advances in medicine, cancer remains one of the foremost global health concerns. Conventional treatments like surgery, radiotherapy, and chemotherapy have advanced with the emergence of targeted and immunotherapy approaches. However, therapeutic resistance and relapse remain major barriers to long-term success in cancer [...] Read more.

Despite advances in medicine, cancer remains one of the foremost global health concerns. Conventional treatments like surgery, radiotherapy, and chemotherapy have advanced with the emergence of targeted and immunotherapy approaches. However, therapeutic resistance and relapse remain major barriers to long-term success in cancer treatment, often driven by cancer stem cells (CSCs). These rare, resilient cells can survive therapy and drive tumour regrowth, urging deeper investigation into the mechanisms underlying their persistence. CSCs express ion channels typical of excitable tissues, which, beyond electrophysiology, critically regulate CSC fate. However, the underlying regulatory mechanisms of these channels in CSCs remain largely unexplored and poorly understood. Nevertheless, the therapeutic potential of targeting CSC ion channels is immense, as it offers a powerful strategy to disrupt vital signalling pathways involved in numerous pathological conditions. In this review, we explore the diverse repertoire of ion channels expressed in CSCs and highlight recent mechanistic insights into how these channels modulate CSC behaviours, dynamics, and functions. We present a concise overview of ion channel-mediated CSC regulation, emphasizing their potential as novel diagnostic markers and therapeutic targets, and identifying key areas for future research. Full article

(This article belongs to the Special Issue Ion Channels as a Potential Target in Pharmaceutical Designs 2.0)

► Show Figures

Figure 1

31 pages, 2317 KiB

Open AccessReview

Roles of Ion Channels in Oligodendrocyte Precursor Cells: From Physiology to Pathology

by Jianing Wang, Yu Shen, Ping Liao, Bowen Yang and Ruotian Jiang

Int. J. Mol. Sci. 2025, 26(15), 7336; https://doi.org/10.3390/ijms26157336 - 29 Jul 2025

Viewed by 255

Abstract

Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse [...] Read more.

Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer’s disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases. Full article

(This article belongs to the Special Issue Ion Channels as a Potential Target in Pharmaceutical Designs 2.0)

► Show Figures

Figure 1

25 pages, 3950 KiB

Open AccessReview

Evaluation of Small-Molecule Candidates as Modulators of M-Type K⁺ Currents: Impacts on Current Amplitude, Gating, and Voltage-Dependent Hysteresis

by Te-Ling Lu, Rasa Liutkevičienė, Vita Rovite, Zi-Han Gao and Sheng-Nan Wu

Int. J. Mol. Sci. 2025, 26(4), 1504; https://doi.org/10.3390/ijms26041504 - 11 Feb 2025

Viewed by 1616

Abstract

The core subunits of the K_V7.2, K_V7.3, and K_V7.5 channels, encoded by the KCNQ2, KCNQ3, and KCNQ5 genes, are expressed across various cell types and play a key role in generating the M-type K⁺ [...] Read more.

The core subunits of the K_V7.2, K_V7.3, and K_V7.5 channels, encoded by the KCNQ2, KCNQ3, and KCNQ5 genes, are expressed across various cell types and play a key role in generating the M-type K⁺ current (I_K(M)). This current is characterized by an activation threshold at low voltages and displays slow activation and deactivation kinetics. Variations in the amplitude and gating kinetics of I_K(M) can significantly influence membrane excitability. Notably, I_K(M) demonstrates distinct voltage-dependent hysteresis when subjected to prolonged isosceles-triangular ramp pulses. In this review, we explore various small-molecule modulators that can either inhibit or enhance the amplitude of I_K(M), along with their perturbations on its gating kinetics and voltage-dependent hysteresis. The inhibitors of I_K(M) highlighted here include bisoprolol, brivaracetam, cannabidiol, nalbuphine, phenobarbital, and remdesivir. Conversely, compounds such as flupirtine, kynurenic acid, naringenin, QO-58, and solifenacin have been shown to enhance I_K(M). These modulators show potential as pharmacological or therapeutic strategies for treating certain disorders linked to gain-of-function or loss-of-function mutations in M-type K⁺ (K_V7x or KCNQx) channels. Full article

(This article belongs to the Special Issue Ion Channels as a Potential Target in Pharmaceutical Designs 2.0)

► Show Figures

Figure 1

12 pages, 899 KiB

Open AccessReview

Exploring the Impact of BK_Ca Channel Function in Cellular Membranes on Cardiac Electrical Activity

by Yin-Chia Chen, Chia-Lung Shih, Chao-Liang Wu, Yi-Hsien Fang, Edmund Cheung So and Sheng-Nan Wu

Int. J. Mol. Sci. 2024, 25(3), 1537; https://doi.org/10.3390/ijms25031537 - 26 Jan 2024

Cited by 1 | Viewed by 2170

Abstract

This review paper delves into the current body of evidence, offering a thorough analysis of the impact of large-conductance Ca²⁺-activated K⁺ (BK_Ca or BK) channels on the electrical dynamics of the heart. Alterations in the activity of BK_Ca [...] Read more.

This review paper delves into the current body of evidence, offering a thorough analysis of the impact of large-conductance Ca²⁺-activated K⁺ (BK_Ca or BK) channels on the electrical dynamics of the heart. Alterations in the activity of BK_Ca channels, responsible for the generation of the overall magnitude of Ca²⁺-activated K⁺ current at the whole-cell level, occur through allosteric mechanisms. The collaborative interplay between membrane depolarization and heightened intracellular Ca²⁺ ion concentrations collectively contribute to the activation of BK_Ca channels. Although fully developed mammalian cardiac cells do not exhibit functional expression of these ion channels, evidence suggests their presence in cardiac fibroblasts that surround and potentially establish close connections with neighboring cardiac cells. When cardiac cells form close associations with fibroblasts, the high single-ion conductance of these channels, approximately ranging from 150 to 250 pS, can result in the random depolarization of the adjacent cardiac cell membranes. While cardiac fibroblasts are typically electrically non-excitable, their prevalence within heart tissue increases, particularly in the context of aging myocardial infarction or atrial fibrillation. This augmented presence of BK_Ca channels’ conductance holds the potential to amplify the excitability of cardiac cell membranes through effective electrical coupling between fibroblasts and cardiomyocytes. In this scenario, this heightened excitability may contribute to the onset of cardiac arrhythmias. Moreover, it is worth noting that the substances influencing the activity of these BK_Ca channels might influence cardiac electrical activity as well. Taken together, the BK_Ca channel activity residing in cardiac fibroblasts may contribute to cardiac electrical function occurring in vivo. Full article

(This article belongs to the Special Issue Ion Channels as a Potential Target in Pharmaceutical Designs 2.0)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Ion Channels as a Potential Target in Pharmaceutical Designs 2.0

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI