RESUMEN
Rationale: Mechanical force plays crucial roles in extracellular vesicle biogenesis, release, composition and activity. However, it is unknown whether mechanical force regulates apoptotic vesicle (apoV) production. Methods: The effects of mechanical unloading on extracellular vesicles of bone marrow were evaluated through morphology, size distribution, yield, and protein mass spectrometry analysis using hindlimb unloading (HU) mouse model. Apoptosis resistance and aging related phenotype were assessed using HU mouse model in vivo and cell microgravity model in vitro. The therapeutic effects of apoVs on HU mouse model were assessed by using microcomputed tomography, histochemical and immunohistochemical, as well as histomorphometry analyses. SiRNA and chemicals were used for gain and loss-of-function assay. Results: In this study, we show that loss of mechanical force led to cellular apoptotic resistance and aging related phenotype, thus reducing the number of apoVs in the circulation due to down-regulated expression of Piezo1 and reduced calcium influx. And systemic infusion of apoVs was able to rescue Piezo1 expression and calcium influx, thereby, rescuing mechanical unloading-induced cellular apoptotic resistance, senescent cell accumulation. Conclusions: This study identified a previously unknown role of mechanical force in maintaining apoptotic homeostasis and eliminating senescent cells. Systemic infusion of mesenchymal stem cell-derived apoVs can effectively rescue apoptotic resistance and eliminate senescent cells in mechanical unloading mice.
Asunto(s)
Apoptosis , Senescencia Celular , Vesículas Extracelulares , Animales , Ratones , Apoptosis/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Senescencia Celular/efectos de los fármacos , Senoterapéuticos/farmacología , Canales Iónicos/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones Endogámicos C57BL , Suspensión Trasera , Calcio/metabolismo , Masculino , Estrés MecánicoRESUMEN
In recent years, the Piezo1 channel has attracted great attention. Piezo1's research has made remarkable advance in many aspects. However, the overall trends and knowledge structures have not been systematically investigated from a worldwide viewpoint. Therefore, it is important to fill this knowledge gap and utilize a proper tool to show the research status, hotspots, and frontiers in the Piezo1 channel. In order to better investigate the hotspots and frontiers of the Piezo1 channel research, we retrieved relevant literature from Web of Science Core Collection (WoSCC) and applied CiteSpace to perform a bibliometric analysis. Our findings might serve as a reference for future research in this area.
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Bibliometría , Canales Iónicos , Canales Iónicos/metabolismo , Humanos , AnimalesRESUMEN
Classical swine fever virus (CSFV) p7 viroporin plays crucial roles in cellular ion balance and permeabilization. The antiviral drug amantadine effectively inhibits viral replication by blocking the activity of CSFV p7 viroporin. However, little information is available for the binding mode of amantadine with CSFV p7 viroporin, due to the lack of a known polymer structure for CSFV p7. In this study, we employed AlphaFold2 to predict CSFV p7 structures. Subsequently, we conducted a docking study to investigate the binding sites of amantadine to CSFV p7. Computational analysis showed that CSFV p7 forms a pore channel in a hexameric structure. Furthermore, molecular dynamics (MD) simulations and mutant analyses further suggest that CSFV p7 likely exists as a hexamer. Docking studies and MD simulations showed that amantadine interacts with the hydrophibic regions of tetramer and pentamer, as well as with the hydrophobic pore channel of the hexamer. Considering the potential hexameric assembly of CSFV p7, along with docking results, MD simulations, and the characteristics of the gated ion channels, we propose a model of CSFV p7 ion channel based on its hexameric configuration. In this model, residues E21, Y25, and R34 are suggested to selectively recruit and dehydrate ions, while residues L28 and L31 likely act as hydrophobic constrictors, thereby restricting the free movement of water. The binding of amantadine to residues I20, E21, V24 and Y25 effectively blocks ion transport. However, this proposed molecular model requires experimental validation. Our findings give a structural insight into the models of CSFV p7 as an ion channel and provide a molecular explanation for the inhibition effects of amantadine on CSFV p7-mediated ion channel conductance.
Asunto(s)
Amantadina , Antivirales , Virus de la Fiebre Porcina Clásica , Canales Iónicos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Proteínas Virales , Amantadina/farmacología , Virus de la Fiebre Porcina Clásica/efectos de los fármacos , Antivirales/farmacología , Antivirales/química , Canales Iónicos/metabolismo , Canales Iónicos/química , Canales Iónicos/antagonistas & inhibidores , Proteínas Virales/metabolismo , Proteínas Virales/química , Animales , Porcinos , Sitios de Unión , Unión ProteicaRESUMEN
Mechanical force is the basis of cardiovascular development, homeostasis, and diseases. The perception and response of mechanical force by the cardiovascular system are crucial. However, the molecular mechanisms mediating mechanotransduction in the cardiovascular system are not yet understood. PIEZO1, a novel transmembrane mechanosensitive cation channel known for its regulation of touch sensation, has been found to be widely expressed in the mammalian cardiovascular system. In this review, we elucidate the role and mechanism of PIEZO1 as a mechanical sensor in cardiovascular development, homeostasis, and disease processes, including embryo survival, angiogenesis, cardiac development repair, vascular inflammation, lymphangiogenesis, blood pressure regulation, cardiac hypertrophy, cardiac fibrosis, ventricular remodeling, and heart failure. We further summarize chemical molecules targeting PIEZO1 for potential translational applications. Finally, we address the controversies surrounding emergent concepts and challenges in future applications.
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Sistema Cardiovascular , Canales Iónicos , Humanos , Animales , Sistema Cardiovascular/metabolismo , Canales Iónicos/metabolismo , Mecanotransducción Celular , Enfermedades Cardiovasculares/metabolismo , Mamíferos/metabolismoRESUMEN
Human voltage-gated proton (hHv1) channels are crucial for regulating essential biological processes such as immune cell respiratory burst, sperm capacitation, and cancer cell migration. Despite the significant concentration difference between protons and other ions in physiological conditions, hHv1 demonstrates remarkable proton selectivity. Our calculations of single-proton, cation, and anion permeation free energy profiles quantitatively demonstrate that the proton selectivity of the wild-type channel originates from its strong proton affinity via the titration of the key residues D112 and D174, although the channel imposes similar kinetic blocking effects for protons compared to other ions. A two-proton knock-on model is proposed to mathematically explain the electrophysiological measurements of the pH-dependent proton conductance in the conductive state. Moreover, it is shown that the anion selectivity of the D112N mutant channel is tied to impaired proton transport and substantial anion leakage.
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Canales Iónicos , Protones , Humanos , Canales Iónicos/metabolismo , Concentración de Iones de Hidrógeno , Activación del Canal Iónico , MutaciónRESUMEN
Otopetrin 1 (OTOP1) is a proton-activated channel crucial for animals' perception of sour taste. Despite its significance, the gating mechanism of OTOP1 remains poorly understood. Here, we demonstrate that carvacrol activates the mouse OTOP1 (mOTOP1) channel under neutral and acidic conditions. Functional analysis showed that carvacrol enhances pH fluorescence signals in OTOP1-expressing cells, with reduced efficacy at lower pH levels. Carvacrol selectively activates mOTOP1, while mOTOP2, mOTOP3, and Chelonia mydas OTOP1 (CmOTOP1) are insensitive to carvacrol activation under neutral pH. Through chimera and point mutation experiments, swapping S134 in transmembrane segment 3 (TM3) and T247 in the TM5-6 linker abolished carvacrol activation of mOTOP1 and conferred activation on CmOTOP1, suggesting these two residues are critical for carvacrol sensitivity. These findings highlight TM3 and TM5-6 linker as pivotal gating apparatus of OTOP1 channels and potential docking sites for drug design.
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Cimenos , Cimenos/farmacología , Animales , Ratones , Activación del Canal Iónico/efectos de los fármacos , Humanos , Células HEK293 , Concentración de Iones de Hidrógeno , Canales Iónicos/metabolismo , Canales Iónicos/genéticaRESUMEN
Piezo proteins have been identified as mechanosensitive ion channels involved in mechanotransduction. Several ion channel dysfunctions may be associated with diseases (including deafness and pain); thus, studying them is critical to understand their role in mechanosensitive disorders and to establish new therapeutic strategies. The current study investigated for the first time the expression patterns of Piezo proteins in zebrafish octavolateralis mechanosensory organs. Piezo 1 and 2 were immunoreactive in the sensory epithelia of the lateral line system and the inner ear. Piezo 1 (28.7 ± 1.55 cells) and Piezo 2 (28.8 ± 3.31 cells) immunopositive neuromast cells were identified based on their ultrastructural features, and their overlapping immunoreactivity to the s100p specific marker (28.6 ± 1.62 cells), as sensory cells. These findings are in favor of Piezo proteins' potential role in sensory cell activation, while their expression on mantle cells reflects their implication in the maintenance and regeneration of the neuromast during cell turnover. In the inner ear, Piezo proteins' colocalization with BDNF introduces their potential implication in neuronal plasticity and regenerative events, typical of zebrafish mechanosensory epithelia. Assessing these proteins in zebrafish could open up new scenarios for the roles of these important ionic membrane channels, for example in treating impairments of sensory systems.
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Oído Interno , Canales Iónicos , Sistema de la Línea Lateral , Mecanotransducción Celular , Proteínas de Pez Cebra , Pez Cebra , Animales , Pez Cebra/metabolismo , Oído Interno/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Canales Iónicos/metabolismo , Canales Iónicos/genética , Sistema de la Línea Lateral/metabolismoRESUMEN
Cells establish the asymmetrical distribution of phospholipids and alter their distribution by phospholipid scrambling (PLS) to adapt to environmental changes. Here, we demonstrate that a protein complex, consisting of the ion channel Tmem63b and the thiamine transporter Slc19a2, induces PLS upon calcium (Ca2+) stimulation. Through revival screening using a CRISPR sgRNA library on high PLS cells, we identify Tmem63b as a PLS-inducing factor. Ca2+ stimulation-mediated PLS is suppressed by deletion of Tmem63b, while human disease-related Tmem63b mutants induce constitutive PLS. To search for a molecular link between Ca2+ stimulation and PLS, we perform revival screening on Tmem63b-overexpressing cells, and identify Slc19a2 and the Ca2+-activated K+ channel Kcnn4 as PLS-regulating factors. Deletion of either of these genes decreases PLS activity. Biochemical screening indicates that Tmem63b and Slc19a2 form a heterodimer. These results demonstrate that a Tmem63b/Slc19a2 heterodimer induces PLS upon Ca2+ stimulation, along with Kcnn4 activation.
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Calcio , Proteínas de Transferencia de Fosfolípidos , Fosfolípidos , Humanos , Calcio/metabolismo , Proteínas de Transferencia de Fosfolípidos/metabolismo , Proteínas de Transferencia de Fosfolípidos/genética , Fosfolípidos/metabolismo , Células HEK293 , Canales Iónicos/metabolismo , Canales Iónicos/genética , Animales , Sistemas CRISPR-CasRESUMEN
Mechanosensitive ion channel Piezo1 is known to mediate a variety of inflammatory pathways and is also involved in the occurrence and development of many orthopedic diseases. Although its role in the inflammatory mechanism of knee osteoarthritis (KOA) has been reported, a systematic explanation is yet to be seen. This article aims to summarize the role of inflammatory responses in the pathogenesis of KOA and elucidate the mechanism by which the Piezo1-mediated inflammatory response contributes to the pathogenesis of KOA, providing a theoretical basis for the prevention and treatment of knee osteoarthritis. The results indicate that in the mechanism leading to knee osteoarthritis, Piezo1 can mediate the inflammatory response through chondrocytes and synovial cells, participating in the pathological progression of KOA. Piezo1 has the potential to become a new target for the prevention and treatment of this disease. Additionally, as pain is one of the most severe manifestations in KOA patients, the inflammatory response mediated by Piezo1, which causes the release of inflammatory mediators and pro-inflammatory factors leading to pain, can be further explored.
Asunto(s)
Inflamación , Canales Iónicos , Osteoartritis de la Rodilla , Canales Iónicos/metabolismo , Humanos , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Inflamación/metabolismo , Animales , Condrocitos/metabolismo , Mecanotransducción CelularRESUMEN
Density reversal of senescent red blood cells has been known for a long time, yet the identity of the candidate ion transporter(s) causing the senescent cells to swell is still elusive. While performing fractionation of RBCs from healthy individuals in Percoll density gradient and characterization of the separated fractions, we identified a subpopulation of cells in low-density fraction (1.02% ± 0.47) showing signs of senescence such as loss of membrane surface area associated with a reduction in band 3 protein abundance, and Phosphatidylserine (PS) exposure to the outer membrane. In addition, we found that these cells are overloaded with Na+ and Ca2+. Using a combination of blockers and activators of ion pumps and channels, we revealed reduced activity of Plasma membrane Ca2+ ATPase and an increase in Ca2+ and Na+ leaks through ion channels in senescent-like cells. Our data revealed that Ca2+ overload in these cells is a result of reduced PMCA activity and facilitated Ca2+ uptake via a hyperactive Piezo1 channel. However, we could not exclude the contribution of other Ca2+-permeable ion channels in this scenario. In addition, we found, as a universal mechanism, that an increase in intracellular Ca2+ reduced the initially high selectivity of Piezo1 channel for Ca2+ and allowed higher Na+ uptake, Na+ accumulation, and swelling.
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Calcio , Eritrocitos , Canales Iónicos , Humanos , Eritrocitos/metabolismo , Canales Iónicos/metabolismo , Calcio/metabolismo , Senescencia Celular , Sodio/metabolismo , ATPasas Transportadoras de Calcio de la Membrana Plasmática/metabolismoRESUMEN
The otopetrin (OTOP) proteins were recently characterized as extracellular proton-activated proton channels. Several recent OTOP channel structures demonstrated that the channels form a dimer with each subunit adopting a double-barrel architecture. However, the structural mechanisms underlying some basic functional properties of the OTOP channels remain unresolved, including extracellular pH activation, proton conducting pathway, and rapid desensitization. In this study, we performed structural and functional characterization of the Caenorhabditis elegans OTOP8 (CeOTOP8) and mouse OTOP2 (mOTOP2) and illuminated a set of conformational changes related to the proton-conducting process in OTOP. The structures of CeOTOP8 reveal the conformational change at the N-terminal part of TM12 that renders the channel in a transiently proton-transferring state, elucidating an inter-barrel, Glu/His-bridged proton passage within each subunit. The structures of mOTOP2 reveal the conformational change at the N-terminal part of TM6 that exposes the central glutamate to the extracellular solution for protonation. In addition, the structural comparison between CeOTOP8 and mOTOP2, along with the structure-based mutagenesis, demonstrates that an inter-subunit movement at the OTOP channel dimer interface plays a central role in regulating channel activity. Combining the structural information from both channels, we propose a working model describing the multi-step conformational changes during the proton conducting process.
Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Canales Iónicos , Protones , Animales , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Ratones , Canales Iónicos/metabolismo , Canales Iónicos/química , Canales Iónicos/genética , Modelos Moleculares , Conformación Proteica , Concentración de Iones de Hidrógeno , Cristalografía por Rayos X , Multimerización de ProteínaRESUMEN
The presence of non-essential metals in the environment as contaminants is prone to cause hazardous health problems following accumulation in the human body and the ensuing toxic effects. This calls for continuous discovery and innovation in the realm of developing easy-to-operate, cheap and sensitive sensors. Herein, we describe the proof of concept approach for designing a molecular receptor-like, chimeric sensor based on the pore-forming peptide alamethicin (Alm), tethered via a linker with an ultrashort peptide nucleic acid (PNA) moiety, capable of generating functional ion channel oligomers in planar lipid membranes. The working principle of the sensor exploits the ability of Hg2+ ions to complex mismatching thymine-thymine sequences between the PNA receptor moiety on Alm oligomers and free, thymine-based, single-stranded DNAs (ssDNAs) in solution, thus creating a stable base pair at the oligomer entrance. This generates a transducing mechanism which converts the metal ion complexation into a specific electrical signature of the self-assembled Alm oligomers, enabling selective Hg2+ ion detection. The platform is programmable, whereby the simple exchange of the PNA sequence and its ssDNA counterpart in solution rendered the system selective for Cu2+ ion detection. With further optimization, the presented solution has the potential to translate into miniaturized, cost-effective biosensors suitable for the real-time, label-free and continuous detection of metal ions or other biomolecules.
Asunto(s)
Cobre , ADN de Cadena Simple , Mercurio , Ácidos Nucleicos de Péptidos , Mercurio/análisis , Mercurio/química , Ácidos Nucleicos de Péptidos/química , Cobre/química , ADN de Cadena Simple/química , Alameticina/química , Canales Iónicos/metabolismo , Canales Iónicos/química , Técnicas Biosensibles , Péptidos Antimicrobianos/química , Péptidos Antimicrobianos/farmacología , Iones/químicaRESUMEN
Our study probed the differences in ion channel gene expression in the endometrium of women with Recurrent Implantation Failure (RIF) compared to fertile women. We analyzed the relative expression of genes coding for T-type Ca2+, ENaC, CFTR, and KCNQ1 channels in endometrial samples from 20 RIF-affected and 10 control women, aged 22-35, via microarray analysis and quantitative real-time PCR. Additionally, we examined DNA methylation in the regulatory region of KCNQ1 using ChIP real-time PCR. The bioinformatics component of our research included Gene Ontology analysis, protein-protein interaction networks, and signaling pathway mapping to identify key biological processes and pathways implicated in RIF. This led to the discovery of significant alterations in the expression of ion channel genes in RIF women's endometrium, most notably an overexpression of CFTR and reduced expression of SCNN1A, SCNN1B, SCNN1G, CACNA1H, and KCNQ1. A higher DNA methylation level of KCNQ1's regulatory region was also observed in RIF patients. Gene-set enrichment analysis highlighted a significant presence of genes involved with ion transport and membrane potential regulation, particularly in sodium and calcium channel complexes, which are vital for cation movement across cell membranes. Genes were also enriched in broader ion channel and transmembrane transporter complexes, underscoring their potential extensive role in cellular ion homeostasis and signaling. These findings suggest a potential involvement of ion channels in the pathology of implantation failure, offering new insights into the mechanisms behind RIF and possible therapeutic targets.
Asunto(s)
Metilación de ADN , Implantación del Embrión , Endometrio , Humanos , Femenino , Endometrio/metabolismo , Adulto , Implantación del Embrión/genética , Canal de Potasio KCNQ1/genética , Canal de Potasio KCNQ1/metabolismo , Regulación de la Expresión Génica , Adulto Joven , Canales Iónicos/genética , Canales Iónicos/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Perfilación de la Expresión Génica , Infertilidad Femenina/genética , Infertilidad Femenina/metabolismo , Canales Epiteliales de Sodio/genética , Canales Epiteliales de Sodio/metabolismoRESUMEN
The development of noninvasive approaches to precisely control neural activity in mammals is highly desirable. Here, we used the ion channel transient receptor potential ankyrin-repeat 1 (TRPA1) as a proof of principle, demonstrating remote near-infrared (NIR) activation of endogenous neuronal channels in mice through an engineered nanoagonist. This achievement enables specific neurostimulation in nongenetically modified mice. Initially, target-based screening identified flavins as photopharmacological agonists, allowing for the photoactivation of TRPA1 in sensory neurons upon ultraviolet A/blue light illumination. Subsequently, upconversion nanoparticles (UCNPs) were customized with an emission spectrum aligned to flavin absorption and conjugated with flavin adenine dinucleotide, creating a nanoagonist capable of NIR activation of TRPA1. Following the intrathecal injection of the nanoagonist, noninvasive NIR stimulation allows precise bidirectional control of nociception in mice through remote activation of spinal TRPA1. This study demonstrates a noninvasive NIR neurostimulation method with the potential for adaptation to various endogenous ion channels and neural processes by combining photochemical toolboxes with customized UCNPs.
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Rayos Infrarrojos , Nanopartículas , Canal Catiónico TRPA1 , Animales , Canal Catiónico TRPA1/metabolismo , Canal Catiónico TRPA1/agonistas , Ratones , Nanopartículas/química , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/fisiología , Células Receptoras Sensoriales/efectos de los fármacos , Canales Iónicos/metabolismo , Nocicepción/efectos de los fármacosRESUMEN
Mechanosensitive PIEZO2 ion channels play roles in touch, proprioception, and inflammatory pain. Currently, there are no small molecule inhibitors that selectively inhibit PIEZO2 over PIEZO1. The TMEM120A protein was shown to inhibit PIEZO2 while leaving PIEZO1 unaffected. Here we find that TMEM120A expression elevates cellular levels of phosphatidic acid and lysophosphatidic acid (LPA), aligning with its structural resemblance to lipid-modifying enzymes. Intracellular application of phosphatidic acid or LPA inhibits PIEZO2 but not PIEZO1 activity. Extended extracellular exposure to the non-hydrolyzable phosphatidic acid and LPA analog carbocyclic phosphatidic acid (ccPA) also inhibits PIEZO2. Optogenetic activation of phospholipase D (PLD), a signaling enzyme that generates phosphatidic acid, inhibits PIEZO2 but not PIEZO1. Conversely, inhibiting PLD leads to increased PIEZO2 activity and increased mechanical sensitivity in mice in behavioral experiments. These findings unveil lipid regulators that selectively target PIEZO2 over PIEZO1, and identify the PLD pathway as a regulator of PIEZO2 activity.
Asunto(s)
Canales Iónicos , Lisofosfolípidos , Ácidos Fosfatidicos , Canales Iónicos/metabolismo , Canales Iónicos/genética , Animales , Ácidos Fosfatidicos/metabolismo , Humanos , Ratones , Lisofosfolípidos/metabolismo , Células HEK293 , Fosfolipasa D/metabolismo , Fosfolipasa D/genética , Mecanotransducción Celular , Ratones Endogámicos C57BL , Masculino , OptogenéticaRESUMEN
Tubular structures exist broadly in biological systems and exhibit important functions including mediating cellular communications. The construction of artificial analogues in living cells would provide a new strategy for chemotherapy. In this report, a kind of supramolecular channel has been constructed within intercellular gaps by mimicking the assembly process and structure of natural gap junctional channels, which consist of hydrophobic tubular modules located in the adjacent cell membranes and hydrophilic modules within the extracellular space. The assembly of the channels was driven by electrostatic interactions. The channels could inhibit tumor cell invasion by preventing cell migration.
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Movimiento Celular , Humanos , Movimiento Celular/efectos de los fármacos , Uniones Comunicantes/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Canales Iónicos/metabolismo , Canales Iónicos/química , Línea Celular TumoralRESUMEN
Connexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore-a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.
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Conexinas , Humanos , Conexinas/metabolismo , Conexinas/genética , Transporte Iónico , Animales , Mutación , Iones/metabolismo , Uniones Comunicantes/metabolismo , Canales Iónicos/metabolismo , Canales Iónicos/genéticaRESUMEN
Natural ion channels are proteins embedded in the cell membrane that control many aspects of cell and human physiology by acting as gatekeepers, regulating the flow of ions in and out of cells. Advances in nanotechnology have influenced the methods for studying ion channels in vitro, as well as ways to unlock the delivery of therapeutics by modulating them in vivo. This review provides an overview of nanotechnology-enabled approaches for ion channel research with a focus on the synthesis and applications of synthetic ion channels. Further, the uses of nanotechnology for therapeutic applications are critically analyzed. Finally, we provide an outlook on the opportunities and challenges at the intersection of nanotechnology and ion channels. This work highlights the key role of nanoscale interactions in the operation and modulation of ion channels, which may prompt insights into nanotechnology-enabled mechanisms to study and exploit these systems in the near future.
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Canales Iónicos , Nanotecnología , Canales Iónicos/metabolismo , Humanos , Animales , Membrana Celular/metabolismo , Membrana Celular/química , Activación del Canal Iónico/efectos de los fármacosRESUMEN
Morphogenetic regulation during embryogenesis and regeneration rely on information transfer and coordination between different regions. Here, we explore theoretically the coupling between bioelectrical and transcriptional oscillations at the individual cell and multicellular levels. The simulations, based on a set of ion channels and intercellular gap junctions, show that bioelectrical and transcriptional waves can electrophysiologically couple distant regions of a model network in phase and antiphase oscillatory states that include synchronization phenomena. In this way, different multicellular regionalizations can be encoded by cell potentials that oscillate between depolarized and polarized states, thus allowing a spatio-temporal coding. Because the electric potential patterns characteristic of development and regeneration are correlated with the spatial distributions of signaling ions and molecules, bioelectricity can act as a template for slow biochemical signals following a hierarchy of experimental times. In particular, bioelectrical gradients that couple cell potentials to transcription rates give to each single cell a rough idea of its location in the multicellular ensemble, thus controlling local differentiation processes that switch on and off crucial parts of the genome.
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Modelos Biológicos , Transcripción Genética , Fenómenos Electrofisiológicos/fisiología , Canales Iónicos/fisiología , Canales Iónicos/metabolismo , Canales Iónicos/genética , Uniones Comunicantes/fisiología , Animales , Humanos , Simulación por ComputadorRESUMEN
Osteoarthritis (OA) is a highly prevalent joint disease that causes substantial disability, yet effective approaches to disease prevention or to the delay of OA progression are lacking. Emerging evidence has pinpointed ion channels as pivotal mediators in OA pathogenesis and as promising targets for disease-modifying treatments. Preclinical studies have assessed the potential of a variety of ion channel modulators to modify disease pathways involved in cartilage degeneration, synovial inflammation, bone hyperplasia and pain, and to provide symptomatic relief in models of OA. Some of these modulators are currently being evaluated in clinical trials. This review explores the structures and functions of ion channels, including transient receptor potential channels, Piezo channels, voltage-gated sodium channels, voltage-dependent calcium channels, potassium channels, acid-sensing ion channels, chloride channels and the ATP-dependent P2XR channels in the osteoarthritic joint. The discussion spans channel-targeting drug discovery and potential clinical applications, emphasizing opportunities for further research, and underscoring the growing clinical impact of ion channel biology in OA.