-
Developmental Dynamics : An Official... Feb 2022Mechanical cues are crucial for vascular development and the proper differentiation of various cell types. Piezo1 and Piezo2 are mechanically activated cationic channels... (Review)
Review
Mechanical cues are crucial for vascular development and the proper differentiation of various cell types. Piezo1 and Piezo2 are mechanically activated cationic channels expressed in various cell types, especially in vascular smooth muscle and endothelial cells. It is present as a transmembrane homotrimeric complex, regulating calcium influx. Local blood flow associated shear stress, in addition to blood pressure associated cell membrane stretching are key Piezo channel activators. There is rising proof, showcasing Piezo channels significance in myocytes, cardiac fibroblast, vascular tone maintenance, atherosclerosis, hypertension, NO generation, and baroreceptor reflex. Here, we review the role of Piezo channels in cardiovascular development and its associated clinical disorders. Also, emphasizing on Piezo channel modulators which might lead to novel therapies for cardiovascular diseases.
Topics: Cardiovascular Diseases; Endothelial Cells; Humans; Ion Channels; Mechanotransduction, Cellular
PubMed: 34255896
DOI: 10.1002/dvdy.401 -
The Journal of Physiology Jan 2020The large-pore channel pannexin 1 (Panx1) is expressed in many cell types and can open upon different, yet not fully established, stimuli. Panx1 permeability is often...
KEY POINTS
The large-pore channel pannexin 1 (Panx1) is expressed in many cell types and can open upon different, yet not fully established, stimuli. Panx1 permeability is often inferred from channel permeability to fluorescent dyes, but it is currently unknown whether dye permeability translates to permeability to other molecules. Cell shrinkage and C-terminal cleavage led to a Panx1 open-state with increased permeability to atomic ions (current), but did not alter ethidium uptake. Panx1 inhibitors affected Panx1-mediated ion conduction differently from ethidium permeability, and inhibitor efficiency towards a given molecule therefore cannot be extrapolated to its effects on the permeability of another. We conclude that ethidium permeability does not reflect equal permeation of other molecules and thus is no measure of general Panx1 activity.
ABSTRACT
Pannexin 1 (Panx1) is a large-pore membrane channel connecting the extracellular milieu with the cell interior. While several activation regimes activate Panx1 in a variety of cell types, the selective permeability of an open Panx1 channel remains unresolved: does a given activation paradigm increase Panx1's permeability towards all permeants equally and does fluorescent dye flux serve as a proxy for biological permeation through an open channel? To explore permeant-selectivity of Panx1 activation and inhibition, we employed Panx1-expressing Xenopus laevis oocytes and HEK293T cells. We report that different mechanisms of activation of Panx1 differentially affected ethidium and atomic ion permeation. Most notably, C-terminal truncation or cell shrinkage elevated Panx1-mediated ion conductance, but had no effect on ethidium permeability. In contrast, extracellular pH changes predominantly affected ethidium permeability but not ionic conductance. High [K ] did not increase the flux of either of the two permeants. Once open, Panx1 demonstrated preference for anionic permeants, such as Cl , lactate and glutamate, while not supporting osmotic water flow. Panx1 inhibitors displayed enhanced potency towards Panx1-mediated currents compared to that of ethidium uptake. We conclude that activation or inhibition of Panx1 display permeant-selectivity and that permeation of ethidium does not necessarily reflect an equal permeation of smaller biological molecules and atomic ions.
Topics: Animals; Connexins; Fluorescent Dyes; Glutamic Acid; HEK293 Cells; Humans; Ion Channels; Lactic Acid; Nerve Tissue Proteins; Oocytes; Xenopus laevis
PubMed: 31698505
DOI: 10.1113/JP278759 -
Cellular Physiology and Biochemistry :... 2019Ion channels residing in the inner (IMM) and outer (OMM) mitochondrial membranes are emerging as noteworthy pharmacological targets in oncology. While these aspects have... (Review)
Review
Ion channels residing in the inner (IMM) and outer (OMM) mitochondrial membranes are emerging as noteworthy pharmacological targets in oncology. While these aspects have not been investigated for all of them, a role in cancer growth and/or metastasis and/or drug resistance has been shown at least for the IMM-residing Ca uniporter complex and K- selective mtK1.3, mtIK, mtSK and mtTASK-3, and for the OMM Voltage-Dependent Anion Channel (mitochondrial porin). A special case is that of the Mitochondrial Permeability Transition Pore, a large pore which forms in the IMM of severely stressed cells, and which may be exploited to precipitate the death of cancerous cells. Here we briefly discuss the oncological relevance of mitochondria and their channels, and summarize the methods that can be adopted to selectively target these intracellular organelles. We then present an updated list of known mitochondrial channels, and review the pharmacology of those with proven relevance for cancer.
Topics: Antineoplastic Agents; Calcium Channels; Humans; Ion Channels; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Neoplasms; Potassium Channels; Small Molecule Libraries; Voltage-Dependent Anion Channels
PubMed: 31834993
DOI: 10.33594/000000192 -
Biochimica Et Biophysica Acta Sep 2007The linear peptide gramicidin forms prototypical ion channels specific for monovalent cations and has been extensively used to study the organization, dynamics and... (Review)
Review
The linear peptide gramicidin forms prototypical ion channels specific for monovalent cations and has been extensively used to study the organization, dynamics and function of membrane-spanning channels. In recent times, the availability of crystal structures of complex ion channels has challenged the role of gramicidin as a model membrane protein and ion channel. This review focuses on the suitability of gramicidin as a model membrane protein in general, and the information gained from gramicidin to understand lipid-protein interactions in particular. Special emphasis is given to the role and orientation of tryptophan residues in channel structure and function and recent spectroscopic approaches that have highlighted the organization and dynamics of the channel in membrane and membrane-mimetic media.
Topics: Cell Membrane; Gramicidin; Ion Channel Gating; Ion Channels; Lipid Bilayers; Models, Biological
PubMed: 17572379
DOI: 10.1016/j.bbamem.2007.05.011 -
Journal of Applied Physiology... Jul 2023Prolonged periods of increased physical demands can elicit anabolic tendon adaptations that increase stiffness and mechanical resilience or conversely can lead to...
Prolonged periods of increased physical demands can elicit anabolic tendon adaptations that increase stiffness and mechanical resilience or conversely can lead to pathological processes that deteriorate tendon structural quality with ensuing pain and potential rupture. Although the mechanisms by which tendon mechanical loads regulate tissue adaptation are largely unknown, the ion channel PIEZO1 has been implicated in tendon mechanotransduction, with human carriers of the PIEZO1 gain-of-function variant E756del displaying improved dynamic vertical jump performance compared with noncarriers. Here, we sought to examine whether increased tendon stiffness in humans could explain this increased performance. We assessed tendon morphological and mechanical properties with ultrasound-based techniques in 77 participants of Middle- and West-African descent, and we measured their vertical jumping performance to assess potential functional consequences in the context of high tendon strain-rate loading. Carrying the E756del gene variant ( = 30) was associated with 46.3 ± 68.3% ( = 0.002) and 45.6 ± 69.2% ( < 0.001) higher patellar tendon stiffness and Young's modulus compared with noncarrying controls, respectively. Although these tissue level measures strongly corroborate the initial postulate that PIEZO1 plays an integral part in regulating tendon material properties and stiffness in humans, we found no detectable correlation between tendon stiffness and jumping performance in the tested population that comprised individuals of highly diverse physical fitness level, dexterity, and jumping ability. The E756del gene variant causes overactivity of the mechanosensitive membrane channel PIEZO1 and is suspected to upregulate tendon collagen cross linking. In human carriers of E756del, we found increased patellar tendon stiffness but similar tendon lengths and cross-sectional areas, directly supporting the premise that PIEZO1 regulates human tendon stiffness at the level of tissue material properties.
Topics: Humans; Gain of Function Mutation; Mechanotransduction, Cellular; Tendons; Patellar Ligament; Elastic Modulus; Ion Channels
PubMed: 37227181
DOI: 10.1152/japplphysiol.00573.2022 -
Scientific Reports Jan 2017The mechanism of selectivity in ion channels is still an open question in biology for more than half a century. Here, we suggest that quantum interference can be a... (Review)
Review
The mechanism of selectivity in ion channels is still an open question in biology for more than half a century. Here, we suggest that quantum interference can be a solution to explain the selectivity mechanism in ion channels since interference happens between similar ions through the same size of ion channels. In this paper, we simulate two neighboring ion channels on a cell membrane with the famous double-slit experiment in physics to investigate whether there is any possibility of matter-wave interference of ions via movement through ion channels. Our obtained decoherence timescales indicate that the quantum states of ions can only survive for short times, i.e. ≈100 picoseconds in each channel and ≈17-53 picoseconds outside the channels, giving the result that the quantum interference of ions seems unlikely due to environmental decoherence. However, we discuss our results and raise few points, which increase the possibility of interference.
Topics: Algorithms; Animals; Humans; Ion Channel Gating; Ion Channels; Ions; Models, Biological; Models, Molecular; Protein Conformation; Structure-Activity Relationship
PubMed: 28134331
DOI: 10.1038/srep41625 -
International Journal of Molecular... Mar 2021Sperm motility is linked to the activation of signaling pathways that trigger movement. These pathways are mainly dependent on Ca, which acts as a secondary messenger.... (Review)
Review
Sperm motility is linked to the activation of signaling pathways that trigger movement. These pathways are mainly dependent on Ca, which acts as a secondary messenger. The maintenance of adequate Ca concentrations is possible thanks to proper concentrations of other ions, such as K and Na, among others, that modulate plasma membrane potential and the intracellular pH. Like in every cell, ion homeostasis in spermatozoa is ensured by a vast spectrum of ion channels supported by the work of ion pumps and transporters. To achieve success in fertilization, sperm ion channels have to be sensitive to various external and internal factors. This sensitivity is provided by specific channel structures. In addition, novel sperm-specific channels or isoforms have been found with compositions that increase the chance of fertilization. Notably, the most significant sperm ion channel is the cation channel of sperm (CatSper), which is a sperm-specific Ca channel required for the hyperactivation of sperm motility. The role of other ion channels in the spermatozoa, such as voltage-gated Ca channels (VGCCs), Ca-activated Cl-channels (CaCCs), SLO K channels or voltage-gated H channels (VGHCs), is to ensure the activation and modulation of CatSper. As the activation of sperm motility differs among metazoa, different ion channels may participate; however, knowledge regarding these channels is still scarce. In the present review, the roles and structures of the most important known ion channels are described in regard to regulation of sperm motility in animals.
Topics: Animals; Calcium; Calcium Channels; Calcium Signaling; Chloride Channels; Humans; Ion Channel Gating; Ion Channels; Male; Potassium Channels; Sodium Channels; Sperm Motility; Spermatozoa; Structure-Activity Relationship
PubMed: 33806823
DOI: 10.3390/ijms22063259 -
IUBMB Life 2001Trafficking of metabolites across the outer mitochondrial membrane is believed to be mediated primarily by the pore-forming voltage-dependent anion channel, VDAC (also... (Review)
Review
Trafficking of metabolites across the outer mitochondrial membrane is believed to be mediated primarily by the pore-forming voltage-dependent anion channel, VDAC (also known as mitochondrial porin). An expanding body of in vitro studies have strongly suggest that the pore formed by VDAC can be regulated in a number of ways that implicate it as a site for the regulation of mitochondrial function, yet technical limitations have prevented the extension these studies to a relevant cellular context. The goal of this brief review is to summarize recent data that examine the role of VDAC and its regulation in the context not of the isolated protein or organelles but in cells, focusing on the application of genetic strategies in a number of experimental systems.
Topics: Animals; Humans; Intracellular Membranes; Ion Channels; Mitochondria; Porins; Voltage-Dependent Anion Channels
PubMed: 11798022
DOI: 10.1080/15216540152845902 -
Viruses Jul 2015Modification of host-cell ionic content is a significant issue for viruses, as several viral proteins displaying ion channel activity, named viroporins, have been... (Review)
Review
Modification of host-cell ionic content is a significant issue for viruses, as several viral proteins displaying ion channel activity, named viroporins, have been identified. Viroporins interact with different cellular membranes and self-assemble forming ion conductive pores. In general, these channels display mild ion selectivity, and, eventually, membrane lipids play key structural and functional roles in the pore. Viroporins stimulate virus production through different mechanisms, and ion channel conductivity has been proved particularly relevant in several cases. Key stages of the viral cycle such as virus uncoating, transport and maturation are ion-influenced processes in many viral species. Besides boosting virus propagation, viroporins have also been associated with pathogenesis. Linking pathogenesis either to the ion conductivity or to other functions of viroporins has been elusive for a long time. This article summarizes novel pathways leading to disease stimulated by viroporin ion conduction, such as inflammasome driven immunopathology.
Topics: Animals; Humans; Ion Channels; Ions; Viral Proteins; Virus Diseases; Virus Replication; Viruses
PubMed: 26151305
DOI: 10.3390/v7072786 -
International Journal of Molecular... Jul 2019Investigations of information dynamics in eukaryotic cells focus almost exclusively on heritable information in the genome. Gene networks are modeled as "central... (Review)
Review
Investigations of information dynamics in eukaryotic cells focus almost exclusively on heritable information in the genome. Gene networks are modeled as "central processors" that receive, analyze, and respond to intracellular and extracellular signals with the nucleus described as a cell's control center. Here, we present a model in which cellular information is a distributed system that includes non-genomic information processing in the cell membrane that may quantitatively exceed that of the genome. Within this model, the nucleus largely acts a source of macromolecules and processes information needed to synchronize their production with temporal variations in demand. However, the nucleus cannot produce microsecond responses to acute, life-threatening perturbations and cannot spatially resolve incoming signals or direct macromolecules to the cellular regions where they are needed. In contrast, the cell membrane, as the interface with its environment, can rapidly detect, process, and respond to external threats and opportunities through the large amounts of potential information encoded within the transmembrane ion gradient. Our model proposes environmental information is detected by specialized protein gates within ion-specific transmembrane channels. When the gate receives a specific environmental signal, the ion channel opens and the received information is communicated into the cell via flow of a specific ion species (i.e., K, Na, Cl, Ca, Mg) along electrochemical gradients. The fluctuation of an ion concentration within the cytoplasm adjacent to the membrane channel can elicit an immediate, local response by altering the location and function of peripheral membrane proteins. Signals that affect a larger surface area of the cell membrane and/or persist over a prolonged time period will produce similarly cytoplasmic changes on larger spatial and time scales. We propose that as the amplitude, spatial extent, and duration of changes in cytoplasmic ion concentrations increase, the information can be communicated to the nucleus and other intracellular structure through ion flows along elements of the cytoskeleton to the centrosome (via microtubules) or proteins in the nuclear membrane (via microfilaments). These dynamics add spatial and temporal context to the more well-recognized information communication from the cell membrane to the nucleus following ligand binding to membrane receptors. Here, the signal is transmitted and amplified through transduction by the canonical molecular (e.g., Mitogen Activated Protein Kinases (MAPK) pathways. Cytoplasmic diffusion allows this information to be broadly distributed to intracellular organelles but at the cost of loss of spatial and temporal information also contained in ligand binding.
Topics: Calcium; Cell Communication; Cell Membrane; Cell Nucleus; Cytoplasm; Cytoskeleton; Eukaryotic Cells; Genome; Ion Channels; Ions; Signal Transduction
PubMed: 31344783
DOI: 10.3390/ijms20153609