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Journal of Molecular Biology Aug 2021Membrane transport is a fundamental means to control basic cellular processes such as apoptosis, inflammation, and neurodegeneration and is mediated by a number of... (Review)
Review
Membrane transport is a fundamental means to control basic cellular processes such as apoptosis, inflammation, and neurodegeneration and is mediated by a number of transporters, pumps, and channels. Accumulating evidence over the last half century has shown that a type of so-called "large-pore channel" exists in various tissues and organs in gap-junctional and non-gap-junctional forms in order to flow not only ions but also metabolites such as ATP. They are formed by a number of protein families with little or no evolutionary linkages including connexin, innexin, pannexin, leucine-rich repeat-containing 8 (LRRC8), and calcium homeostasis modulator (CALHM). This review summarizes the history and concept of large-pore channels starting from connexin gap junction channels to the more recent developments in innexin, pannexin, LRRC8, and CALHM. We describe structural and functional features of large-pore channels that are crucial for their diverse functions on the basis of available structures.
Topics: Animals; Biological Transport; Gap Junctions; Humans; Ion Channels; Ions
PubMed: 33865869
DOI: 10.1016/j.jmb.2021.166994 -
Redox Biology Jun 2021Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially... (Review)
Review
Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially expressed and/or regulated in cancer cells in comparison to healthy ones, this strategy may selectively eliminate the former. Perturbation of ion fluxes across the outer and inner membranes is linked to alterations of redox state, membrane potential and bioenergetic efficiency. This leads to indirect modulation of oxidative phosphorylation, which is/may be fundamental for both cancer and cancer stem cell survival. Furthermore, given the crucial contribution of mitochondria to intrinsic apoptosis, modulation of their ion channels leading to cytochrome c release may be of great advantage in case of resistance to drugs triggering apoptotic events upstream of the mitochondrial phase. In the present review, we give an overview of the known mitochondrial ion channels and of their modulators capable of killing cancer cells. In addition, we discuss state-of-the-art strategies using mitochondriotropic drugs or peptide-based approaches allowing a more efficient and selective targeting of mitochondrial ion channel-linked events.
Topics: Apoptosis; Cytochromes c; Humans; Ion Channels; Mitochondria; Neoplasms
PubMed: 33419703
DOI: 10.1016/j.redox.2020.101846 -
The Journal of Physiology May 2021
Topics: Glutamic Acid; Ion Channels; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate
PubMed: 33987842
DOI: 10.1113/JP281513 -
The EMBO Journal Jul 2023There is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling...
There is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na /Ca signature required for persistent invasion. We identify the Na leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca oscillations required for invadopodia formation. Indeed, NALCN-mediated Na influx into cancer cells maintains intracellular Ca oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na /Ca exchangers, SERCA and store-operated channels. This signaling cascade promotes activity of the NACLN-colocalized proto-oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller.
Topics: Male; Humans; Sodium; Ion Channels; Ion Transport; Prostatic Neoplasms; Membrane Proteins
PubMed: 37278161
DOI: 10.15252/embj.2022112198 -
The Journal of Physiology May 2022Selective ion channel modulators play a critical role in physiology in defining the contribution of specific ion channels to physiological function and as proof of... (Review)
Review
Selective ion channel modulators play a critical role in physiology in defining the contribution of specific ion channels to physiological function and as proof of concept for novel therapeutic strategies. Antibodies are valuable research tools that have broad uses including defining the expression and localization of ion channels in native tissue, and capturing ion channel proteins for subsequent analyses. In this review, we detail how renewable and recombinant antibodies can be used to control ion channel function. We describe the different forms of renewable and recombinant antibodies that have been used and the mechanisms by which they modulate ion channel function. We highlight the use of recombinant antibodies that are expressed intracellularly (intrabodies) as genetically encoded tools to control ion channel function. We also offer perspectives of avenues of future research that may be opened by the application of emerging technologies for engineering recombinant antibodies for enhanced utility in ion channel research. Overall, this review provides insights that may help stimulate and guide interested researchers to develop and incorporate renewable and recombinant antibodies as valuable tools to control ion channel function.
Topics: Antibodies; Ion Channels
PubMed: 35238051
DOI: 10.1113/JP282403 -
Cells Sep 2021Both inherited and acquired cardiac arrhythmias are often associated with the abnormal functional expression of ion channels at the cellular level. The complex machinery... (Review)
Review
Both inherited and acquired cardiac arrhythmias are often associated with the abnormal functional expression of ion channels at the cellular level. The complex machinery that continuously traffics, anchors, organizes, and recycles ion channels at the plasma membrane of a cardiomyocyte appears to be a major source of channel dysfunction during cardiac arrhythmias. This has been well established with the discovery of mutations in the genes encoding several ion channels and ion channel partners during inherited cardiac arrhythmias. Fibrosis, altered myocyte contacts, and post-transcriptional protein changes are common factors that disorganize normal channel trafficking during acquired cardiac arrhythmias. Channel availability, described notably for hERG and K1.5 channels, could be another potent arrhythmogenic mechanism. From this molecular knowledge on cardiac arrhythmias will emerge novel antiarrhythmic strategies.
Topics: Animals; Arrhythmias, Cardiac; Biological Transport; Cell Membrane; ERG1 Potassium Channel; Humans; Ion Channels; Kv1.5 Potassium Channel
PubMed: 34572065
DOI: 10.3390/cells10092417 -
Cell Reports Oct 2019Recent rapid progress in the field of mechanobiology has been driven by novel emerging tools and methodologies and growing interest from different scientific... (Review)
Review
Recent rapid progress in the field of mechanobiology has been driven by novel emerging tools and methodologies and growing interest from different scientific disciplines. Specific progress has been made toward understanding how cell mechanics is linked to intracellular signaling and the regulation of gene expression in response to a variety of mechanical stimuli. There is a direct link between the mechanoreceptors at the cell surface and intracellular biochemical signaling, which in turn controls downstream effector molecules. Among the mechanoreceptors in the cell membrane, mechanosensitive (MS) ion channels are essential for the ultra-rapid (millisecond) transduction of mechanical stimuli into biologically relevant signals. The three decades of research on mechanosensitive channels resulted in the formulation of two basic principles of mechanosensitive channel gating: force-from-lipids and force-from-filament. In this review, we revisit the biophysical principles that underlie the innate force-sensing ability of mechanosensitive channels as contributors to the force-dependent evolution of life forms.
Topics: Animals; Biophysics; Cell Membrane; Humans; Ion Channels; Mechanoreceptors; Mechanotransduction, Cellular; Signal Transduction
PubMed: 31577940
DOI: 10.1016/j.celrep.2019.08.075 -
ELife Dec 2022Piezo1 is the stretch activated Ca channel in red blood cells that mediates homeostatic volume control. Here, we study the organization of Piezo1 in red blood cells...
Piezo1 is the stretch activated Ca channel in red blood cells that mediates homeostatic volume control. Here, we study the organization of Piezo1 in red blood cells using a combination of super-resolution microscopy techniques and electron microscopy. Piezo1 adopts a non-uniform distribution on the red blood cell surface, with a bias toward the biconcave 'dimple'. Trajectories of diffusing Piezo1 molecules, which exhibit confined Brownian diffusion on short timescales and hopping on long timescales, also reflect a bias toward the dimple. This bias can be explained by 'curvature coupling' between the intrinsic curvature of the Piezo dome and the curvature of the red blood cell membrane. Piezo1 does not form clusters with itself, nor does it colocalize with F-actin, Spectrin, or the Gardos channel. Thus, Piezo1 exhibits the properties of a force-through-membrane sensor of curvature and lateral tension in the red blood cell.
Topics: Ion Channels; Erythrocytes; Mechanical Phenomena; Erythrocyte Membrane; Membranes; Mechanotransduction, Cellular
PubMed: 36515266
DOI: 10.7554/eLife.82621 -
Cells Jul 2023Ion channels are the second largest class of drug targets after G protein-coupled receptors. In addition to well-recognized ones like voltage-gated Na/K/Ca channels in... (Review)
Review
Ion channels are the second largest class of drug targets after G protein-coupled receptors. In addition to well-recognized ones like voltage-gated Na/K/Ca channels in the heart and neurons, novel ion channels are continuously discovered in both excitable and non-excitable cells and demonstrated to play important roles in many physiological processes and diseases such as developmental disorders, neurodegenerative diseases, and cancer. However, in the field of ion channel discovery, there are an unignorable number of published studies that are unsolid and misleading. Despite being the gold standard of a functional assay for ion channels, electrophysiological recordings are often accompanied by electrical noise, leak conductance, and background currents of the membrane system. These unwanted signals, if not treated properly, lead to the mischaracterization of proteins with seemingly unusual ion-conducting properties. In the recent ten years, the technical revolution of cryo-electron microscopy (cryo-EM) has greatly advanced our understanding of the structures and gating mechanisms of various ion channels and also raised concerns about the pore-forming ability of some previously identified channel proteins. In this review, we summarize cryo-EM findings on ion channels with molecular identities recognized or disputed in recent ten years and discuss current knowledge of proposed channel proteins awaiting cryo-EM analyses. We also present a classification of ion channels according to their architectures and evolutionary relationships and discuss the possibility and strategy of identifying more ion channels by analyzing structures of transmembrane proteins of unknown function. We propose that cross-validation by electrophysiological and structural analyses should be essentially required for determining molecular identities of novel ion channels.
Topics: Cryoelectron Microscopy; Ion Channels; Membrane Proteins
PubMed: 37508534
DOI: 10.3390/cells12141870 -
Proceedings of the National Academy of... Feb 2023Cells throughout the human body detect mechanical forces. While it is known that the rapid (millisecond) detection of mechanical forces is mediated by force-gated ion...
Cells throughout the human body detect mechanical forces. While it is known that the rapid (millisecond) detection of mechanical forces is mediated by force-gated ion channels, a detailed quantitative understanding of cells as sensors of mechanical energy is still lacking. Here, we combine atomic force microscopy with patch-clamp electrophysiology to determine the physical limits of cells expressing the force-gated ion channels (FGICs) Piezo1, Piezo2, TREK1, and TRAAK. We find that, depending on the ion channel expressed, cells can function either as proportional or nonlinear transducers of mechanical energy and detect mechanical energies as little as ~100 fJ, with a resolution of up to ~1 fJ. These specific energetic values depend on cell size, channel density, and cytoskeletal architecture. We also make the surprising discovery that cells can transduce forces either nearly instantaneously (<1 ms) or with a substantial time delay (~10 ms). Using a chimeric experimental approach and simulations, we show how such delays can emerge from channel-intrinsic properties and the slow diffusion of tension in the membrane. Overall, our experiments reveal the capabilities and limits of cellular mechanosensing and provide insights into molecular mechanisms that different cell types may employ to specialize for their distinct physiological roles.
Topics: Humans; Mechanotransduction, Cellular; Ion Channels; Cytoskeleton
PubMed: 36795747
DOI: 10.1073/pnas.2215747120