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1
IMOTO, KEIJI. „Molecular Aspects of Ion Permeation through Channels“. Annals of the New York Academy of Sciences 707, Nr. 1 Molecular Bas (Dezember 1993): 38–50. http://dx.doi.org/10.1111/j.1749-6632.1993.tb38040.x.
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2
Vacher, Helene, Durga P. Mohapatra und James S. Trimmer. „Localization and Targeting of Voltage-Dependent Ion Channels in Mammalian Central Neurons“. Physiological Reviews 88, Nr. 4 (Oktober 2008): 1407–47. http://dx.doi.org/10.1152/physrev.00002.2008.
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The intrinsic electrical properties and the synaptic input-output relationships of neurons are governed by the action of voltage-dependent ion channels. The localization of specific populations of ion channels with distinct functional properties at discrete sites in neurons dramatically impacts excitability and synaptic transmission. Molecular cloning studies have revealed a large family of genes encoding voltage-dependent ion channel principal and auxiliary subunits, most of which are expressed in mammalian central neurons. Much recent effort has focused on determining which of these subunits coassemble into native neuronal channel complexes, and the cellular and subcellular distributions of these complexes, as a crucial step in understanding the contribution of these channels to specific aspects of neuronal function. Here we review progress made on recent studies aimed to determine the cellular and subcellular distribution of specific ion channel subunits in mammalian brain neurons using in situ hybridization and immunohistochemistry. We also discuss the repertoire of ion channel subunits in specific neuronal compartments and implications for neuronal physiology. Finally, we discuss the emerging mechanisms for determining the discrete subcellular distributions observed for many neuronal ion channels.
3
Fahlke, Christoph. „Ion permeation and selectivity in ClC-type chloride channels“. American Journal of Physiology-Renal Physiology 280, Nr. 5 (01.05.2001): F748—F757. http://dx.doi.org/10.1152/ajprenal.2001.280.5.f748.
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Voltage-gated anion channels are present in almost every living cell and have many physiological functions. Recently, a novel gene family encoding voltage-gated chloride channels, the ClC family, was identified. The knowledge of primary amino acid sequences has allowed for the study of these anion channels in heterologous expression systems and made possible the combination of site-directed mutagenesis and high-resolution electrophysiological measurements as a means of gaining insights into the molecular basis of channel function. This review focuses on one particular aspect of chloride channel function, the selective transport of anions through biological membranes. I will describe recent experiments using a combination of cellular electrophysiology, molecular genetics, and recombinant DNA technology to study the molecular basis of ion permeation and selection in ClC-type chloride channels. These novel tools have provided new insights into basic mechanisms underlying the function of these biologically important channels.
4
Tiffner, Adéla, Valentina Hopl und Isabella Derler. „CRAC and SK Channels: Their Molecular Mechanisms Associated with Cancer Cell Development“. Cancers 15, Nr. 1 (23.12.2022): 101. http://dx.doi.org/10.3390/cancers15010101.
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Cancer represents a major health burden worldwide. Several molecular targets have been discovered alongside treatments with positive clinical outcomes. However, the reoccurrence of cancer due to therapy resistance remains the primary cause of mortality. Endeavors in pinpointing new markers as molecular targets in cancer therapy are highly desired. The significance of the co-regulation of Ca2+-permeating and Ca2+-regulated ion channels in cancer cell development, proliferation, and migration make them promising molecular targets in cancer therapy. In particular, the co-regulation of the Orai1 and SK3 channels has been well-studied in breast and colon cancer cells, where it finally leads to an invasion-metastasis cascade. Nevertheless, many questions remain unanswered, such as which key molecular components determine and regulate their interplay. To provide a solid foundation for a better understanding of this ion channel co-regulation in cancer, we first shed light on the physiological role of Ca2+ and how this ion is linked to carcinogenesis. Then, we highlight the structure/function relationship of Orai1 and SK3, both individually and in concert, their role in the development of different types of cancer, and aspects that are not yet known in this context.
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Arcangeli, Annarosa. „Ion channels and transporters in cancer. 3. Ion channels in the tumor cell-microenvironment cross talk“. American Journal of Physiology-Cell Physiology 301, Nr. 4 (Oktober 2011): C762—C771. http://dx.doi.org/10.1152/ajpcell.00113.2011.
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The traditional view of cancer as a collection of proliferating cells must be reconsidered, and cancer must be viewed as a “tissue” constituted by both transformed cells and a heterogeneous microenvironment, that tumor cells construct and remodel during multistep tumorigenesis. The “tumor microenvironment” (TM) is formed by mesenchymal, endothelial, and immune cells immersed in a network of extracellular matrix (ECM) proteins and soluble factors. The TM strongly contributes to tumor progression, through long distance, cell-to-cell or cell-to-matrix signals, which influence different aspects of tumor cell behavior. Understanding the relationships among the different components of the cancer tissue is crucial to design and develop new therapeutic strategies. Ion channels are emerging as relevant players in the cross talk between tumor cells and their TM. Ion channels are expressed on tumor cells, as well as in the different cellular components of the TM. In all these cells, ion channels are in a strategic position to sense and transmit extracellular signals into the intracellular machinery. Often, this transmission is mediated by integrin adhesion receptors, which can be functional partners of ion channels since they form molecular complexes with the channel protein in the context of the plasma membrane. The same relevant role is exerted by ion transporters, which also contribute to determine two facets of the cancer tissue: hypoxia and the acidic extracellular pH. On the whole, it is conceivable to prospect the targeting of ion channels for new therapeutic strategies aimed at better controlling the malignant progression of the cancer tissue.
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Hernández-Araiza, Ileana, Sara L. Morales-Lázaro, Jesús Aldair Canul-Sánchez, León D. Islas und Tamara Rosenbaum. „Role of lysophosphatidic acid in ion channel function and disease“. Journal of Neurophysiology 120, Nr. 3 (01.09.2018): 1198–211. http://dx.doi.org/10.1152/jn.00226.2018.
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Lysophosphatidic acid (LPA) is a bioactive phospholipid that exhibits a wide array of functions that include regulation of protein synthesis and adequate development of organisms. LPA is present in the membranes of cells and in the serum of several mammals and has also been shown to participate importantly in pathophysiological conditions. For several decades it was known that LPA produces some of its effects in cells through its interaction with specific G protein-coupled receptors, which in turn are responsible for signaling pathways that regulate cellular function. Among the target proteins for LPA receptors are ion channels that modulate diverse aspects of the physiology of cells and organs where they are expressed. However, recent studies have begun to unveil direct effects of LPA on ion channels, highlighting this phospholipid as a direct agonist and adding to the knowledge of the field of lipid-protein interactions. Moreover, the roles of LPA in pathophysiological conditions associated with the function of some ion channels have also begun to be clarified, and molecular mechanisms have been identified. This review focuses on the effects of LPA on ion channel function under normal and pathological conditions and highlights our present knowledge of the mechanisms by which it regulates the function and expression of N- and T-type Ca++ channels; M-type K+ channel and inward rectifier K+ channel subunit 2.1; transient receptor potential (TRP) melastatin 2, TRP vanilloid 1, and TRP ankyrin 1 channels; and TWIK-related K+ channel 1 (TREK-1), TREK-2, TWIK-related spinal cord K+ channel (TRESK), and TWIK-related arachidonic acid-stimulated K+ channel (TRAAK).
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Kytikova, Oxana Yu, Tatyana P. Novgorodtseva, Yulia K. Denisenko, Denis E. Naumov, Tatyana A. Gvozdenko und Juliy M. Perelman. „Thermosensory Transient Receptor Potential Ion Channels and Asthma“. Biomedicines 9, Nr. 7 (14.07.2021): 816. http://dx.doi.org/10.3390/biomedicines9070816.
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Asthma is a widespread chronic disease of the bronchopulmonary system with a heterogeneous course due to the complex etiopathogenesis. Natural-climatic and anthropogenic factors play an important role in the development and progression of this pathology. The reception of physical and chemical environmental stimuli and the regulation of body temperature are mediated by thermosensory channels, members of a subfamily of transient receptor potential (TRP) ion channels. It has been found that genes encoding vanilloid, ankyrin, and melastatin TRP channels are involved in the development of some asthma phenotypes and in the formation of exacerbations of this pathology. The review summarizes modern views on the role of high and low temperatures in airway inflammation in asthma. The participation of thermosensory TRP channels (vanilloid, ankyrin, and melastatin TRP channels) in the reaction to high and low temperatures and air humidity as well as in the formation of bronchial hyperreactivity and respiratory symptoms accompanying asthma is described. The genetic aspects of the functioning of thermosensory TRP channels are discussed. It is shown that new methods of treatment of asthma exacerbations caused by the influence of temperature and humidity should be based on the regulation of channel activity.
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Weissmann, Carina, Adriana A. Albanese, Natalia E. Contreras, María N. Gobetto, Libia C. Salinas Castellanos und Osvaldo D. Uchitel. „Ion channels and pain in Fabry disease“. Molecular Pain 17 (Januar 2021): 174480692110331. http://dx.doi.org/10.1177/17448069211033172.
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Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A (α-Gal A) activity which results in progressive accumulation of globotriaosylceramide (Gb3) and related metabolites. One prominent feature of Fabry disease is neuropathic pain. Accumulation of Gb3 has been documented in dorsal root ganglia (DRG) as well as other neurons, and has lately been associated with the mechanism of pain though the pathophysiology is still unclear. Small fiber (SF) neuropathy in FD differs from other entities in several aspects related to the perception of pain, alteration of fibers as well as drug therapies used in the practice with patients, with therapies far from satisfying. In order to develop better treatments, more information on the underlying mechanisms of pain is needed. Research in neuropathy has gained momentum from the development of preclinical models where different aspects of pain can be modelled and further analyzed. This review aims at describing the different in vitro and FD animal models that have been used so far, as well as some of the insights gained from their use. We focus especially in recent findings associated with ion channel alterations -that apart from the vascular alterations-, could provide targets for improved therapies in pain.
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Turner, Kathryn L., und Harald Sontheimer. „Cl − and K + channels and their role in primary brain tumour biology“. Philosophical Transactions of the Royal Society B: Biological Sciences 369, Nr. 1638 (19.03.2014): 20130095. http://dx.doi.org/10.1098/rstb.2013.0095.
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Profound cell volume changes occur in primary brain tumours as they proliferate, invade surrounding tissue or undergo apoptosis. These volume changes are regulated by the flux of Cl − and K + ions and concomitant movement of water across the membrane, making ion channels pivotal to tumour biology. We discuss which specific Cl − and K + channels are involved in defined aspects of glioma biology and how these channels are regulated. Cl − is accumulated to unusually high concentrations in gliomas by the activity of the NKCC1 transporter and serves as an osmolyte and energetic driving force for volume changes. Cell volume condensation is required as cells enter M phase of the cell cycle and this pre-mitotic condensation is caused by channel-mediated ion efflux. Similarly, Cl − and K + channels dynamically regulate volume in invading glioma cells allowing them to adjust to small extracellular brain spaces. Finally, cell condensation is a hallmark of apoptosis and requires the concerted activation of Cl − and Ca 2+ -activated K + channels. Given the frequency of mutation and high importance of ion channels in tumour biology, the opportunity exists to target them for treatment.
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Flaxer, Eli. „Comprehensive Controller for Super Sonic Molecular Beam Gas Chromatograph Mass Spectrometer“. Separations 9, Nr. 12 (07.12.2022): 417. http://dx.doi.org/10.3390/separations9120417.
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This paper presents a new, comprehensive digital circuit used for the control of a novel gas chromatograph mass spectrometer (GC-MS) interface that is based on supersonic molecular beam (SMB). The circuit includes a Texas Instruments 150 MHz digital signal controller (DSC), high voltage amplifiers for 8 independent channels and 4 independent channels of high resolution pulse width modulation (PWM). The circuit, along with a sophisticated embedded program and a custom made personal computer (PC) application, control all aspects of the interface: smart filament emission-current stabilization, static and scanning mass-dependent ion-source voltages, transfer-line heater proportional integral differential (PID) controls with thermocouple feedbacks, on/off valves, relays and several peripheral device controls that enable the full operation of a turbo-molecular vacuum pump, and of gas flow and pressure controllers. All aspects of this comprehensive controller were successfully tested. The signal for the 450 Th ion (C32H66) for example increased by 123% which is a significant increase. It is obvious that correctly tuned dynamic voltages can guarantee the optimal signal for each mass.
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Keynes, R. D. „Current Topics in Membranes and Transport, Vol. 21: Ion Channels: Molecular and Physiological Aspects“. Trends in Neurosciences 8 (Januar 1985): 226. http://dx.doi.org/10.1016/0166-2236(85)90089-x.
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12
Kyriacou, E. „Reconstitution of Single Potassium Channels from Bovine Gallbladder Epithelium“. Journal of International Medical Research 26, Nr. 4 (August 1998): 188–99. http://dx.doi.org/10.1177/030006059802600403.
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The study of molecular transport across gall-bladder epithelium may contribute to our understanding of the pathophysiology of gall-bladder disease. The aim of this study was to reconstitute and characterize single potassium ion channels in bovine gall-bladder epithelial mucosa – both apical and basolateral aspects. Standard subcellular fractionation techniques were used to form either apical or basolateral closed-membrane vesicles from the mucosal epithelium of fresh gall bladders from healthy young adult cattle. Vesicular ion channels were incorporated into voltage-clamped planar lipid bilayers under known ionic conditions and their conductances, reversal potentials, and voltages were characterized. Low-conductance voltage-insensitive apical membrane vesicle channels of at least four conductance levels were found (mean ± SD): 12 ± 4 pS, n = 10; 40 ± 12 pS, n = 4; 273 ± 31 pS, n = 3; and 151 ± 24 pS, n = 5. Conductances of potassium ion channels in basolateral membrane vesicles were in the range 9–450 pS, and these channels included high-conductance calcium-activated potassium-ion channels ‘K(Ca)’ which were voltage- and calcium-dependent.
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Moody, William J., und Martha M. Bosma. „Ion Channel Development, Spontaneous Activity, and Activity-Dependent Development in Nerve and Muscle Cells“. Physiological Reviews 85, Nr. 3 (Juli 2005): 883–941. http://dx.doi.org/10.1152/physrev.00017.2004.
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At specific stages of development, nerve and muscle cells generate spontaneous electrical activity that is required for normal maturation of intrinsic excitability and synaptic connectivity. The patterns of this spontaneous activity are not simply immature versions of the mature activity, but rather are highly specialized to initiate and control many aspects of neuronal development. The configuration of voltage- and ligand-gated ion channels that are expressed early in development regulate the timing and waveform of this activity. They also regulate Ca2+ influx during spontaneous activity, which is the first step in triggering activity-dependent developmental programs. For these reasons, the properties of voltage- and ligand-gated ion channels expressed by developing neurons and muscle cells often differ markedly from those of adult cells. When viewed from this perspective, the reasons for complex patterns of ion channel emergence and regression during development become much clearer.
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López-Vera, Estuardo, Luis Martínez-Hernández, Manuel B. Aguilar, Elisa Carrillo und Joanna Gajewiak. „Studies of Conorfamide-Sr3 on Human Voltage-Gated Kv1 Potassium Channel Subtypes“. Marine Drugs 18, Nr. 8 (13.08.2020): 425. http://dx.doi.org/10.3390/md18080425.
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Recently, Conorfamide-Sr3 (CNF-Sr3) was isolated from the venom of Conus spurius and was demonstrated to have an inhibitory concentration-dependent effect on the Shaker K+ channel. The voltage-gated potassium channels play critical functions on cellular signaling, from the regeneration of action potentials in neurons to the regulation of insulin secretion in pancreatic cells, among others. In mammals, there are at least 40 genes encoding voltage-gated K+ channels and the process of expression of some of them may include alternative splicing. Given the enormous variety of these channels and the proven use of conotoxins as tools to distinguish different ligand- and voltage-gated ion channels, in this work, we explored the possible effect of CNF-Sr3 on four human voltage-gated K+ channel subtypes homologous to the Shaker channel. CNF-Sr3 showed a 10 times higher affinity for the Kv1.6 subtype with respect to Kv1.3 (IC50 = 2.7 and 24 μM, respectively) and no significant effect on Kv1.4 and Kv1.5 at 10 µM. Thus, CNF-Sr3 might become a novel molecular probe to study diverse aspects of human Kv1.3 and Kv1.6 channels.
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Nagaeva, E. I., N. N. Potapieva und D. B. Tikhonov. „The Effect of Hydrophobic Monoamines on Acid-Sensing Ion Channels ASIC1B“. Acta Naturae 7, Nr. 2 (15.06.2015): 95–101. http://dx.doi.org/10.32607/20758251-2015-7-2-95-101.
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Acid-sensing ion channels (ASICs) are widely distributed in both the central and peripheral nervous systems of vertebrates. The pharmacology of these receptors remains poorly investigated, while the search for new ASIC modulators is very important. Recently, we found that some monoamines, which are blockers of NMDA receptors, inhibit and/or potentiate acid-sensing ion channels, depending on the subunit composition of the channels. The effect of 9-aminoacridine, IEM-1921, IEM-2117, and memantine both on native receptors and on recombinant ASIC1a, ASIC2a, and ASIC3 homomers was studied. In the present study, we have investigated the effect of these four compounds on homomeric ASIC1b channels. Experiments were performed on recombinant receptors expressed in CHO cells using the whole-cell patch clamp technique. Only two compounds, 9-aminoacridine and memantine, inhibited ASIC1b channels. IEM-1921 and IEM-2117 were inactive even at a 1000 M concentration. In most aspects, the effect of the compounds on ASIC1b was similar to their effect on ASIC1a. The distinguishing feature of homomeric ASIC1b channels is a steep activation-dependence, indicating cooperative activation by protons. In our experiments, the curve of the concentration dependence of ASIC1b inhibition by 9-aminoacridine also had a slope (Hill coefficient) of 3.8, unlike ASIC1a homomers, for which the Hill coefficient was close to 1. This finding indicates that the inhibitory effect of 9-aminoacridine is associated with changes in the activation properties of acid-sensing ion channels.
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Roux, Benoît, Toby Allen, Simon Bernèche und Wonpil Im. „Theoretical and computational models of biological ion channels“. Quarterly Reviews of Biophysics 37, Nr. 1 (Februar 2004): 15–103. http://dx.doi.org/10.1017/s0033583504003968.
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1. Introduction 172. Dynamics of many-body systems 192.1 Effective dynamics of reduced systems 212.2 The constraint of thermodynamic equilibrium 242.3 Mean-field theories 253. Solvation free energy and electrostatics 273.1 Microscopic view of the Born model 273.2 Ion–Ion interactions in bulk solution 293.3 Continuum electrostatics and the PB equation 293.4 Limitations of continuum dielectric models 323.5 The dielectric barrier 333.6 The transmembrane potential and the PB-V equation 354. Statistical mechanical equilibrium theory 404.1 Multi-ion PMF 404.2 Equilibrium probabilities of occupancy 434.3 Coupling to the membrane potential 444.4 Ionic selectivity 484.5 Reduction to a one-dimensional (1D) free-energy profile 495. From MD toI–V: a practical guide 505.1 Extracting the essential ingredients from MD 515.1.1 Channel conductance from equilibrium and non-equilibrium MD 515.1.2 PMF techniques 525.1.3 Friction and diffusion coefficient techniques 535.1.4 About computational times 555.2 Ion permeation models 565.2.1 The 1D-NP electrodiffusion theory 565.2.2 Discrete-state Markov chains 575.2.3 The GCMC/BD algorithm 585.2.4 PNP electrodiffusion theory 626. Computational studies of ion channels 636.1 Computational studies of gA 656.1.1 Free-energy surface for K+ permeation 666.1.2 Mean-force decomposition 696.1.3 Cation-binding sites 696.1.4 Channel conductance 706.1.5 Selectivity 726.2 Computational studies of KcsA 726.2.1 Multi-ion free-energy surface and cation-binding sites 736.2.2 Channel conductance 746.2.3 Mechanism of ion conduction 776.2.4 Selectivity 786.3 Computational studies of OmpF 796.3.1 The need to compare the different level of approximations 796.3.2 Equilibrium protein fluctuations and ion distribution 806.3.3 Non-equilibrium ion fluxes 806.3.4 Reversal potential and selectivity 846.4 Successes and limitations 876.4.1 Channel structure 876.4.2 Ion-binding sites 876.4.3 Ion conduction 886.4.4 Ion selectivity 897. Conclusion 908. Acknowledgments 939. References 93The goal of this review is to establish a broad and rigorous theoretical framework to describe ion permeation through biological channels. This framework is developed in the context of atomic models on the basis of the statistical mechanical projection-operator formalism of Mori and Zwanzig. The review is divided into two main parts. The first part introduces the fundamental concepts needed to construct a hierarchy of dynamical models at different level of approximation. In particular, the potential of mean force (PMF) as a configuration-dependent free energy is introduced, and its significance concerning equilibrium and non-equilibrium phenomena is discussed. In addition, fundamental aspects of membrane electrostatics, with a particular emphasis on the influence of the transmembrane potential, as well as important computational techniques for extracting essential information from all-atom molecular dynamics (MD) simulations are described and discussed. The first part of the review provides a theoretical formalism to ‘translate’ the information from the atomic structure into the familiar language of phenomenological models of ion permeation. The second part is aimed at reviewing and contrasting results obtained in recent computational studies of three very different channels; the gramicidin A (gA) channel, which is a narrow one-ion pore (at moderate concentration), the KcsA channel from Streptomyces lividans, which is a narrow multi-ion pore, and the outer membrane matrix porin F (OmpF) from Escherichia coli, which is a trimer of three β-barrel subunits each forming wide aqueous multi-ion pores. Comparison with experiments demonstrates that current computational models are approaching semi-quantitative accuracy and are able to provide significant insight into the microscopic mechanisms of ion conduction and selectivity. We conclude that all-atom MD with explicit water molecules can represent important structural features of complex biological channels accurately, including such features as the location of ion-binding sites along the permeation pathway. We finally discuss the broader issue of the validity of ion permeation models and an outlook to the future.
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Walker, R. J., und L. Holden-Dye. „Evolutionary aspects of transmitter molecules, their receptors and channels“. Parasitology 102, S1 (Januar 1991): S7—S29. http://dx.doi.org/10.1017/s0031182000073261.
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Classical transmitters are present in all phyla that have been studied; however, our detailed understanding of the process of neurotransmission in these phyla is patchy and has centred on those neurotransmitter receptor mechanisms which are amenable to study with the tools available at the time, for example, high-affinity ligands, tissues with high density of receptor protein, suitable electrophysio-logical recording systems. Studies also clearly show that many neurones exhibit co-localization of classical transmitters and neuropeptides. However, the physiological implications of this co-localization have yet to be elucidated in the vast majority of examples.The application of molecular biological techniques to the study of neurotransmitter receptors (to date mainly in vertebrates) is contributing to our understanding of the evolution of these proteins. Striking similarities in the structure of ligand-gated receptors have been revealed. Thus, although ligand-gated receptors differ markedly in terms of the endogenous ligands they recognize and the ion channels that they gate, the structural similarities suggest a strong evolutionary relationship. Pharmacological differences also exist between receptors that recognize the same neurotransmitter but in different phyla, and this may also be exploited to further the understanding of structure-function relationships for receptors. Thus, for instance, some invertebrate GABA receptors are similar to mammalian GABAa receptors but lack a modulatory site operated by benzodiazepines. Knowledge of the structure and subunit composition of these receptors and comparison with those that have already been elucidated for the mammalian nervous system might indicate the functional importance of certain amino acid residues or receptor subunits. These differences could also be exploited in the development of new agents to control agrochemical pests and parasites of medical importance.The study of the pharmacology of receptor proteins for neurotransmitters in invertebrates, together with the application of biochemical and molecular biological techniques to elucidate the structure of these molecules, is now gathering momentum. For certain receptors, e.g. the nicotinic receptor, we can expect to have fundamental information on the function of this receptor at the molecular level in both invertebrates and vertebrates in the near future.
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Pla-Casillanis, Adrià, Laura Ferigle, Marta Alonso-Gardón, Efren Xicoy-Espaulella, Ekaitz Errasti-Murugarren, Daniela Marazziti und Raúl Estévez. „GPR37 Receptors and Megalencephalic Leukoencephalopathy with Subcortical Cysts“. International Journal of Molecular Sciences 23, Nr. 10 (16.05.2022): 5528. http://dx.doi.org/10.3390/ijms23105528.
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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of vacuolating leukodystrophy (white matter disorder), which is mainly caused by defects in MLC1 or glial cell adhesion molecule (GlialCAM) proteins. In addition, autoantibodies to GlialCAM are involved in the pathology of multiple sclerosis. MLC1 and GLIALCAM genes encode for membrane proteins of unknown function, which has been linked to the regulation of different ion channels and transporters, such as the chloride channel VRAC (volume regulated anion channel), ClC-2 (chloride channel 2), and connexin 43 or the Na+/K+-ATPase pump. However, the mechanisms by which MLC proteins regulate these ion channels and transporters, as well as the exact function of MLC proteins remain obscure. It has been suggested that MLC proteins might regulate signalling pathways, but the mechanisms involved are, at present, unknown. With the aim of answering these questions, we have recently described the brain GlialCAM interactome. Within the identified proteins, we could validate the interaction with several G protein-coupled receptors (GPCRs), including the orphan GPRC5B and the proposed prosaposin receptors GPR37L1 and GPR37. In this review, we summarize new aspects of the pathophysiology of MLC disease and key aspects of the interaction between GPR37 receptors and MLC proteins.
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Cassinelli, Silvia, Carla Viñola-Renart, Anna Benavente-Garcia, María Navarro-Pérez, Jesusa Capera und Antonio Felipe. „Palmitoylation of Voltage-Gated Ion Channels“. International Journal of Molecular Sciences 23, Nr. 16 (19.08.2022): 9357. http://dx.doi.org/10.3390/ijms23169357.
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Protein lipidation is one of the most common forms of posttranslational modification. This alteration couples different lipids, such as fatty acids, phospho- and glycolipids and sterols, to cellular proteins. Lipidation regulates different aspects of the protein’s physiology, including structure, stability and affinity for cellular membranes and protein–protein interactions. In this scenario, palmitoylation is the addition of long saturated fatty acid chains to amino acid residues of the proteins. The enzymes responsible for this modification are acyltransferases and thioesterases, which control the protein’s behavior by performing a series of acylation and deacylation cycles. These enzymes target a broad repertoire of substrates, including ion channels. Thus, protein palmitoylation exhibits a pleiotropic role by differential modulation of the trafficking, spatial organization and electrophysiological properties of ion channels. Considering voltage-gated ion channels (VGICs), dysregulation of lipidation of both the channels and the associated ancillary subunits correlates with the development of various diseases, such as cancer or mental disorders. Therefore, a major role for protein palmitoylation is currently emerging, affecting not only the dynamism and differential regulation of a moiety of cellular proteins but also linking to human health. Therefore, palmitoylation of VGIC, as well as related enzymes, constitutes a novel pharmacological tool for drug development to target related pathologies.
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Sahlender, Daniela A., Iaroslav Savtchouk und Andrea Volterra. „What do we know about gliotransmitter release from astrocytes?“ Philosophical Transactions of the Royal Society B: Biological Sciences 369, Nr. 1654 (19.10.2014): 20130592. http://dx.doi.org/10.1098/rstb.2013.0592.
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Astrocytes participate in information processing by actively modulating synaptic properties via gliotransmitter release. Various mechanisms of astrocytic release have been reported, including release from storage organelles via exocytosis and release from the cytosol via plasma membrane ion channels and pumps. It is still not fully clear which mechanisms operate under which conditions, but some of them, being Ca 2+ -regulated, may be physiologically relevant. The properties of Ca 2+ -dependent transmitter release via exocytosis or via ion channels are different and expected to produce different extracellular transmitter concentrations over time and to have distinct functional consequences. The molecular aspects of these two release pathways are still under active investigation. Here, we discuss the existing morphological and functional evidence in support of either of them. Transgenic mouse models, specific antagonists and localization studies have provided insight into regulated exocytosis, albeit not in a systematic fashion. Even more remains to be uncovered about the details of channel-mediated release. Better functional tools and improved ultrastructural approaches are needed in order fully to define specific modalities and effects of astrocytic gliotransmitter release pathways.
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Pullman, A. „Molecular aspects of channel formation and ion transport through membranes“. Pure and Applied Chemistry 60, Nr. 2 (01.01.1988): 259–64. http://dx.doi.org/10.1351/pac198860020259.
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Schneider, Nicole, Sönke Cordeiro, Jan-Philipp Machtens, Simona Braams, Thomas Rauen und Christoph Fahlke. „Functional Properties of the Retinal Glutamate Transporters GLT-1c and EAAT5“. Journal of Biological Chemistry 289, Nr. 3 (04.12.2013): 1815–24. http://dx.doi.org/10.1074/jbc.m113.517177.
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In the mammalian retina, glutamate uptake is mediated by members of a family of glutamate transporters known as “excitatory amino acid transporters (EAATs).” Here we cloned and functionally characterized two retinal EAATs from mouse, the GLT-1/EAAT2 splice variant GLT-1c, and EAAT5. EAATs are glutamate transporters and anion-selective ion channels, and we used heterologous expression in mammalian cells, patch-clamp recordings and noise analysis to study and compare glutamate transport and anion channel properties of both EAAT isoforms. We found GLT-1c to be an effective glutamate transporter with high affinity for Na+ and glutamate that resembles original GLT-1/EAAT2 in all tested functional aspects. EAAT5 exhibits glutamate transport rates too low to be accurately measured in our experimental system, with significantly lower affinities for Na+ and glutamate than GLT-1c. Non-stationary noise analysis demonstrated that GLT-1c and EAAT5 also differ in single-channel current amplitudes of associated anion channels. Unitary current amplitudes of EAAT5 anion channels turned out to be approximately twice as high as single-channel amplitudes of GLT-1c. Moreover, at negative potentials open probabilities of EAAT5 anion channels were much larger than for GLT-1c. Our data illustrate unique functional properties of EAAT5, being a low-affinity and low-capacity glutamate transport system, with an anion channel optimized for anion conduction in the negative voltage range.
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Chauhan, Anurag Singh, Ganesh Chandra Sahoo, Manas Ranjan Dikhit und Pradeep Das. „Acid-Sensing Ion Channels Structural Aspects, Pathophysiological Importance and Experimental Mutational Data Available Across Various Species to Target Human ASIC1“. Current Drug Targets 20, Nr. 1 (27.11.2018): 111–21. http://dx.doi.org/10.2174/1389450119666180820103316.
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The H+-gated (proton) currents are widely present in brain sensory neuronal system and various studies identified the structural units and deciphered the physiological and pathological function of ion channels. The normal neuron requires an optimal pH to carry out its functions. In acidosis, the ASICs (Acid-sensing Ion Channels) are activated in both the CNS (central nervous system) and PNS (peripheral nervous system). ASICs are related to degenerin channels (DEGs), epithelial sodium cation channels (ENaCs), and FMRF-amide (Phe-Met-Arg-Phe-NH2)-gated channels (FaNaC). Its activation leads physiologically to pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. It detects the level of acid fluctuation in the extracellular environment and responds to acidic pH by increasing the rate of membrane depolarization. It conducts cations like Na+ (Sodium) and Ca2+ (Calcium) ions across the membrane upon protonation. The ASICs subtypes are characterized by differing biophysical properties and pH sensitivities. The subtype ASIC1 is involved in various CNS diseases and therefore focusing on its specific functional properties will guide in drug design methods. The review highlights the cASIC1 (Chicken ASIC1) crystal structures, involvement in physiological environment and limitations of currently available inhibitors. In addition, it details the mutational data available to design an inhibitor against hASIC1 (Human ASIC1).
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Rubaiy, Hussein Nori. „A Short Guide to Electrophysiology and Ion Channels“. Journal of Pharmacy & Pharmaceutical Sciences 20 (15.03.2017): 48. http://dx.doi.org/10.18433/j32p6r.
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The birth and discovery of electrophysiological science took place in the 18th century laying the path for our understanding of nerve membrane ionic currents. The pore-forming proteins, ion channels, are involved and play critical roles in very important physiological and pathological processes, such as neuronal signaling and cardiac excitability, therefore, they serve as therapeutic drug targets. The study of physiological, pharmacological and biophysical properties of ion channels can be done by patch clamp, a gold standard and powerful electrophysiological technique. The current review, in addition to highlight and cover the history of electrophysiology, patch clamp (conventional and automated) technique, and different types of ion channels, will also discuss the importance of ion channels in different neurological diseases and disorders. As the field of neuroscience is growing, this manuscript is intended as a guide to help in understanding the importance of ion channels, particularly in neuroscience, and also in using the patch clamp technique for the study of molecular physiology, pathophysiology, and pharmacology of neuronal ion channels. Importantly, this review will spotlight on the therapeutic aspect of neuronal ion channels. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Barros, Francisco, Luis Pardo, Pedro Domínguez, Luisa Sierra und Pilar de la Peña. „New Structures and Gating of Voltage-Dependent Potassium (Kv) Channels and Their Relatives: A Multi-Domain and Dynamic Question“. International Journal of Molecular Sciences 20, Nr. 2 (10.01.2019): 248. http://dx.doi.org/10.3390/ijms20020248.
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Voltage-dependent potassium channels (Kv channels) are crucial regulators of cell excitability that participate in a range of physiological and pathophysiological processes. These channels are molecular machines that display a mechanism (known as gating) for opening and closing a gate located in a pore domain (PD). In Kv channels, this mechanism is triggered and controlled by changes in the magnitude of the transmembrane voltage sensed by a voltage-sensing domain (VSD). In this review, we consider several aspects of the VSD–PD coupling in Kv channels, and in some relatives, that share a common general structure characterized by a single square-shaped ion conduction pore in the center, surrounded by four VSDs located at the periphery. We compile some recent advances in the knowledge of their architecture, based in cryo-electron microscopy (cryo-EM) data for high-resolution determination of their structure, plus some new functional data obtained with channel variants in which the covalent continuity between the VSD and PD modules has been interrupted. These advances and new data bring about some reconsiderations about the use of exclusively a classical electromechanical lever model of VSD–PD coupling by some Kv channels, and open a view of the Kv-type channels as allosteric machines in which gating may be dynamically influenced by some long-range interactional/allosteric mechanisms.
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Agnati, Luigi F., Manuela Marcoli, Guido Maura, Kjell Fuxe und Diego Guidolin. „The multi-facet aspects of cell sentience and their relevance for the integrative brain actions: role of membrane protein energy landscape“. Reviews in the Neurosciences 27, Nr. 4 (01.06.2016): 347–63. http://dx.doi.org/10.1515/revneuro-2015-0049.
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AbstractSeveral ion channels can be randomly and spontaneously in an open state, allowing the exchange of ion fluxes between extracellular and intracellular environments. We propose that the random changes in the state of ion channels could be also due to proteins exploring their energy landscapes. Indeed, proteins can modify their steric conformation under the effects of the physicochemical parameters of the environments with which they are in contact, namely, the extracellular, intramembrane and intracellular environments. In particular, it is proposed that the random walk of proteins in their energy landscape is towards attractors that can favor the open or close condition of the ion channels and/or intrinsic activity of G-protein-coupled receptors. The main aspect of the present proposal is that some relevant physicochemical parameters of the environments (e.g. molecular composition, temperature, electrical fields) with which some signaling-involved plasma membrane proteins are in contact alter their conformations. In turn, these changes can modify their information handling via a modulatory action on their random walk towards suitable attractors of their energy landscape. Thus, spontaneous and/or signal-triggered electrical activities of neurons occur that can have emergent properties capable of influencing the integrative actions of brain networks. Against this background, Cook’s hypothesis on ‘cell sentience’ is developed by proposing that physicochemical parameters of the environments with which the plasma-membrane proteins of complex cellular networks are in contact fulfill a fundamental role in their spontaneous and/or signal-triggered activity. Furthermore, it is proposed that a specialized organelle, the primary cilium, which is present in most cells (also neurons and astrocytes), could be of peculiar importance to pick up chemical signals such as ions and transmitters and to detect physical signals such as pressure waves, thermal gradients, and local field potentials.
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Fink, Martin, und Denis Noble. „Markov models for ion channels: versatility versus identifiability and speed“. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 367, Nr. 1896 (13.06.2009): 2161–79. http://dx.doi.org/10.1098/rsta.2008.0301.
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Markov models (MMs) represent a generalization of Hodgkin–Huxley models. They provide a versatile structure for modelling single channel data, gating currents, state-dependent drug interaction data, exchanger and pump dynamics, etc. This paper uses examples from cardiac electrophysiology to discuss aspects related to parameter estimation. (i) Parameter unidentifiability (found in 9 out of 13 of the considered models) results in an inability to determine the correct layout of a model, contradicting the idea that model structure and parameters provide insights into underlying molecular processes. (ii) The information content of experimental voltage step clamp data is discussed, and a short but sufficient protocol for parameter estimation is presented. (iii) MMs have been associated with high computational cost (owing to their large number of state variables), presenting an obstacle for multicellular whole organ simulations as well as parameter estimation. It is shown that the stiffness of models increases computation time more than the number of states. (iv) Algorithms and software programs are provided for steady-state analysis, analytical solutions for voltage steps and numerical derivation of parameter identifiability. The results provide a new standard for ion channel modelling to further the automation of model development, the validation process and the predictive power of these models.
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Gasimova, Yegana Aydin. „Modern neurochemical and molecular genetic aspects of the pathogenesis of neonatal seizures“. Modern pediatrics. Ukraine, Nr. 6(110) (30.10.2020): 32–35. http://dx.doi.org/10.15574/sp.2020.110.32.
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The article is devoted to the modern aspects of the pathogenesis of neonatal seizures (NS). The main mechanisms of the development of perinatal brain injuries, which are fundamental in the genesis of NS, are considered, the prospects for research devoted to the study of the possibilities of molecular genetic prediction of the individual risk of ischemia and the development of NS are outlined. The mechanisms of ischemic brain damage during the neonatal period and the role of glutamate, the main excitatory neurotransmitter acting on NMDA receptors that regulate the electrical activity of neurons, are described in detail. The review focuses on the involvement of metalloproteinases, primarily MMP-9, which destroys type IV collagen, which is the main component of the basement membrane of the cerebral endothelium, and creates conditions for cell migration across the BBB, thereby causing a cytokine storm and the development of inflammation, leading to NS. The possible role of calcium-dependent proteinases — calpains in the development of NS is analyzed, since in some forms of CNS pathology, uncontrolled hyperactivation of calpains is observed, leading to a disruption of the regulation of neurotransmitter transmission, which can, in turn, become an additional factor for the development of the neurodegenerative process in the brain and the development of seizures. Also are presented the results of studies devoted to the role of ion channels, providing synaptic transmission of excitation from an excited neuron to other cells. It has been shown that molecular defects in ion channels can be one of the factors that create prerequisites for the development of NS. The article shows the prospects for studying the genetic polymorphism of enzymes involved in the pathogenesis of ischemic brain damage, based on ideas about the pathogenesis of cerebral disorders in newborns, which are based on oxidative damage. The concluding part of the article outlines the modern principles of NS therapy, their main goal is to relieve the symptoms of the underlying disease, to ensure the normalization of blood circulation and brain metabolism, to optimize the conditions for the functioning of the preserved brain structures to prevent the formation of severe neurological complications, as well as to maintain optimal parameters of respiration, glucose-electrolyte composition of blood and thermal regime. Based on the data presented, it is concluded that early diagnosis of NS is necessary, which is determined by the fact that seizures in newborns are usually caused by serious damage to the child's brain, and in some cases — by life-threatening conditions, the timely diagnosis of which contributes to the early onset of specific treatment. No conflict of interest was declared by the author. Key words: newborn, cerebral ischemia, neonatal seizures.
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PERRAUD, A. „Novel aspects of signaling and ion-homeostasis regulation in immunocytesThe TRPM ion channels and their potential role in modulating the immune response“. Molecular Immunology 41, Nr. 6-7 (Juli 2004): 657–73. http://dx.doi.org/10.1016/j.molimm.2004.04.013.
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Golukhova, E. Z., O. I. Gromova, R. A. Shomahov, N. I. Bulaeva und L. A. Bockeria. „Monogenec Arrhythmic Syndromes: From Molecular and Genetic Aspects to Bedside“. Acta Naturae 8, Nr. 2 (15.06.2016): 62–74. http://dx.doi.org/10.32607/20758251-2016-8-2-62-74.
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The abrupt cessation of effective cardiac function that is generally due to heart rhythm disorders can cause sudden and unexpected death at any age and is referred to as a syndrome called sudden cardiac death (SCD). Annually, about 400,000 cases of SCD occur in the United States alone. Less than 5% of the resuscitation techniques are effective. The prevalence of SCD in a population rises with age according to the prevalence of coronary artery disease, which is the most common cause of sudden cardiac arrest. However, there is a peak in SCD incidence for the age below 5 years, which is equal to 17 cases per 100,000 of the population. This peak is due to congenital monogenic arrhythmic canalopathies. Despite their relative rarity, these cases are obviously the most tragic. The immediate causes, or mechanisms, of SCD are comprehensive. Generally, it is arrhythmic death due to ventricular tachyarrythmias - sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Bradyarrhythmias and pulseless electrical activity account for no more than 40% of all registered cardiac arrests, and they are more often the outcome of the abovementioned arrhythmias. Our current understanding of the mechanisms responsible for SCD has emerged from decades of basic science investigation into the normal electrophysiology of the heart, the molecular physiology of cardiac ion channels, the fundamental cellular and tissue events associated with cardiac arrhythmias, and the molecular genetics of monogenic disorders of the heart rhythm (for example, the long QT syndrome). This review presents an overview of the molecular and genetic basis of SCD in the long QT syndrome, Brugada syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia and idiopathic ventricular fibrillation, and arrhythmogenic right ventricular dysplasia, and sudden cardiac death prevention strategies by modern techniques (including implantable cardioverter-defibrillator).
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Berridge, M. J. „Elementary and global aspects of calcium signalling.“ Journal of Experimental Biology 200, Nr. 2 (01.01.1997): 315–19. http://dx.doi.org/10.1242/jeb.200.2.315.
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Calcium is a ubiquitous second messenger used to regulate a wide range of cellular processes. This role in signalling has to be conducted against the rigid homeostatic mechanisms that ensure that the resting level of Ca2+ is kept low (i.e. between 20 and 100 nmol l-1) in order to avoid the cytotoxic effects of a prolonged elevation of [Ca2+]. Cells have evolved a sophisticated signalling system based on the generation of brief pulses of Ca2+ which enables this ion to be used as a messenger, thus avoiding its toxic effects. Such Ca2+ spikes usually result from the coordinated release of Ca2+ from internal stores using either inositol 1,4,5-trisphosphate or ryanodine receptors. Using Ca2+ imaging techniques, the opening of individual channels has now been visualized and models have been proposed to explain how these elementary events are coordinated to generate the global Ca2+ signals that regulate cellular activity.
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Fraser, Scott P., Iley Ozerlat-Gunduz, William J. Brackenbury, Elizabeth M. Fitzgerald, Thomas M. Campbell, R. Charles Coombes und Mustafa B. A. Djamgoz. „Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation“. Philosophical Transactions of the Royal Society B: Biological Sciences 369, Nr. 1638 (19.03.2014): 20130105. http://dx.doi.org/10.1098/rstb.2013.0105.
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Although ion channels are increasingly being discovered in cancer cells in vitro and in vivo , and shown to contribute to different aspects and stages of the cancer process, much less is known about the mechanisms controlling their expression. Here, we focus on voltage-gated Na + channels (VGSCs) which are upregulated in many types of carcinomas where their activity potentiates cell behaviours integral to the metastatic cascade. Regulation of VGSCs occurs at a hierarchy of levels from transcription to post-translation. Importantly, mainstream cancer mechanisms, especially hormones and growth factors, play a significant role in the regulation. On the whole, in major hormone-sensitive cancers, such as breast and prostate cancer, there is a negative association between genomic steroid hormone sensitivity and functional VGSC expression. Activity-dependent regulation by positive feedback has been demonstrated in strongly metastatic cells whereby the VGSC is self-sustaining, with its activity promoting further functional channel expression. Such auto-regulation is unlike normal cells in which activity-dependent regulation occurs mostly via negative feedback. Throughout, we highlight the possible clinical implications of functional VGSC expression and regulation in cancer.
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Summhammer, Johann, Georg Sulyok, Gustav Bernroider und Massimo Cocchi. „The Optimized Conformation Dynamics of the KcsA Filter as a Probe for Lateral Membrane Effects; A First Principle Based Femto-Sec Resolution MD Study“. Membranes 12, Nr. 12 (24.11.2022): 1183. http://dx.doi.org/10.3390/membranes12121183.
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We provide a high resolution, all-atom, femto-second molecular dynamics (MD) simulation of the passage of K+ ions and H2O molecules through the selectivity filter of the KcsA potassium ion channel, based on first principle physical methods. Our results show that a change in the length of the selectivity filter of as little as 3%, regardless of whether the filter is made longer or shorter, will reduce the K+ ion current by around 50%. In addition, further squeezing or stretching by about 9% can effectively stop the current. Our results demonstrate optimized conformational dynamics that associate an increased mobility of parts in the filter linings with a standard configuration, leading to maximized conduction rates that are highly sensitive to geometrical distortions. We discuss this latter aspect in relation to lateral membrane effects on the filter region of ion channels and the ‘force from lipids’ hypothesis.
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Deutsch, Matthias, Carina Stegmayr, Sabine Balfanz und Arnd Baumann. „Loss of HCN2 in Dorsal Hippocampus of Young Adult Mice Induces Specific Apoptosis of the CA1 Pyramidal Neuron Layer“. International Journal of Molecular Sciences 22, Nr. 13 (22.06.2021): 6699. http://dx.doi.org/10.3390/ijms22136699.
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Neurons inevitably rely on a proper repertoire and distribution of membrane-bound ion-conducting channels. Among these proteins, the family of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels possesses unique properties giving rise to the corresponding Ih-current that contributes to various aspects of neural signaling. In mammals, four genes (hcn1-4) encode subunits of HCN channels. These subunits can assemble as hetero- or homotetrameric ion-conducting channels. In order to elaborate on the specific role of the HCN2 subunit in shaping electrical properties of neurons, we applied an Adeno-associated virus (AAV)-mediated, RNAi-based knock-down strategy of hcn2 gene expression both in vitro and in vivo. Electrophysiological measurements showed that HCN2 subunit knock-down resulted in specific yet anticipated changes in Ih-current properties in primary hippocampal neurons and, in addition, corroborated that the HCN2 subunit participates in postsynaptic signal integration. To further address the role of the HCN2 subunit in vivo, we injected recombinant (r)AAVs into the dorsal hippocampus of young adult male mice. Behavioral and biochemical analyses were conducted to assess the contribution of HCN2-containing channels in shaping hippocampal network properties. Surprisingly, knock-down of hcn2 expression resulted in a severe degeneration of the CA1 pyramidal cell layer, which did not occur in mice injected with control rAAV constructs. This finding might pinpoint to a vital and yet unknown contribution of HCN2 channels in establishing or maintaining the proper function of CA1 pyramidal neurons of the dorsal hippocampus.
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Mantegazza, Massimo, Sandrine Cestèle und William A. Catterall. „Sodium channelopathies of skeletal muscle and brain“. Physiological Reviews 101, Nr. 4 (01.10.2021): 1633–89. http://dx.doi.org/10.1152/physrev.00025.2020.
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Voltage-gated sodium channels initiate action potentials in nerve, skeletal muscle, and other electrically excitable cells. Mutations in them cause a wide range of diseases. These channelopathy mutations affect every aspect of sodium channel function, including voltage sensing, voltage-dependent activation, ion conductance, fast and slow inactivation, and both biosynthesis and assembly. Mutations that cause different forms of periodic paralysis in skeletal muscle were discovered first and have provided a template for understanding structure, function, and pathophysiology at the molecular level. More recent work has revealed multiple sodium channelopathies in the brain. Here we review the well-characterized genetics and pathophysiology of the periodic paralyses of skeletal muscle and then use this information as a foundation for advancing our understanding of mutations in the structurally homologous α-subunits of brain sodium channels that cause epilepsy, migraine, autism, and related comorbidities. We include studies based on molecular and structural biology, cell biology and physiology, pharmacology, and mouse genetics. Our review reveals unexpected connections among these different types of sodium channelopathies.
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Donato, Luigi, Concetta Scimone, Simona Alibrandi, Ebtesam Mohamed Abdalla, Karim Mahmoud Nabil, Rosalia D’Angelo und Antonina Sidoti. „New Omics—Derived Perspectives on Retinal Dystrophies: Could Ion Channels-Encoding or Related Genes Act as Modifier of Pathological Phenotype?“ International Journal of Molecular Sciences 22, Nr. 1 (23.12.2020): 70. http://dx.doi.org/10.3390/ijms22010070.
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Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. Here, ion channels play a role in several physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to a wide spectrum of ocular diseases collectively called channelopathies, a subgroup of inherited retinal dystrophies. Such mutations result in either a loss or gain-of channel functions affecting the structure, assembly, trafficking and localization of channel proteins. We investigated the probands of seven Italian and Egyptian families affected by not completely defined forms of inherited retinal dystrophies, by whole exome sequencing (WES) experiments, and found interesting variants in already known causative genes probably able to impair retinal functionalities. However, because such variants did not completely explain the phenotype manifested by each patient, we proceed to further investigate possible related genes carrying mutations that might complement previously found data, based on the common aspect linked to neurotransmission impairments. We found 10 mutated genes whose variants might alter important ligand binding sites differently distributed through all considered patients. Such genes encode for ion channels, or their regulatory proteins, and strictly interact with known causative genes, also sharing with them synaptic-related pathways. Taking into account several limitations that will be resolved by further experiments, we believe that our exploratory investigation will help scientists to provide a new promising paradigm for precise diagnosis of retinal dystrophies to facilitate the development of rational treatments.
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Cagomoc, Charisse Marie D., Michiro Isobe, Eric A. Hudson und Satoshi Hamaguchi. „Molecular dynamics simulation of oxide-nitride bilayer etching with energetic fluorocarbon ions“. Journal of Vacuum Science & Technology A 40, Nr. 6 (Dezember 2022): 063006. http://dx.doi.org/10.1116/6.0002182.
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In 3D NAND devices, the number of stacked layers dictates the storage capacity. In the fabrication of such devices, hole channels with a high-aspect ratio (HAR) are etched through these layers. The higher the aspect ratio becomes, the more difficulties the HAR etching faces. In this study, molecular dynamics simulation was performed to examine the etching of silicon dioxide (SiO2), silicon nitride (SiN), and oxide-nitride (ON) stacked layers by energetic fluorocarbon ions. Good agreement of etching yields obtained from the simulations and ion beam experiments was observed for the etching of SiO2 and SiN by [Formula: see text] ions for the incident ion energy ranging from 200 to 2000 eV. As to the etching of the ON bilayer, the SiO2 and SiN layers were observed to be etched with their own etch rates at low ion incident energy. However, at sufficiently high incident ion energy, the oxide and nitride layers were mixed by energetic ion impact and the depth of the mixing layer exceeded the thickness of the top SiO2 layer thickness, resulting in a single etch rate limited by the etch rate of a much deeper underlying SiN material. This suggests that if the incident ion energy is high enough such that the thicknesses of the multilayers are lower than the ion penetration depth, the ON stacked layer exhibits a single etch rate determined by the mixed material of the oxide and nitride.
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HAMM-ALVAREZ, SARAH F., und MICHAEL P. SHEETZ. „Microtubule-Dependent Vesicle Transport: Modulation of Channel and Transporter Activity in Liver and Kidney“. Physiological Reviews 78, Nr. 4 (01.10.1998): 1109–29. http://dx.doi.org/10.1152/physrev.1998.78.4.1109.
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Hamm-Alvarez, Sarah F., and Michael P. Sheetz. Microtubule-Dependent Vesicle Transport: Modulation of Channel and Transporter Activity in Liver and Kidney. Physiol. Rev. 78: 1109–1129, 1998. — Microtubule-based vesicle transport driven by kinesin and cytoplasmic dynein motor proteins facilitates several membrane-trafficking steps including elements of endocytosis and exocytosis in many different cell types. Most early studies on the role of microtubule-dependent vesicle transport in membrane trafficking focused either on neurons or on simple cell lines. More recently, other work has considered the role of microtubule-based vesicle transport in other physiological systems, including kidney and liver. Investigation of the role of microtubule-based vesicle transport in membrane trafficking in cells of the kidney and liver suggests a major role for microtubule-based vesicle transport in the rapid and directed movement of ion channels and transporters to and from the apical plasma membranes, events essential for kidney and liver function and homeostasis. This review discusses the evidence supporting a role for microtubule-based vesicle transport and the motor proteins, kinesin and cytoplasmic dynein, in different aspects of membrane trafficking in cells of the kidney and liver, with emphasis on those functions such as maintenance of ion channel and transporter composition in apical membranes that are specialized functions of these organs. Evidence that defects in microtubule-based transport contribute to diseases of the kidney and liver is also discussed.
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Pałasz, A., und P. Czekaj. „Toxicological and cytophysiological aspects of lanthanides action.“ Acta Biochimica Polonica 47, Nr. 4 (31.12.2000): 1107–14. http://dx.doi.org/10.18388/abp.2000_3963.
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Lanthanides, also called rare-earth elements, are an interesting group of 15 chemically active, mainly trivalent, f-electronic, silvery-white metals. In fact, lanthanides are not as rare as the name implies, except for promethium, a radioactive artificial element not found in nature. The mean concentrations of lanthanides in the earth's crust are comparable to those of life-important elements like iodine, cobalt and selenium. Many lanthanide compounds show particular magnetic, catalytic and optic properties, and that is why their technical applications are so extensive. Numerous industrial sources enable lanthanides to penetrate into the human body and therefore detailed toxicological studies of these metals are necessary. In the liver, gadolinium selectively inhibits secretion by Kupffer cells and it decreases cytochrome P450 activity in hepatocytes, thereby protecting liver cells against toxic products of xenobiotic biotransformation. Praseodymium ion (Pr3+) produces the same protective effect in liver tissue cultures. Cytophysiological effects of lanthanides appear to result from the similarity of their cationic radii to the size of Ca2+ ions. Trivalent lanthanide ions, especially La3+ and Gd3+, block different calcium channels in human and animal cells. Lanthanides can affect numerous enzymes: Dy3+ and La3+ block Ca2+-ATPase and Mg2+-ATPase, while Eu3+ and Tb3+ inhibit calcineurin. In neurons, lanthanide ions regulate the transport and release of synaptic transmitters and block some membrane receptors, e.g. GABA and glutamate receptors. It is likely that lanthanides significantly and uniquely affect biochemical pathways, thus altering physiological processes in the tissues of humans and animals.
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Salmin, V. V., A. V. Morgun, R. Ya Olovyannikova, V. A. Kutyakov, E. V. Lychkovskaya, E. B. Brusina und A. B. Salmina. „Atmospheric reactive oxygen species and some aspects of the antiviral protection of the respiratory epithelium“. Biomeditsinskaya Khimiya 67, Nr. 5 (2021): 383–93. http://dx.doi.org/10.18097/pbmc20216705383.
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The review focuses on molecular and biochemical mechanisms of nonspecific protection of respiratory epithelium. The authors provide a comprehensive analysis of up-to-date data on the activity of the lactoperoxidase system expressed on the surface of the respiratory epithelium which provides the generation of hypothiocyanate and hypoiodite in the presence of locally produced or inhaled hydrogen peroxide. Molecular mechanisms of production of active compounds with antiviral and antibacterial effects, expression profiles of enzymes, transporters and ion channels involved in the generation of hypothiocyanite and hypoiodate in the mucous membrane of the respiratory system in physiological and pathological conditions (inflammation) are discussed. In the context of antibacterial and antiviral defense special attention is paid to recent data confirming the effects of atmospheric air composition on the efficiency of hypothiocyanite and hypoiodate synthesis in the respiratory epithelium. The causes and outcomes of lactoperoxidase system impairment due to the action of atmospheric factors are discussed in the context of controlling the sensitivity of the epithelium to the action of bacterial agents and viruses. Restoration of the lactoperoxidase system activity can be achieved by application of pharmacological agents aimed to compensate for the lack of halides in tissues, and by the control of chemical composition of the inhaled air.
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Chioccioli Altadonna, Ginevra, Alberto Montalbano, Jessica Iorio, Andrea Becchetti, Annarosa Arcangeli und Claudia Duranti. „The Interaction between hERG1 and β1 Integrins Modulates hERG1 Current in Different Pathological Cell Models“. Membranes 12, Nr. 11 (18.11.2022): 1162. http://dx.doi.org/10.3390/membranes12111162.
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Ion channels are implicated in various diseases, including cancer, in which they modulate different aspects of cancer progression. In particular, potassium channels are often aberrantly expressed in cancers, a major example being provided by hERG1. The latter is generally complexed with β1 integrin in tumour cells, and such a molecular complex represents a new druggable hub. The present study focuses on the characterization of the functional consequences of the interaction between hERG1 and β1 integrins on different substrates over time. To this purpose, we studied the interplay alteration on the plasma membrane through patch clamp techniques in a cellular model consisting of human embryonic kidney (HEK) cells stably transfected with hERG1 and in a cancer cell model consisting of SH-SY5Y neuroblastoma cells, endogenously expressing the channel. Cells were seeded on different substrates known to stimulate β1 integrins, such as fibronectin (FN) for HEK-hERG1 and laminin (LMN) for SH-SY5Y. In HEK cells stably overexpressing hERG1, we observed a hERG1 current density increase accompanied by Vrest hyperpolarization after cell seeding onto FN. Notably, a similar behaviour was shown by SH-SY5Y neuroblastoma cells plated onto LMN. Interestingly, we did not observe this phenomenon when plating the cells on substrates such as Bovine Serum Albumin (BSA) or Polylysine (PL), thus suggesting a crucial involvement of ECM proteins as well as of β1 integrin activation.
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Fiorio Pla, Alessandra, und Dimitra Gkika. „Ca2+ Channel Toolkit in Neuroendocrine Tumors“. Neuroendocrinology 110, Nr. 1-2 (10.06.2019): 147–54. http://dx.doi.org/10.1159/000501397.
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Neuroendocrine tumors (NET) constitute a heterogeneous group of malignancies with various clinical presentations and growth rates but a common origin in neuroendocrine cells located all over the body. NET are a relatively low-frequency disease mostly represented by gastroenteropancreatic (GEP) and bronchopulmonary tumors (pNET); on the other hand, an increasing frequency and prevalence have been associated with NET. Despite great efforts in recent years, the management of NET is still a critical unmet need due to the lack of knowledge of the biology of the disease, the lack of adequate biomarkers, late presentation, the relative insensitivity of imaging modalities, and a paucity of predictably effective treatment options. In this context Ca2+ signals, being pivotal molecular devices in sensing and integrating signals from the microenvironment, are emerging to be particularly relevant in cancer, where they mediate interactions between tumor cells and the tumor microenvironment to drive different aspects of neoplastic progression (e.g., cell proliferation and survival, cell invasiveness, and proangiogenetic programs). Indeed, ion channels represent good potential pharmacological targets due to their location on the plasma membrane, where they can be easily accessed by drugs. The present review aims to provide a critical and up-to-date overview of NET development integrating Ca2+ signal involvement. In this perspective, we first give an introduction to NET and Ca2+ channels and then describe the different families of Ca2+ channels implicated in NET, i.e., ionotropic receptors, voltage-dependent Ca2+ channels, and transient receptor potential channels, as well as intracellular Ca2+ channels and their signaling molecules.
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Szuts, Viktoria, Dalma Ménesi, Zoltán Varga-Orvos, Ágnes Zvara, Nazanin Houshmand, Miklós Bitay, Gábor Bogáts et al. „Altered expression of genes for Kir ion channels in dilated cardiomyopathy“. Canadian Journal of Physiology and Pharmacology 91, Nr. 8 (August 2013): 648–56. http://dx.doi.org/10.1139/cjpp-2012-0413.
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Dilated cardiomyopathy (DCM) is a multifactorial disease characterized by left ventricular dilation that is associated with systolic dysfunction and increased action potential duration. The Kir2.x K+ channels (encoded by KCNJ genes) regulate the inward rectifier current (IK1) contributing to the final repolarization in cardiac muscle. Here, we describe the transitions in the gene expression profiles of 4 KCNJ genes from healthy or dilated cardiomyopathic human hearts. In the healthy adult ventricles, KCNJ2, KCNJ12, and KCNJ4 (Kir2.1–2.3, respectively) genes were expressed at high levels, while expression of the KCNJ14 (Kir2.4) gene was low. In DCM ventricles, the levels of Kir2.1 and Kir2.3 were upregulated, but those of Kir2.2 channels were downregulated. Additionally, the expression of the DLG1 gene coding for the synapse-associated protein 97 (SAP97) anchoring molecule exhibited a 2-fold decline with increasing age in normal hearts, and it was robustly downregulated in young DCM patients. These adaptations could offer a new aspect for the explanation of the generally observed physiological and molecular alterations found in DCM.
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Roy, Sisir, und Rodolfo Llinás. „Relevance of quantum mechanics on some aspects of ion channel function“. Comptes Rendus Biologies 332, Nr. 6 (Juni 2009): 517–22. http://dx.doi.org/10.1016/j.crvi.2008.11.009.
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Nishida, Hirofumi, Toshiaki Sato, Takehiko Ogura und Haruaki Nakaya. „New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Mitochondrial Ion Channels and Cardioprotection“. Journal of Pharmacological Sciences 109, Nr. 3 (2009): 341–47. http://dx.doi.org/10.1254/jphs.08r24fm.
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Fedosov, A. E., S. A. Moshkovskii, K. G. Kuznetsova und B. M. Olivera. „Conotoxins: from the biodiversity of gastropods to new drugs“. Biomeditsinskaya Khimiya 59, Nr. 3 (2013): 267–94. http://dx.doi.org/10.18097/pbmc20135903267.
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A review describes general trends in research of conotoxins that are peptide toxins isolated from sea gastropods of the Conus genus, since the toxins were discovered in 1970 . There are disclosed a conotoxin classification, their structure diversity and different ways of action to their molecular targets, mainly, ion channels. In the applied aspect of conotoxin research, drug discovery and development is discussed, the drugs being based on conotoxin structure. A first exemplary drug is a ziconotide, which is an analgesic of new generation.
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Jegorov, Alexandr, Béla Paizs, Martin Žabka, Marek Kuzma, Vladimír Havlíček, Anastassios E. Giannakopulos und Peter J. Derrick. „Profiling of Cyclic Hexadepsipeptides Roseotoxins Synthesized In Vitro and In Vivo: A Combined Tandem Mass Spectrometry and Quantum Chemical Study“. European Journal of Mass Spectrometry 9, Nr. 2 (April 2003): 105–16. http://dx.doi.org/10.1255/ejms.531.
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High-performance liquid chromatography and tandem mass spectrometry (HPLC/MS/MS) was used for the detection of cyclic hexadepsipeptides roseotoxins produced by Trichothecium roseum. Roseotoxins were found in both submerged standard cultivation on Czapek–Dox medium and in vivo cultivation extract obtained from an apple. Roseotoxin chromatographic profiles from these two experiments were compared. Product-ion collision-induced dissociation (CID) spectra obtained on an ion trap (electrospray ionisation, ESI) were used for the identification of natural roseotoxins A, B, C and of minor destruxins A and B. The dissociation behavior of roseotoxins is discussed in terms of a fragmentation scheme proposed for describing the dissociation pathways of cyclic peptides. This scheme involves opening of the cyclopeptide ring via formation of oxazolone derivatives and fragmentation of the resulting linear species, which have a free N-terminus and an oxazolone ring at the C-terminus. Some aspects of this fragmentation scheme are underlined by modeling the dissociation channels of roseotoxin A using quantum chemical calculations. The structures of roseotoxin A and destruxin B were verified by nuclear magnetic resonance (NMR) spectroscopy. Structures of three new minor natural roseotoxins [Val4]RosA, [MeLxx4]RosA and [MeLxx4]RosB were deduced by ion cyclotron resonance Fourier transform mass spectrometry (ICR-FT-MS) and ion trap tandem mass spectrometry by examining the pre-separated roseotoxin fraction.
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Mangold, Kathryn E., Wei Wang, Eric K. Johnson, Druv Bhagavan, Jonathan D. Moreno, Jeanne M. Nerbonne und Jonathan R. Silva. „Identification of structures for ion channel kinetic models“. PLOS Computational Biology 17, Nr. 8 (16.08.2021): e1008932. http://dx.doi.org/10.1371/journal.pcbi.1008932.
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Markov models of ion channel dynamics have evolved as experimental advances have improved our understanding of channel function. Past studies have examined limited sets of various topologies for Markov models of channel dynamics. We present a systematic method for identification of all possible Markov model topologies using experimental data for two types of native voltage-gated ion channel currents: mouse atrial sodium currents and human left ventricular fast transient outward potassium currents. Successful models identified with this approach have certain characteristics in common, suggesting that aspects of the model topology are determined by the experimental data. Incorporating these channel models into cell and tissue simulations to assess model performance within protocols that were not used for training provided validation and further narrowing of the number of acceptable models. The success of this approach suggests a channel model creation pipeline may be feasible where the structure of the model is not specified a priori.
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Veetil, Aneesh T., Maulik S. Jani und Yamuna Krishnan. „Chemical control over membrane-initiated steroid signaling with a DNA nanocapsule“. Proceedings of the National Academy of Sciences 115, Nr. 38 (12.03.2018): 9432–37. http://dx.doi.org/10.1073/pnas.1712792115.
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Membrane-initiated steroid signaling (MISS) is a recently discovered aspect of steroidal control over cell function that has proved highly challenging to study due to its rapidity and ultrasensitivity to the steroid trigger [Chow RWY, Handelsman DJ, Ng MKC (2010) Endocrinology 151:2411–2422]. Fundamental aspects underlying MISS, such as receptor binding, kinetics of ion-channel opening, and production of downstream effector molecules remain obscure because a pristine molecular technology that could trigger the release of signaling steroids was not available. We have recently described a prototype DNA nanocapsule which can be programmed to release small molecules upon photoirradiation [Veetil AT, et al. (2017) Nat Nanotechnol 12:1183–1189]. Here we show that this DNA-based molecular technology can now be programmed to chemically trigger MISS, significantly expanding its applicability to systems that are refractory to photoirradiation.
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Ranchoux, Benoît, Lloyd D. Harvey, Ramon J. Ayon, Aleksandra Babicheva, Sebastien Bonnet, Stephen Y. Chan, Jason X. J. Yuan und Vinicio de Jesus Perez. „Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover Conference Series)“. Pulmonary Circulation 8, Nr. 1 (28.12.2017): 204589321775291. http://dx.doi.org/10.1177/2045893217752912.
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Endothelial dysfunction is a major player in the development and progression of vascular pathology in pulmonary arterial hypertension (PAH), a disease associated with small vessel loss and obstructive vasculopathy that leads to increased pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past ten years, there has been tremendous progress in our understanding of pulmonary endothelial biology as it pertains to the genetic and molecular mechanisms that orchestrate the endothelial response to direct or indirect injury, and how their dysregulation can contribute to the pathogenesis of PAH. As one of the major topics included in the 2017 Grover Conference Series, discussion centered on recent developments in four areas of pulmonary endothelial biology: (1) angiogenesis; (2) endothelial-mesenchymal transition (EndMT); (3) epigenetics; and (4) biology of voltage-gated ion channels. The present review will summarize the content of these discussions and provide a perspective on the most promising aspects of endothelial dysfunction that may be amenable for therapeutic development.