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International Journal of Molecular... Feb 2020Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca signaling from... (Review)
Review
Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca signaling from the extracellular medium depends both on membrane potential, especially controlled by ion channels selective to K, and direct permeation of this cation through specialized channels. Calmodulin (CaM), through direct binding to these proteins, participates in setting the membrane potential and the overall permeability to Ca. Over the past years many structures of complete channels in complex with CaM at near atomic resolution have been resolved. In combination with mutagenesis-function, structural information of individual domains and functional studies, different mechanisms employed by CaM to control channel gating are starting to be understood at atomic detail. Here, new insights regarding four types of tetrameric channels with six transmembrane (6TM) architecture, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1-5, and its regulation by CaM are described structurally. Different CaM regions, N-lobe, C-lobe and EF3/EF4-linker play prominent signaling roles in different complexes, emerging the realization of crucial non-canonical interactions between CaM and its target that are only evidenced in the full-channel structure. Different mechanisms to control gating are used, including direct and indirect mechanical actuation over the pore, allosteric control, indirect effect through lipid binding, as well as direct plugging of the pore. Although each CaM lobe engages through apparently similar alpha-helices, they do so using different docking strategies. We discuss how this allows selective action of drugs with great therapeutic potential.
Topics: Allosteric Regulation; Calcium Signaling; Calmodulin; Humans; Ion Channels; Potassium Channels; Protein Domains; Transient Receptor Potential Channels
PubMed: 32075037
DOI: 10.3390/ijms21041285 -
Nature Reviews. Neuroscience Sep 2019Light-controllable tools provide powerful means to manipulate and interrogate brain function with relatively low invasiveness and high spatiotemporal precision. Although... (Review)
Review
Light-controllable tools provide powerful means to manipulate and interrogate brain function with relatively low invasiveness and high spatiotemporal precision. Although optogenetic approaches permit neuronal excitation or inhibition at the network level, other technologies, such as optopharmacology (also known as photopharmacology) have emerged that provide molecular-level control by endowing light sensitivity to endogenous biomolecules. In this Review, we discuss the challenges and opportunities of photocontrolling native neuronal signalling pathways, focusing on ion channels and neurotransmitter receptors. We describe existing strategies for rendering receptors and channels light sensitive and provide an overview of the neuroscientific insights gained from such approaches. At the crossroads of chemistry, protein engineering and neuroscience, optopharmacology offers great potential for understanding the molecular basis of brain function and behaviour, with promises for future therapeutics.
Topics: Animals; Humans; Ion Channel Gating; Ion Channels; Membrane Transport Modulators; Neurons; Optogenetics; Photochemical Processes; Receptors, G-Protein-Coupled
PubMed: 31289380
DOI: 10.1038/s41583-019-0197-2 -
The Journal of General Physiology Jul 2014Ion channels are membrane-bound enzymes whose catalytic sites are ion-conducting pores that open and close (gate) in response to specific environmental stimuli. Ion... (Review)
Review
Ion channels are membrane-bound enzymes whose catalytic sites are ion-conducting pores that open and close (gate) in response to specific environmental stimuli. Ion channels are important contributors to cell signaling and homeostasis. Our current understanding of gating is the product of 60 plus years of voltage-clamp recording augmented by intervention in the form of environmental, chemical, and mutational perturbations. The need for good phenomenological models of gating has evolved in parallel with the sophistication of experimental technique. The goal of modeling is to develop realistic schemes that not only describe data, but also accurately reflect mechanisms of action. This review covers three areas that have contributed to the understanding of ion channels: traditional Eyring kinetic theory, molecular dynamics analysis, and statistical thermodynamics. Although the primary emphasis is on voltage-dependent channels, the methods discussed here are easily generalized to other stimuli and could be applied to any ion channel and indeed any macromolecule.
Topics: Animals; Forecasting; Humans; Ion Channel Gating; Ion Channels; Models, Biological
PubMed: 24935742
DOI: 10.1085/jgp.201311130 -
American Journal of Physiology. Cell... May 2021Ion channels in plasma membrane play a principal role in different physiological processes, including cell volume regulation, signal transduction, and modulation of... (Review)
Review
Ion channels in plasma membrane play a principal role in different physiological processes, including cell volume regulation, signal transduction, and modulation of membrane potential in living cells. Actin-based cytoskeleton, which exists in a dynamic balance between monomeric and polymeric forms (globular and fibrillar actin), can be directly or indirectly involved in various cellular responses including modulation of ion channel activity. In this mini-review, we present an overview of the role of submembranous actin dynamics in the regulation of ion channels in excitable and nonexcitable cells. Special attention is focused on the important data about the involvement of actin assembly/disassembly and some actin-binding proteins in the control of the epithelial Na channel (ENaC) and mechanosensitive Piezo channels whose integral activity has a potential impact on membrane transport and multiple coupled cellular reactions. Growing evidence suggests that actin elements of the cytoskeleton can represent a "converging point" of various signaling pathways modulating the activity of ion transport proteins in cell membranes.
Topics: Actin Cytoskeleton; Actins; Animals; Cell Membrane; Epithelial Sodium Channels; Humans; Ion Channel Gating; Ion Channels; Mechanotransduction, Cellular; Protein Conformation; Structure-Activity Relationship
PubMed: 33471624
DOI: 10.1152/ajpcell.00368.2020 -
Molecular BioSystems Mar 2012In the past decade among the main developments in the field of bionanotechnology is the application of proteins in devices. Research focuses on the modification of... (Review)
Review
In the past decade among the main developments in the field of bionanotechnology is the application of proteins in devices. Research focuses on the modification of enzyme systems by means of chemical and physical tools in order to achieve full control of their function and to employ them for specific tasks. Membrane protein channels are intriguing biological devices as they allow the recognition and passage of a variety of macromolecules through an otherwise impermeable lipid bilayer. Hence, membrane proteins can be used as sensory devices for detection or as molecular nanovalves to allow for the controlled release of molecules. Here, we discuss the structure and function of three different channel proteins that mediate the membrane passage of macromolecules using different mechanisms. These systems are described in a comparative manner and an overview is provided of the technological advances in employing these proteins in external (or human) controllable devices.
Topics: Humans; Ion Channels; Membrane Proteins; Models, Biological; Protein Conformation
PubMed: 22258412
DOI: 10.1039/c2mb05433g -
Neuroscience Bulletin Aug 2012Ion channels, as membrane proteins, are the sensors of the cell. They act as the first line of communication with the world beyond the plasma membrane and transduce... (Review)
Review
Ion channels, as membrane proteins, are the sensors of the cell. They act as the first line of communication with the world beyond the plasma membrane and transduce changes in the external and internal environments into unique electrical signals to shape the responses of excitable cells. Because of their importance in cellular communication, ion channels have been intensively studied at the structural and functional levels. Here, we summarize the diverse approaches, including molecular and cellular, chemical, optical, biophysical, and computational, used to probe the structural and functional rearrangements that occur during channel activation (or sensitization), inactivation (or desensitization), and various forms of modulation. The emerging insights into the structure and function of ion channels by multidisciplinary approaches allow the development of new pharmacotherapies as well as new tools useful in controlling cellular activity.
Topics: Animals; Biophysical Phenomena; Cell Membrane; Electrophysiology; Humans; Ion Channels; Membrane Proteins
PubMed: 22833035
DOI: 10.1007/s12264-012-1248-0 -
Circulation Research Jun 2015The movement of ions across specific channels embedded on the membrane of individual cardiomyocytes is crucial for the generation and propagation of the cardiac electric... (Review)
Review
The movement of ions across specific channels embedded on the membrane of individual cardiomyocytes is crucial for the generation and propagation of the cardiac electric impulse. Emerging evidence over the past 20 years strongly suggests that the normal electric function of the heart is the result of dynamic interactions of membrane ion channels working in an orchestrated fashion as part of complex molecular networks. Such networks work together with exquisite temporal precision to generate each action potential and contraction. Macromolecular complexes play crucial roles in transcription, translation, oligomerization, trafficking, membrane retention, glycosylation, post-translational modification, turnover, function, and degradation of all cardiac ion channels known to date. In addition, the accurate timing of each cardiac beat and contraction demands, a comparable precision on the assembly and organizations of sodium, calcium, and potassium channel complexes within specific subcellular microdomains, where physical proximity allows for prompt and efficient interaction. This review article, part of the Compendium on Sudden Cardiac Death, discusses the major issues related to the role of ion channel macromolecular assemblies in normal cardiac electric function and the mechanisms of arrhythmias leading to sudden cardiac death. It provides an idea of how these issues are being addressed in the laboratory and in the clinic, which important questions remain unanswered, and what future research will be needed to improve knowledge and advance therapy.
Topics: Animals; Arrhythmias, Cardiac; Calcium Channels, L-Type; Cell Compartmentation; Channelopathies; Death, Sudden, Cardiac; Disease Models, Animal; Heart Conduction System; Humans; Ion Channel Gating; Ion Channels; KATP Channels; Macromolecular Substances; Membrane Proteins; Mice; NAV1.5 Voltage-Gated Sodium Channel; Potassium Channels, Inwardly Rectifying; Protein Interaction Mapping; Protein Subunits
PubMed: 26044251
DOI: 10.1161/CIRCRESAHA.116.305017 -
Neurotherapeutics : the Journal of the... Jan 2007This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of... (Review)
Review
This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the alpha subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, alpha2-delta voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na+ channels and GABA(A) receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca2+ channel subunits and auxiliary proteins, A- or M-type voltage-gated K+ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA(B) and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current Ih; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na+ channels underlying persistent Na+ currents or GABA(A) receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.
Topics: Animals; Anticonvulsants; Brain; Drug Design; Epilepsy; Humans; Ion Channels; Neurotransmitter Transport Proteins
PubMed: 17199015
DOI: 10.1016/j.nurt.2006.11.010 -
Annual Review of Physiology 2009Distinct potassium, anion, and calcium channels in the plasma membrane and vacuolar membrane of plant cells have been identified and characterized by patch clamping.... (Review)
Review
Distinct potassium, anion, and calcium channels in the plasma membrane and vacuolar membrane of plant cells have been identified and characterized by patch clamping. Primarily owing to advances in Arabidopsis genetics and genomics, and yeast functional complementation, many of the corresponding genes have been identified. Recent advances in our understanding of ion channel genes that mediate signal transduction and ion transport are discussed here. Some plant ion channels, for example, ALMT and SLAC anion channel subunits, are unique. The majority of plant ion channel families exhibit homology to animal genes; such families include both hyperpolarization- and depolarization-activated Shaker-type potassium channels, CLC chloride transporters/channels, cyclic nucleotide-gated channels, and ionotropic glutamate receptor homologs. These plant ion channels offer unique opportunities to analyze the structural mechanisms and functions of ion channels. Here we review gene families of selected plant ion channel classes and discuss unique structure-function aspects and their physiological roles in plant cell signaling and transport.
Topics: Arabidopsis; Calcium Channels; Genomics; Ion Channel Gating; Ion Channels; Plant Proteins; Potassium Channels
PubMed: 18842100
DOI: 10.1146/annurev.physiol.010908.163204 -
FASEB Journal : Official Publication of... Dec 2014The bacterial mechanosensitive channel of large conductance (MscL) serves as a biological emergency release valve, preventing the occurrence of cell lysis caused by...
The bacterial mechanosensitive channel of large conductance (MscL) serves as a biological emergency release valve, preventing the occurrence of cell lysis caused by acute osmotic stress. Its tractable nature allows it to serve as a paradigm for how a protein can directly sense membrane tension. Although much is known of the importance of the hydrophobicity of specific residues in channel gating, it has remained unclear whether electrostatics at the membrane plays any role. We studied MscL chimeras derived from functionally distinct orthologues: Escherichia coli and Staphylococcus aureus. Dissection of one set led to an observation that changing the charge of a single residue, K101, of E. coli (Ec)-MscL, effects a channel phenotype: when mutated to a negative residue, the channel is less mechanosensitive and has longer open dwell times. Assuming electrostatic interactions, we determined whether they are due to protein-protein or protein-lipid interactions by performing site-directed mutagenesis elsewhere in the protein and reconstituting channels into defined lipids, with and without negative head groups. We found that although both interactions appear to play some role, the primary determinant of the channel phenotype seems to be protein-lipid electrostatics. The data suggest a model for the role of electrostatic interactions in the dynamics of MscL gating.
Topics: Amino Acid Sequence; Cell Membrane; Escherichia coli Proteins; Ion Channel Gating; Ion Channels; Kinetics; Molecular Sequence Data; Mutagenesis, Site-Directed; Sequence Homology, Amino Acid; Static Electricity
PubMed: 25223610
DOI: 10.1096/fj.14-259309