Synthesis and functional studies of THF–gramicidin hybrid ion channels

2003 ◽  
Vol 1 (16) ◽  
pp. 2983-2997 ◽  
Author(s):  
Andrea Vescovi ◽  
Andrea Knoll ◽  
Ulrich Koert
Keyword(s):  
Ion Channels ◽  
Functional Studies

scholarly journals Computational Methods for Structural and Functional Studies of Alzheimer’s Amyloid Ion Channels

2016 ◽  
pp. 251-268 ◽  
Author(s):  
Hyunbum Jang ◽  
Fernando Teran Arce ◽  
Joon Lee ◽  
Alan L. Gillman ◽  
Srinivasan Ramachandran ◽  
...  
Keyword(s):  
Ion Channels ◽  
Computational Methods ◽  
Functional Studies

scholarly journals Atomistic Insights of Calmodulin Gating of Complete Ion Channels

2020 ◽  
Vol 21 (4) ◽  
pp. 1285 ◽  
Author(s):  
Eider Núñez ◽  
Arantza Muguruza-Montero ◽  
Alvaro Villarroel
Keyword(s):  
Membrane Potential ◽  
Ion Channels ◽  
Therapeutic Potential ◽  
Structural Information ◽  
Lipid Binding ◽  
Channel Structure ◽  
Extracellular Medium ◽  
Alpha Helices ◽  
Functional Studies ◽  
Direct Binding

Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca2+ 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 Ca2+. 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.

CLC-0 and CFTR: Chloride Channels Evolved From Transporters

2008 ◽  
Vol 88 (2) ◽  
pp. 351-387 ◽  
Author(s):  
Tsung-Yu Chen ◽  
Tzyh-Chang Hwang
Keyword(s):  
Ion Channels ◽  
Membrane Transport ◽  
Chloride Channels ◽  
Transport Proteins ◽  
Transmembrane Conductance Regulator ◽  
Protein Families ◽  
Transmembrane Conductance ◽  
Functional Studies ◽  
Membrane Transport Proteins ◽  
Cystic Fibrosis Transmembrane

CLC-0 and cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channels play important roles in Cl− transport across cell membranes. These two proteins belong to, respectively, the CLC and ABC transport protein families whose members encompass both ion channels and transporters. Defective function of members in these two protein families causes various hereditary human diseases. Ion channels and transporters were traditionally viewed as distinct entities in membrane transport physiology, but recent discoveries have blurred the line between these two classes of membrane transport proteins. CLC-0 and CFTR can be considered operationally as ligand-gated channels, though binding of the activating ligands appears to be coupled to an irreversible gating cycle driven by an input of free energy. High-resolution crystallographic structures of bacterial CLC proteins and ABC transporters have led us to a better understanding of the gating properties for CLC and CFTR Cl− channels. Furthermore, the joined force between structural and functional studies of these two protein families has offered a unique opportunity to peek into the evolutionary link between ion channels and transporters. A promising byproduct of this exercise is a deeper mechanistic insight into how different transport proteins work at a fundamental level.

scholarly journals Chemical activation of the mechanotransduction channel Piezo1

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ruhma Syeda ◽  
Jie Xu ◽  
Adrienne E Dubin ◽  
Bertrand Coste ◽  
Jayanti Mathur ◽  
...  
Keyword(s):  
Ion Channels ◽  
Lipid Bilayers ◽  
Chemical Activation ◽  
Pressure Sensors ◽  
Inactivation Kinetics ◽  
Mechanical Stimuli ◽  
Functional Studies ◽  
A Cell ◽  
And Function ◽  
Cellular Components

Piezo ion channels are activated by various types of mechanical stimuli and function as biological pressure sensors in both vertebrates and invertebrates. To date, mechanical stimuli are the only means to activate Piezo ion channels and whether other modes of activation exist is not known. In this study, we screened ∼3.25 million compounds using a cell-based fluorescence assay and identified a synthetic small molecule we termed Yoda1 that acts as an agonist for both human and mouse Piezo1. Functional studies in cells revealed that Yoda1 affects the sensitivity and the inactivation kinetics of mechanically induced responses. Characterization of Yoda1 in artificial droplet lipid bilayers showed that Yoda1 activates purified Piezo1 channels in the absence of other cellular components. Our studies demonstrate that Piezo1 is amenable to chemical activation and raise the possibility that endogenous Piezo1 agonists might exist. Yoda1 will serve as a key tool compound to study Piezo1 regulation and function.

Functional Studies of Synthetic Gramicidin Hybrid Ion Channels in CHO Cells

ChemBioChem ◽  
2007 ◽  
Vol 8 (5) ◽  
pp. 513-520 ◽  
Author(s):  
Ryszard Wesolowski ◽  
Anna Sommer ◽  
Hans-Dieter Arndt ◽  
Ulrich Koert ◽  
Philipp Reiß ◽  
...  
Keyword(s):  
Ion Channels ◽  
Cho Cells ◽  
Functional Studies

scholarly journals Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Maria Koromina ◽  
Miles Flitton ◽  
Alix Blockley ◽  
Ian R. Mellor ◽  
Helen M. Knight
Keyword(s):  
Intellectual Disability ◽  
Ion Channels ◽  
Autism Spectrum ◽  
Decay Rates ◽  
Kainate Receptors ◽  
Sequencing Data ◽  
Missense Variants ◽  
Functional Studies ◽  
Neurodevelopmental Disease ◽  
Functional Variants

AbstractSchizophrenia (Scz), autism spectrum disorder (ASD) and intellectual disability are common complex neurodevelopmental disorders. Kainate receptors (KARs) are ionotropic glutamate ion channels involved in synaptic plasticity which are modulated by auxiliary NETO proteins. Using UK10K exome sequencing data, we interrogated the coding regions of KAR and NETO genes in individuals with Scz, ASD or intellectual disability and population controls; performed follow-up genetic replication studies; and, conducted in silico and in vitro functional studies. We found an excess of Loss-of-Function and missense variants in individuals with Scz compared with control individuals (p = 1.8 × 10−10), and identified a significant burden of functional variants for Scz (p < 1.6 × 10−11) and ASD (p = 6.9 × 10−18). Single allele associations for 6 damaging missense variants were significantly replicated (p < 5.0 × 10−15) and confirmed GRIK3 S310A as a protective genetic factor. Functional studies demonstrated that three missense variants located within GluK2 and GluK4, GluK2 (K525E) and GluK4 (Y555N, L825W), affect agonist sensitivity and current decay rates. These findings establish that genetic variation in KAR receptor ion channels confers risk for schizophrenia, autism and intellectual disability and provide new genetic and pharmacogenetic biomarkers for neurodevelopmental disease.

scholarly journals Peptide models for membrane channels

1996 ◽  
Vol 315 (2) ◽  
pp. 345-361 ◽  
Author(s):  
Derek MARSH
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Lipid Bilayer Membranes ◽  
Transmembrane Peptides ◽  
Functional Studies ◽  
Critical Issues ◽  
Peptide Models ◽  
Ion Channel Proteins ◽  
Voltage Gated Ion Channels ◽  
Pore Lining

Peptides may be synthesized with sequences corresponding to putative transmembrane domains and/or pore-lining regions that are deduced from the primary structures of ion channel proteins. These can then be incorporated into lipid bilayer membranes for structural and functional studies. In addition to the ability to invoke ion channel activity, critical issues are the secondary structures adopted and the mode of assembly of these short transmembrane peptides in the reconstituted systems. The present review concentrates on results obtained with peptides from ligand-gated and voltage-gated ion channels, as well as proton-conducting channels. These are considered within the context of current molecular models and the limited data available on the structure of native ion channels and natural channel-forming peptides.

scholarly journals Asymmetric mechanosensitivity in a eukaryotic ion channel

2017 ◽  
Vol 114 (40) ◽  
pp. E8343-E8351 ◽  
Author(s):  
Michael V. Clausen ◽  
Viwan Jarerattanachat ◽  
Elisabeth P. Carpenter ◽  
Mark S. P. Sansom ◽  
Stephen J. Tucker
Keyword(s):  
Ion Channels ◽  
Molecular Mechanisms ◽  
Asymmetric Structure ◽  
Single Channels ◽  
Mechanical Stimuli ◽  
Diverse Range ◽  
Mechanosensitive Ion Channels ◽  
Functional Studies ◽  
Living Organisms ◽  
Pore Domain

Living organisms perceive and respond to a diverse range of mechanical stimuli. A variety of mechanosensitive ion channels have evolved to facilitate these responses, but the molecular mechanisms underlying their exquisite sensitivity to different forces within the membrane remains unclear. TREK-2 is a mammalian two-pore domain (K2P) K+ channel important for mechanosensation, and recent studies have shown how increased membrane tension favors a more expanded conformation of the channel within the membrane. These channels respond to a complex range of mechanical stimuli, however, and it is uncertain how differences in tension between the inner and outer leaflets of the membrane contribute to this process. To examine this, we have combined computational approaches with functional studies of oppositely oriented single channels within the same lipid bilayer. Our results reveal how the asymmetric structure of TREK-2 allows it to distinguish a broad profile of forces within the membrane, and illustrate the mechanisms that eukaryotic mechanosensitive ion channels may use to detect and fine-tune their responses to different mechanical stimuli.

scholarly journals Peimine, an Anti-Inflammatory Compound from Chinese Herbal Extracts, Modulates Muscle-Type Nicotinic Receptors

2021 ◽  
Vol 22 (20) ◽  
pp. 11287
Author(s):  
Armando Alberola-Die ◽  
José Antonio Encinar ◽  
Raúl Cobo ◽  
Gregorio Fernández-Ballester ◽  
José Manuel González-Ros ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ion Channels ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Transmembrane Domain ◽  
Muscle Type ◽  
Functional Studies ◽  
Voltage Dependent ◽  
Neuronal Tissues ◽  
Anti Inflammatory

Fritillaria bulbs are used in Traditional Chinese Medicine to treat several illnesses. Peimine (Pm), an anti-inflammatory compound from Fritillaria, is known to inhibit some voltage-dependent ion channels and muscarinic receptors, but its interaction with ligand-gated ion channels remains unexplored. We have studied if Pm affects nicotinic acetylcholine receptors (nAChRs), since they play broad functional roles, both in the nervous system and non-neuronal tissues. Muscle-type nAChRs were incorporated to Xenopus oocytes and the action of Pm on the membrane currents elicited by ACh (IAChs) was assessed. Functional studies were combined with virtual docking and molecular dynamics assays. Co-application of ACh and Pm reversibly blocked IACh, with an IC50 in the low micromolar range. Pm inhibited nAChR by: (i) open-channel blockade, evidenced by the voltage-dependent inhibition of IAch, (ii) enhancement of nAChR desensitization, revealed by both an accelerated IACh decay and a decelerated IACh deactivation, and (iii) resting-nAChR blockade, deduced from the IACh inhibition elicited by Pm when applied before ACh superfusion. In good concordance, virtual docking and molecular dynamics assays demonstrated that Pm binds to different sites at the nAChR, mostly at the transmembrane domain. Thus, Pm from Fritillaria bulbs, considered therapeutic herbs, targets nAChRs with high affinity, which might account for its anti-inflammatory actions.

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