Voltage-Gated Sodium Channels

Oakes, Victoria; Furini, Simone; Domene, Carmen

doi:10.1016/bs.ctm.2015.12.002

Cited by 7 publications

(2 citation statements)

References 104 publications

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“…Recent structural analysis, simulation/modeling, and experimental studies of both eukaryotic and prokaryotic Nav channels provide a rich background for interpretation of our data (see [9]), and for guided speculation about underlying molecular bases of our observations. Molecular simulations have been reviewed in a variety of functional and evolutionary issues [33,34,35,36,37,38]. Other discussions deal with modulation, and potential roles of tissue- or organ-specific Nav channel gating [39,40,41,42,43,44].…”

Section: Discussionmentioning

confidence: 99%

Extremely Potent Block of Bacterial Voltage-Gated Sodium Channels by µ-Conotoxin PIIIA

et al. 2019

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µ-Conotoxin PIIIA, in the sub-picomolar, range inhibits the archetypal bacterial sodium channel NaChBac (NavBh) in a voltage- and use-dependent manner. Peptide µ-conotoxins were first recognized as potent components of the venoms of fish-hunting cone snails that selectively inhibit voltage-gated skeletal muscle sodium channels, thus preventing muscle contraction. Intriguingly, computer simulations predicted that PIIIA binds to prokaryotic channel NavAb with much higher affinity than to fish (and other vertebrates) skeletal muscle sodium channel (Nav 1.4). Here, using whole-cell voltage clamp, we demonstrate that PIIIA inhibits NavBac mediated currents even more potently than predicted. From concentration-response data, with [PIIIA] varying more than 6 orders of magnitude (10−12 to 10−5 M), we estimated an IC50 = ~5 pM, maximal block of 0.95 and a Hill coefficient of 0.81 for the inhibition of peak currents. Inhibition was stronger at depolarized holding potentials and was modulated by the frequency and duration of the stimulation pulses. An important feature of the PIIIA action was acceleration of macroscopic inactivation. Docking of PIIIA in a NaChBac (NavBh) model revealed two interconvertible binding modes. In one mode, PIIIA sterically and electrostatically blocks the permeation pathway. In a second mode, apparent stabilization of the inactivated state was achieved by PIIIA binding between P2 helices and trans-membrane S5s from adjacent channel subunits, partially occluding the outer pore. Together, our experimental and computational results suggest that, besides blocking the channel-mediated currents by directly occluding the conducting pathway, PIIIA may also change the relative populations of conducting (activated) and non-conducting (inactivated) states.

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Section: Discussionmentioning

confidence: 99%

Extremely Potent Block of Bacterial Voltage-Gated Sodium Channels by µ-Conotoxin PIIIA

et al. 2019

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“…The structural organization of the K + channel pore was uncovered using crystallography 4 , 5 , while detailed understanding of permeation mechanism was greatly facilitated by numerous molecular dynamics (MD) and quantum mechanics (QM) studies 2 , 6 – 18 . Selectivity of specialized sodium channels to sodium was explored using the bacterial Na + channel Na V Ab as a template 2 , 19 – 24 . Recent improved understanding of the mechanisms of monovalent ion permeation has been progressing in parallel with rapid advances in computational structural biology.…”

Section: Introductionmentioning

confidence: 99%

Ion Permeation Mechanism in Epithelial Calcium Channel TRVP6

Sakipov

Sobolevsky

Kurnikova

2018

Sci Rep

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Calcium is the most abundant metal in the human body that plays vital roles as a cellular electrolyte as well as the smallest and most frequently used signaling molecule. Calcium uptake in epithelial tissues is mediated by tetrameric calcium-selective transient receptor potential (TRP) channels TRPV6 that are implicated in a variety of human diseases, including numerous forms of cancer. We used TRPV6 crystal structures as templates for molecular dynamics simulations to identify ion binding sites and to study the permeation mechanism of calcium and other ions through TRPV6 channels. We found that at low Ca2+ concentrations, a single calcium ion binds at the selectivity filter narrow constriction formed by aspartates D541 and allows Na+ permeation. In the presence of ions, no water binds to or crosses the pore constriction. At high Ca2+ concentrations, calcium permeates the pore according to the knock-off mechanism that includes formation of a short-lived transition state with three calcium ions bound near D541. For Ba2+, the transition state lives longer and the knock-off permeation occurs slower. Gd3+ binds at D541 tightly, blocks the channel and prevents Na+ from permeating the pore. Our results provide structural foundations for understanding permeation and block in tetrameric calcium-selective ion channels.

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Role of Bioinformatics in the Study of Ionic Channels

Kurczynska

Konopka

Kotulska

2017

Transport Across Natural and Modified Biological Membranes and Its Implications in Physiology and Therapy

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Ionic channels belong to the group of the most important proteins. Not only do they enable transmembrane transport but they are also the key factors for proper cell function. Mutations changing their structure and functionality often lead to severe diseases called channelopathies. On the other hand, transmembrane channels are very difficult objects for experimental studies. Only 2% of experimentally identified structures are transmembrane proteins, while genomic studies show that transmembrane proteins make up 30% of all coded proteins. This gap could be diminished by bioinformatical methods which enable modeling unknown protein structures, functions, transmembrane location, and ligand binding. Several in silico methods dedicated to transmembrane proteins have been developed; some general methods could also be used. They provide the information unavailable from experiments. Current modeling tools use a variety of computational methods, which provide results of surprisingly high quality.

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Voltage-Gated Sodium Channels

Cited by 7 publications

References 104 publications

Extremely Potent Block of Bacterial Voltage-Gated Sodium Channels by µ-Conotoxin PIIIA

Extremely Potent Block of Bacterial Voltage-Gated Sodium Channels by µ-Conotoxin PIIIA

Ion Permeation Mechanism in Epithelial Calcium Channel TRVP6

Role of Bioinformatics in the Study of Ionic Channels

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