Conversion of a scorpion toxin agonist into an antagonist highlights an acidic residue involved in voltage sensor trapping during activation of neuronal Na + channels

2004 ◽  
Vol 18 (6) ◽  
pp. 683-689 ◽  
Author(s):  
Karbat Izhar ◽  
Cohen Lior ◽  
Gilles Nicolas ◽  
Gordon Dalia ◽  
Gurevitz Michael
Keyword(s):  
Voltage Sensor ◽  
Scorpion Toxin ◽  
Na Channels

scholarly journals Interactions among DIV voltage-sensor movement, fast inactivation, and resurgent Na current induced by the NaVβ4 open-channel blocking peptide

2013 ◽  
Vol 142 (3) ◽  
pp. 191-206 ◽  
Author(s):  
Amanda H. Lewis ◽  
Indira M. Raman
Keyword(s):  
Open Channel ◽  
Voltage Sensor ◽  
Channel Block ◽  
Na Channels ◽  
Fast Inactivation ◽  
Na Current ◽  
Open Channel Block ◽  
Channel Blocking ◽  
Open States ◽  
Resurgent Currents

Resurgent Na current flows as voltage-gated Na channels recover through open states from block by an endogenous open-channel blocking protein, such as the NaVβ4 subunit. The open-channel blocker and fast-inactivation gate apparently compete directly, as slowing the onset of fast inactivation increases resurgent currents by favoring binding of the blocker. Here, we tested whether open-channel block is also sensitive to deployment of the DIV voltage sensor, which facilitates fast inactivation. We expressed NaV1.4 channels in HEK293t cells and assessed block by a free peptide replicating the cytoplasmic tail of NaVβ4 (the “β4 peptide”). Macroscopic fast inactivation was disrupted by mutations of DIS6 (L443C/A444W; “CW” channels), which reduce fast-inactivation gate binding, and/or by the site-3 toxin ATX-II, which interferes with DIV movement. In wild-type channels, the β4 peptide competed poorly with fast inactivation, but block was enhanced by ATX. With the CW mutation, large peptide-induced resurgent currents were present even without ATX, consistent with increased open-channel block upon depolarization and slower deactivation after blocker unbinding upon repolarization. The addition of ATX greatly increased transient current amplitudes and further enlarged resurgent currents, suggesting that pore access by the blocker is actually decreased by full deployment of the DIV voltage sensor. ATX accelerated recovery from block at hyperpolarized potentials, however, suggesting that the peptide unbinds more readily when DIV voltage-sensor deployment is disrupted. These results are consistent with two open states in Na channels, dependent on the DIV voltage-sensor position, which differ in affinity for the blocking protein.

scholarly journals Resurgent Current and Voltage Sensor Trapping Enhanced Activation by a β-Scorpion Toxin Solely in Nav1.6 Channel

2006 ◽  
Vol 281 (29) ◽  
pp. 20326-20337 ◽  
Author(s):  
Emanuele Schiavon ◽  
Tiziana Sacco ◽  
Rita Restano Cassulini ◽  
Georgina Gurrola ◽  
Filippo Tempia ◽  
...  
Keyword(s):  
Voltage Sensor ◽  
Scorpion Toxin ◽  
Resurgent Current

The effect ofTityus serrulatus scorpion toxin γ on Na channels in neuroblastoma cells

1984 ◽  
Vol 401 (3) ◽  
pp. 297-303 ◽  
Author(s):  
Henk P. M. Vijberberg ◽  
David Pauron ◽  
Michel Lazdunski
Keyword(s):  
Neuroblastoma Cells ◽  
Scorpion Toxin ◽  
Na Channels

One-to-one binding of a purified scorpion toxin to Na channels

Nature ◽  
1977 ◽  
Vol 266 (5601) ◽  
pp. 465-468 ◽  
Author(s):  
HARUMASA OKAMOTO ◽  
KUNITARO TAKAHASHI ◽  
NAOHIDE YAMASHITA
Keyword(s):  
Scorpion Toxin ◽  
Na Channels ◽  
One To One

scholarly journals Neutralization of Gating Charges in Domain II of the Sodium Channel α Subunit Enhances Voltage-Sensor Trapping by a β-Scorpion Toxin

2001 ◽  
Vol 118 (3) ◽  
pp. 291-302 ◽  
Author(s):  
Sandrine Cestèle ◽  
Todd Scheuer ◽  
Massimo Mantegazza ◽  
Hervé Rochat ◽  
William A. Catterall
Keyword(s):  
Sodium Channel ◽  
Sodium Channels ◽  
Voltage Dependence ◽  
Membrane Potentials ◽  
Voltage Sensor ◽  
Scorpion Toxin ◽  
Channel Activation ◽  
Α Subunit ◽  
Gating Charges

β-Scorpion toxins shift the voltage dependence of activation of sodium channels to more negative membrane potentials, but only after a strong depolarizing prepulse to fully activate the channels. Their receptor site includes the S3–S4 loop at the extracellular end of the S4 voltage sensor in domain II of the α subunit. Here, we probe the role of gating charges in the IIS4 segment in β-scorpion toxin action by mutagenesis and functional analysis of the resulting mutant sodium channels. Neutralization of the positively charged amino acid residues in the IIS4 segment by mutation to glutamine shifts the voltage dependence of channel activation to more positive membrane potentials and reduces the steepness of voltage-dependent gating, which is consistent with the presumed role of these residues as gating charges. Surprisingly, neutralization of the gating charges at the outer end of the IIS4 segment by the mutations R850Q, R850C, R853Q, and R853C markedly enhances β-scorpion toxin action, whereas mutations R856Q, K859Q, and K862Q have no effect. In contrast to wild-type, the β-scorpion toxin Css IV causes a negative shift of the voltage dependence of activation of mutants R853Q and R853C without a depolarizing prepulse at holding potentials from −80 to −140 mV. Reaction of mutant R853C with 2-aminoethyl methanethiosulfonate causes a positive shift of the voltage dependence of activation and restores the requirement for a depolarizing prepulse for Css IV action. Enhancement of sodium channel activation by Css IV causes large tail currents upon repolarization, indicating slowed deactivation of the IIS4 voltage sensor by the bound toxin. Our results are consistent with a voltage-sensor–trapping model in which the β-scorpion toxin traps the IIS4 voltage sensor in its activated position as it moves outward in response to depolarization and holds it there, slowing its inward movement on deactivation and enhancing subsequent channel activation. Evidently, neutralization of R850 and R853 removes kinetic barriers to binding of the IIS4 segment by Css IV, and thereby enhances toxin-induced channel activation.

scholarly journals Structure and Function of the Voltage Sensor of Sodium Channels Probed by a β-Scorpion Toxin

2006 ◽  
Vol 281 (30) ◽  
pp. 21332-21344 ◽  
Author(s):  
Sandrine Cestèle ◽  
Vladimir Yarov-Yarovoy ◽  
Yusheng Qu ◽  
François Sampieri ◽  
Todd Scheuer ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Structure And Function ◽  
Voltage Sensor ◽  
Scorpion Toxin ◽  
And Function

scholarly journals β-Scorpion Toxin Modifies Gating Transitions in All Four Voltage Sensors of the Sodium Channel

2007 ◽  
Vol 130 (3) ◽  
pp. 257-268 ◽  
Author(s):  
Fabiana V. Campos ◽  
Baron Chanda ◽  
Paulo S.L. Beirão ◽  
Francisco Bezanilla
Keyword(s):  
Sodium Channel ◽  
Sodium Channels ◽  
Integrated Approach ◽  
Voltage Sensor ◽  
Scorpion Toxin ◽  
Charge Voltage ◽  
Voltage Sensors ◽  
Fluorescence Measurements ◽  
Voltage Gated Sodium Channels ◽  
Activated State

Several naturally occurring polypeptide neurotoxins target specific sites on the voltage-gated sodium channels. Of these, the gating modifier toxins alter the behavior of the sodium channels by stabilizing transient intermediate states in the channel gating pathway. Here we have used an integrated approach that combines electrophysiological and spectroscopic measurements to determine the structural rearrangements modified by the β-scorpion toxin Ts1. Our data indicate that toxin binding to the channel is restricted to a single binding site on domain II voltage sensor. Analysis of Cole-Moore shifts suggests that the number of closed states in the activation sequence prior to channel opening is reduced in the presence of toxin. Measurements of charge–voltage relationships show that a fraction of the gating charge is immobilized in Ts1-modified channels. Interestingly, the charge–voltage relationship also shows an additional component at hyperpolarized potentials. Site-specific fluorescence measurements indicate that in presence of the toxin the voltage sensor of domain II remains trapped in the activated state. Furthermore, the binding of the toxin potentiates the activation of the other three voltage sensors of the sodium channel to more hyperpolarized potentials. These findings reveal how the binding of β-scorpion toxin modifies channel function and provides insight into early gating transitions of sodium channels.

Photoaffinity labeling of scorpion toxin receptors associated with insect synaptosomal Na+ channels

1988 ◽  
Vol 151 (1) ◽  
pp. 187-192 ◽  
Author(s):  
Maria Elena de Lima ◽  
Francois Couraud ◽  
Bruno Lapied ◽  
Marcel Pelhate ◽  
Carlos Ribeiro Diniz ◽  
...  
Keyword(s):  
Photoaffinity Labeling ◽  
Scorpion Toxin ◽  
Na Channels

scholarly journals Mapping the Interaction Site for a β-Scorpion Toxin in the Pore Module of Domain III of Voltage-gated Na+Channels

2012 ◽  
Vol 287 (36) ◽  
pp. 30719-30728 ◽  
Author(s):  
Joel Z. Zhang ◽  
Vladimir Yarov-Yarovoy ◽  
Todd Scheuer ◽  
Izhar Karbat ◽  
Lior Cohen ◽  
...  
Keyword(s):  
Scorpion Toxin ◽  
Na Channels ◽  
Interaction Site ◽  
Voltage Gated ◽  
Domain Iii
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