scholarly journals Role of the disulfide bond on the structure and activity of μ-conotoxin PIIIA in the inhibition of NaV1.4

RSC Advances ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 668-674 ◽  
Author(s):  
Xiaoxiao Xu ◽  
Qingliang Xu ◽  
Fangling Chen ◽  
Juan Shi ◽  
Yuntian Liu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channel ◽  
Disulfide Bond ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Peptide Toxin ◽  
Structure And Activity

μ-Conotoxin PIIIA, a peptide toxin isolated from Conus purpurascens, blocks the skeletal muscle voltage-gated sodium channel NaV1.4 with significant potency.

scholarly journals Manipulation of a spider peptide toxin alters its affinity for lipid bilayers and potency and selectivity for voltage-gated sodium channel subtype 1.7

2020 ◽  
Vol 295 (15) ◽  
pp. 5067-5080 ◽  
Author(s):  
Akello J. Agwa ◽  
Poanna Tran ◽  
Alexander Mueller ◽  
Hue N. T. Tran ◽  
Jennifer R. Deuis ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Lipid Bilayer ◽  
Lipid Bilayers ◽  
Lipid Membrane ◽  
Surface Profile ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Gating Modifier ◽  
Peptide Toxin

Huwentoxin-IV (HwTx-IV) is a gating modifier peptide toxin from spiders that has weak affinity for the lipid bilayer. As some gating modifier toxins have affinity for model lipid bilayers, a tripartite relationship among gating modifier toxins, voltage-gated ion channels, and the lipid membrane surrounding the channels has been proposed. We previously designed an HwTx-IV analogue (gHwTx-IV) with reduced negative charge and increased hydrophobic surface profile, which displays increased lipid bilayer affinity and in vitro activity at the voltage-gated sodium channel subtype 1.7 (NaV1.7), a channel targeted in pain management. Here, we show that replacements of the positively-charged residues that contribute to the activity of the peptide can improve gHwTx-IV's potency and selectivity for NaV1.7. Using HwTx-IV, gHwTx-IV, [R26A]gHwTx-IV, [K27A]gHwTx-IV, and [R29A]gHwTx-IV variants, we examined their potency and selectivity at human NaV1.7 and their affinity for the lipid bilayer. [R26A]gHwTx-IV consistently displayed the most improved potency and selectivity for NaV1.7, examined alongside off-target NaVs, compared with HwTx-IV and gHwTx-IV. The lipid affinity of each of the three novel analogues was weaker than that of gHwTx-IV, but stronger than that of HwTx-IV, suggesting a possible relationship between in vitro potency at NaV1.7 and affinity for lipid bilayers. In a murine NaV1.7 engagement model, [R26A]gHwTx-IV exhibited an efficacy comparable with that of native HwTx-IV. In summary, this study reports the development of an HwTx-IV analogue with improved in vitro selectivity for the pain target NaV1.7 and with an in vivo efficacy similar to that of native HwTx-IV.

scholarly journals Functional role of the C-terminus of voltage-gated sodium channel Nav1.8

FEBS Letters ◽  
2004 ◽  
Vol 572 (1-3) ◽  
pp. 256-260 ◽  
Author(s):  
Jin-Sung Choi ◽  
Lynda Tyrrell ◽  
Stephen G Waxman ◽  
Sulayman D Dib-Hajj
Keyword(s):  
Sodium Channel ◽  
Functional Role ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
C Terminus

Role of auxiliary β1-, β2-, and β3-subunits and their interaction with Nav1.8 voltage-gated sodium channel

2004 ◽  
Vol 319 (2) ◽  
pp. 531-540 ◽  
Author(s):  
Kausalia Vijayaragavan ◽  
Andrew J. Powell ◽  
Ian J. Kinghorn ◽  
Mohamed Chahine
Keyword(s):  
Sodium Channel ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated

scholarly journals Activation and Inactivation of the Voltage-Gated Sodium Channel: Role of Segment S5 Revealed by a Novel Hyperkalaemic Periodic Paralysis Mutation

1999 ◽  
Vol 19 (12) ◽  
pp. 4762-4771 ◽  
Author(s):  
Saı̈d Bendahhou ◽  
Theodore R. Cummins ◽  
Rabi Tawil ◽  
Stephen G. Waxman ◽  
Louis J. Ptácek
Keyword(s):  
Sodium Channel ◽  
Periodic Paralysis ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated
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