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Mar. Drugs 2016, 14(11), 213;

The Role of Individual Disulfide Bonds of μ-Conotoxin GIIIA in the Inhibition of NaV1.4

College of Science, National University of Defense Technology, Changsha 410073, Hunan, China
Beijing Institute of Pharmaceutical Chemistry, Beijing 102205, China
Author to whom correspondence should be addressed.
Academic Editor: Peer B. Jacobson
Received: 28 September 2016 / Revised: 31 October 2016 / Accepted: 11 November 2016 / Published: 18 November 2016
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μ-Conotoxin GIIIA, a peptide toxin isolated from Conus geographus, preferentially blocks the skeletal muscle sodium channel NaV1.4. GIIIA folds compactly to a pyramidal structure stabilized by three disulfide bonds. To assess the contributions of individual disulfide bonds of GIIIA to the blockade of NaV1.4, seven disulfide-deficient analogues were prepared and characterized, each with one, two, or three pairs of disulfide-bonded Cys residues replaced with Ala. The inhibitory potency of the analogues against NaV1.4 was assayed by whole cell patch-clamp on rNaV1.4, heterologously expressed in HEK293 cells. The corresponding IC50 values were 0.069 ± 0.005 μM for GIIIA, 2.1 ± 0.3 μM for GIIIA-1, 3.3 ± 0.2 μM for GIIIA-2, and 15.8 ± 0.8 μM for GIIIA-3 (-1, -2 and -3 represent the removal of disulfide bridges Cys3–Cys15, Cys4–Cys20 and Cys10–Cys21, respectively). Other analogues were not active enough for IC50 measurement. Our results indicate that all three disulfide bonds of GIIIA are required to produce effective inhibition of NaV1.4, and the removal of any one significantly lowers its sodium channel binding affinity. Cys10–Cys21 is the most important for the NaV1.4 potency. View Full-Text
Keywords: μ-conotoxin; GIIIA; disulfide bond; NaV1.4; electrophysiology μ-conotoxin; GIIIA; disulfide bond; NaV1.4; electrophysiology

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Han, P.; Wang, K.; Dai, X.; Cao, Y.; Liu, S.; Jiang, H.; Fan, C.; Wu, W.; Chen, J. The Role of Individual Disulfide Bonds of μ-Conotoxin GIIIA in the Inhibition of NaV1.4. Mar. Drugs 2016, 14, 213.

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