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Molecular basis of the inhibition of the fast inactivation of voltage-gated sodium channel Nav1.5 by tarantula toxin Jingzhaotoxin-II.
Peptides. 2015 Jun; 68:175-82.P

Abstract

Jingzhaotoxin-II (JZTX-II) is a 32-residue peptide from the Chinese tarantula Chilobrachys jingzhao venom, and preferentially inhibits the fast inactivation of the voltage-gated sodium channels (VGSCs) in rat cardiac myocytes. In the present study, we elucidated the action mechanism of JZTX-II inhibiting hNav1.5, a VGSC subtype mainly distributed in human cardiac myocytes. Among the four VGSC subtypes tested, hNav1.5 was the most sensitive to JZTX-II (EC50=125±4nM). Although JZTX-II had little or no effect on steady-state inactivation of the residual currents conducted by hNav1.5, it caused a 10mV hyperpolarized shift of activation. Moreover, JZTX-II increased the recovery rate of hNav1.5 channels, which should lead to a shorter transition from the inactivation to closed state. JZTX-II dissociated from toxin-channel complex via extreme depolarization and subsequently rebound to the channel upon repolarization. Mutagenesis analyses showed that the domain IV (DIV) voltage-sensor domain (VSD) was critical for JZTX-II binding to hNav1.5 and some mutations located in S1-S2 and S3-S4 extracellular loops of hNav1.5 DIV additively reduced the toxin sensitivity of hNav1.5. Our data identified the mechanism underlying JZTX-II inhibiting hNav1.5, similar to scorpion α-toxins, involving binding to neurotoxin receptor site 3.

Authors+Show Affiliations

College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China.College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China.College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China.College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China.Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China.College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China.College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China. Electronic address: liuzh@hunnu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25817910

Citation

Huang, Ying, et al. "Molecular Basis of the Inhibition of the Fast Inactivation of Voltage-gated Sodium Channel Nav1.5 By Tarantula Toxin Jingzhaotoxin-II." Peptides, vol. 68, 2015, pp. 175-82.
Huang Y, Zhou X, Tang C, et al. Molecular basis of the inhibition of the fast inactivation of voltage-gated sodium channel Nav1.5 by tarantula toxin Jingzhaotoxin-II. Peptides. 2015;68:175-82.
Huang, Y., Zhou, X., Tang, C., Zhang, Y., Tao, H., Chen, P., & Liu, Z. (2015). Molecular basis of the inhibition of the fast inactivation of voltage-gated sodium channel Nav1.5 by tarantula toxin Jingzhaotoxin-II. Peptides, 68, 175-82. https://doi.org/10.1016/j.peptides.2015.03.012
Huang Y, et al. Molecular Basis of the Inhibition of the Fast Inactivation of Voltage-gated Sodium Channel Nav1.5 By Tarantula Toxin Jingzhaotoxin-II. Peptides. 2015;68:175-82. PubMed PMID: 25817910.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular basis of the inhibition of the fast inactivation of voltage-gated sodium channel Nav1.5 by tarantula toxin Jingzhaotoxin-II. AU - Huang,Ying, AU - Zhou,Xi, AU - Tang,Cheng, AU - Zhang,Yunxiao, AU - Tao,Huai, AU - Chen,Ping, AU - Liu,Zhonghua, Y1 - 2015/03/25/ PY - 2015/01/26/received PY - 2015/03/13/revised PY - 2015/03/16/accepted PY - 2015/3/31/entrez PY - 2015/3/31/pubmed PY - 2016/3/2/medline KW - Action mechanism KW - Jingzhaotoxin-II KW - Nav1.5 SP - 175 EP - 82 JF - Peptides JO - Peptides VL - 68 N2 - Jingzhaotoxin-II (JZTX-II) is a 32-residue peptide from the Chinese tarantula Chilobrachys jingzhao venom, and preferentially inhibits the fast inactivation of the voltage-gated sodium channels (VGSCs) in rat cardiac myocytes. In the present study, we elucidated the action mechanism of JZTX-II inhibiting hNav1.5, a VGSC subtype mainly distributed in human cardiac myocytes. Among the four VGSC subtypes tested, hNav1.5 was the most sensitive to JZTX-II (EC50=125±4nM). Although JZTX-II had little or no effect on steady-state inactivation of the residual currents conducted by hNav1.5, it caused a 10mV hyperpolarized shift of activation. Moreover, JZTX-II increased the recovery rate of hNav1.5 channels, which should lead to a shorter transition from the inactivation to closed state. JZTX-II dissociated from toxin-channel complex via extreme depolarization and subsequently rebound to the channel upon repolarization. Mutagenesis analyses showed that the domain IV (DIV) voltage-sensor domain (VSD) was critical for JZTX-II binding to hNav1.5 and some mutations located in S1-S2 and S3-S4 extracellular loops of hNav1.5 DIV additively reduced the toxin sensitivity of hNav1.5. Our data identified the mechanism underlying JZTX-II inhibiting hNav1.5, similar to scorpion α-toxins, involving binding to neurotoxin receptor site 3. SN - 1873-5169 UR - https://www.unboundmedicine.com/medline/citation/25817910/Molecular_basis_of_the_inhibition_of_the_fast_inactivation_of_voltage_gated_sodium_channel_Nav1_5_by_tarantula_toxin_Jingzhaotoxin_II_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0196-9781(15)00070-4 DB - PRIME DP - Unbound Medicine ER -