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Natural mutations change the affinity of μ-theraphotoxin-Hhn2a to voltage-gated sodium channels.
Toxicon. 2015 Jan; 93:24-30.T

Abstract

μ-Theraphotoxin-Hhn2a (HNTX-III) isolated from the venom of the spider Ornithoctonus hainana is a selective antagonist of neuronal tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channels (VGSCs). Intriguingly, previous transcriptomic study revealed HNTX-III family consists of more than 15 precursors, in which the 20(th) and 24(th) residues of the mature sequences are variable. Try20 and Ser24 of HNTX-III are mutated to His20 and Asn24 of other members, respectively. In addition, the alkaline residue His26 of the potent VGSC inhibitor HNTX-III is substituted by acidic residue Asp of the weak VGSC inhibitor HNTX-I. Therefore, four mutants of HNTX-III, HNTX-III-Y20H, -S24N, -H26D and -Y20H/24N, were synthesized to examine the effects of these natural mutations on the inhibitory activity of HNTX-III. They were subjected to an electrophysiological screening on five VGSC subtypes (Nav1.3-1.5, Nav1.7 and Nav1.8) expressed on HEK293 cells by whole-cell patch clamp. Like HNTX-III, all mutants only displayed inhibitory activity on Nav1.3 and Nav1.7 among the five subtypes, but the inhibitory potency was much lower than that of HNTX-III. Regarding Nav1.7, the IC50 values of HNTX-III-Y20H, -S24N, -H26D and -Y20H/S24N were increased by approximately 62-, 8.4-, 49- and 19.5-folds compared with that of HNTX-III, respectively. Similar data were obtained for Nav1.3. Our results provide new insights into the activity-related residues of HNTX-III at genic level. Furthermore, the reduced potency of the four mutants probably reflects natural selection might favor and reserve the most potent bioactivity of HNTX-III which is one of the most abundant fractions of the venom.

Authors+Show Affiliations

College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.College of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang 414006, China.College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China. Electronic address: liuzh@hunnu.edu.cn.College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China. Electronic address: liangsp@hunnu.edu.cn.

Pub Type(s)

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

Language

eng

PubMed ID

25447770

Citation

Zhang, Fan, et al. "Natural Mutations Change the Affinity of μ-theraphotoxin-Hhn2a to Voltage-gated Sodium Channels." Toxicon : Official Journal of the International Society On Toxinology, vol. 93, 2015, pp. 24-30.
Zhang F, Liu Y, Zhang C, et al. Natural mutations change the affinity of μ-theraphotoxin-Hhn2a to voltage-gated sodium channels. Toxicon. 2015;93:24-30.
Zhang, F., Liu, Y., Zhang, C., Li, J., Yang, Z., Gong, X., Gan, Y., Chen, P., Liu, Z., & Liang, S. (2015). Natural mutations change the affinity of μ-theraphotoxin-Hhn2a to voltage-gated sodium channels. Toxicon : Official Journal of the International Society On Toxinology, 93, 24-30. https://doi.org/10.1016/j.toxicon.2014.11.220
Zhang F, et al. Natural Mutations Change the Affinity of μ-theraphotoxin-Hhn2a to Voltage-gated Sodium Channels. Toxicon. 2015;93:24-30. PubMed PMID: 25447770.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Natural mutations change the affinity of μ-theraphotoxin-Hhn2a to voltage-gated sodium channels. AU - Zhang,Fan, AU - Liu,Yu, AU - Zhang,Changxin, AU - Li,Jing, AU - Yang,Zuqin, AU - Gong,Xue, AU - Gan,Yunxiang, AU - Chen,Ping, AU - Liu,Zhonghua, AU - Liang,Songping, Y1 - 2014/11/06/ PY - 2014/08/28/received PY - 2014/10/29/revised PY - 2014/11/05/accepted PY - 2014/12/3/entrez PY - 2014/12/3/pubmed PY - 2015/8/27/medline KW - Natural mutations KW - Spider toxin KW - Voltage-gated sodium channels SP - 24 EP - 30 JF - Toxicon : official journal of the International Society on Toxinology JO - Toxicon VL - 93 N2 - μ-Theraphotoxin-Hhn2a (HNTX-III) isolated from the venom of the spider Ornithoctonus hainana is a selective antagonist of neuronal tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channels (VGSCs). Intriguingly, previous transcriptomic study revealed HNTX-III family consists of more than 15 precursors, in which the 20(th) and 24(th) residues of the mature sequences are variable. Try20 and Ser24 of HNTX-III are mutated to His20 and Asn24 of other members, respectively. In addition, the alkaline residue His26 of the potent VGSC inhibitor HNTX-III is substituted by acidic residue Asp of the weak VGSC inhibitor HNTX-I. Therefore, four mutants of HNTX-III, HNTX-III-Y20H, -S24N, -H26D and -Y20H/24N, were synthesized to examine the effects of these natural mutations on the inhibitory activity of HNTX-III. They were subjected to an electrophysiological screening on five VGSC subtypes (Nav1.3-1.5, Nav1.7 and Nav1.8) expressed on HEK293 cells by whole-cell patch clamp. Like HNTX-III, all mutants only displayed inhibitory activity on Nav1.3 and Nav1.7 among the five subtypes, but the inhibitory potency was much lower than that of HNTX-III. Regarding Nav1.7, the IC50 values of HNTX-III-Y20H, -S24N, -H26D and -Y20H/S24N were increased by approximately 62-, 8.4-, 49- and 19.5-folds compared with that of HNTX-III, respectively. Similar data were obtained for Nav1.3. Our results provide new insights into the activity-related residues of HNTX-III at genic level. Furthermore, the reduced potency of the four mutants probably reflects natural selection might favor and reserve the most potent bioactivity of HNTX-III which is one of the most abundant fractions of the venom. SN - 1879-3150 UR - https://www.unboundmedicine.com/medline/citation/25447770/Natural_mutations_change_the_affinity_of_μ_theraphotoxin_Hhn2a_to_voltage_gated_sodium_channels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-0101(14)00581-9 DB - PRIME DP - Unbound Medicine ER -