U-shaped dose-dependent effects of BmK AS, a unique scorpion polypeptide toxin, on voltage-gated sodium channels.
OBJECTIVE
Buthus martensi Karsch (BmK) AS is a scorpion polypeptide toxin, said to target the voltage-gated sodium channels (VGSCs). However, the mechanism of action of BmK AS on the VGSCs has yet to be defined.


METHODS
We examined the electrophysiological effects of BmK AS in a wide dose range on the rat brain-type VGSC alpha-subunit, rNav1.2a, heterologously expressed in Xenopus oocytes and on the VGSCs endogenously expressed in the dorsal root ganglion neuroblastoma ND7-23 cell line.


RESULTS
In the oocytes, BmK AS depolarized the voltage dependence of activation and inactivation of rNav1.2a at 0.1 and 500 nM whereas these parameters were hyperpolarized at 1 nM. In ND7-23 cells, BmK AS hyperpolarized the voltage dependence of activation and inactivation at 0.1, 1 and 100 nM but not 10 nM. BmK AS also hyperpolarized the voltage dependence of recovery from inactivation at 0.1 and 100 nM and slowed the recovery kinetics at all concentrations, but the effects of 1 and 10 nM were relatively smaller than those at 0.1 and 100 nM. Moreover, the inactivation of VGSCs was potentiated by 10 nM BmK AS in both systems, whereas it was inhibited by 0.1 or 100 nM BmK AS in the oocytes or ND7-23 cells respectively.


CONCLUSIONS
BmK AS modulated the VGSCs in a unique U-shaped dose-dependent manner, which could be due to the opposing effects of binding to two distinct receptor sites on the VGSCs.
Zhu
Mang-Mang
MM
School of Life Sciences, Shanghai University, Shanghai, China.
Tao
Jie
J
Tan
Miao
M
Yang
Hong-Tian
HT
Ji
Yong-Hua
YH
D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D051379:Mice; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D009447:Neuroblastoma / Q000378:metabolism*; D009865:Oocytes; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D012604:Scorpion Venoms / Q000008:administration & dosage / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D014982:Xenopus laevis
C119407:BmK AS polypeptide; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D010455:Peptides; C568253:Scn2A protein, rat; C000654500:Scn2a protein, mouse; D012604:Scorpion Venoms; D015222:Sodium Channels