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[摘要]：BmK I. a site-3-specific modulator of VGSCs (voltage-gated sodium channels) from the Chinese scorpion Blain's martens' Karsch. can induce spontaneous nociception and hyperalgesia and generate epileptiform responses in rats. which is attributed to the modulation of VGSCs in the neural system However, which VGSC subtype is targeted by BmK I remains to be identified. Using two-electrode voltage-clamp recording. we studied the efficacy and selectivity of BmK I to three neuronal VGSCs co-expressed with the auxiliary p I subunit in Xenopus oocytes Results revealed that BmK I induced a lame increase in both transient and persistent currents in mNa(v)1.6 alpha/beta 1 (where in indicates mouse), which correlated with a prominent reduction in the fast component of in current In comparison, BmK I-increased currents of rNa(v) 1 2 alpha/beta 1 (where r indicates rat) and rNa(v)1.3 alpha/beta 1 were much smaller. The EC50 values of BmK I for rNa(v) 1 2 alpha/beta 1 (252 +/- 6(1 nM) and mNa, 1 6 alpha/beta 1 (214 +/- 30 nM) were similar and roughly half of that for rNav 1 3 alpha/beta 1 (565 +/- 16 nM) Moreover, BmK I only accelerated the slow inactivation development and delay recovery of mNa, 1.6 alpha/beta 1 through binding to the channel in the open state Residue-swap analysis verified that an acidic residue (c Asp(1602) in mNa(v)1 6) within the domain IV S3-S4 extracellular loop of VGSCs was crucial for the selectivity and modulation pattern of BmK 1 Our findings thus provide the molecular determinant explaining the divergent and intringuing behaviour of neuronal VGSCs in response to site-3-specific modulators, indicating that these subtypes play different roles in BmK I-induced hyperexcitablity in rat models |
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