Abstract
Jingzhaotoxin-34 (JZTX-34) is a selective inhibitor of tetrodotoxin-sensitive (TTX-S) sodium channels. In this study, we found that JZTX-34 selectively acted on Nav1.7 with little effect on other sodium channel subtypes including Nav1.5. If the DIIS3-S4 linker of Nav1.5 is substituted by the correspond linker of Nav1.7, the sensitivity of Nav1.5 to JZTX-34 extremely increases to 1.05 µM. Meanwhile, a mutant D816R in the DIIS3-S4 linker of Nav1.7 decreases binding affinity of Nav1.7 to JZTX-34 about 32-fold. The reverse mutant R800D at the corresponding position in Nav1.5 greatly increased its binding affinity to JZTX-34. This implies that JZTX-34 binds to DIIS3-S4 linker of Nav1.7 and the critical residue of Nav1.7 is D816. Unlike β-scorpion toxin trapping sodium channel in an open state, activity of JZTX-34 requires the sodium channel to be in a resting state. JZTX-34 exhibits an obvious analgesic effect in a rodent pain model. Especially, it shows a longer duration and is more effective than morphine in hot pain models. In a formalin-induced pain model, JZTX-34 at dose of 2 mg/kg is equipotent with morphine (5 mg/kg) in the first phase and several-fold more effective than morphine in second phase. Taken together, our data indicate that JZTX-34 releases pain by selectively binding to the domain II voltage sensor of Nav1.7 in a closed configuration.
Highlights
Voltage-gated sodium channels (VGSCs) are transmembrane proteins that control the voltage-dependent increase in sodium permeability and play a critical role in initiating and propagating action potentials in excitable cells [1,2]
We investigated the effects of thishas toxin ondemonstrated the gating properties of Nav1.7
Nav1.5 channel is resistant to the inhibition of JZTX-34, we investigated the site of JZTX-34 to Nav1.7 by constructing chimeric channels betweenbetween
Summary
Voltage-gated sodium channels (VGSCs) are transmembrane proteins that control the voltage-dependent increase in sodium permeability and play a critical role in initiating and propagating action potentials in excitable cells [1,2]. HWTX-IV and ProTx-II are very potent Nav1.7 blockers, which selectively inhibited Nav1.7 by docking on IIS3-S4 linker (site 4) to trap the voltage sensor in a closed state [14,15]. Another Nav1.7 toxin, μ-TRTX-Hhn1b, can efficiently relieve inflammatory pain and neuropathic pain in an animal model [16]. JZTX-34 was found to have a selective effect on tetrodotoxin-sensitive (TTX-S) sodium channels from dorsal root ganglia (DRG) neurons It exhibited no inhibition on tetrodotoxin-resistant (TTX-R) sodium currents [18]. The analgesic effect and mechanism of JZTX-34 on pain were investigated
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