Modulation of human Na_v1.7 channel gating by synthetic α-scorpion toxin OD1 and its analogs

Abstract

Nine different voltage-gated sodium channel isoforms are responsible for inducing and propagating action potentials in the mammalian nervous system. The Nav1.7 channel isoform plays an important role in conducting nociceptive signals. Specific mutations of this isoform may impair gating behavior of the channel resulting in several pain syndromes. In addition to channel mutations, similar or opposite changes in gating may be produced by spider and scorpion toxins binding to different parts of the voltage-gated sodium channel. In the present study, we analyzed the effects of the α-scorpion toxin OD1 and 2 synthetic toxin analogs on the gating properties of the Nav1.7 sodium channel. All toxins potently inhibited channel inactivation, however, both toxin analogs showed substantially increased potency by more than one order of magnitude when compared with that of wild-type OD1. The decay phase of the whole-cell Na(+) current was substantially slower in the presence of toxins than in their absence. Single-channel recordings in the presence of the toxins revealed that Na(+) current inactivation slowed due to prolonged flickering of the channel between open and closed states. Our findings support the voltage-sensor trapping model of α-scorpion toxin action, in which the toxin prevents a conformational change in the domain IV voltage sensor that normally leads to fast channel inactivation.

On the role of Nav1.7 sodium channels in chronic pain: an experimental and computational study

“…In a second series of simulations we explored the inactivation properties of Nav1.7 channels (parameter sets displayed in Table 1). The scorpion toxin OD1 has been reported to increase the rate at which Nav1.7 inactivation is removed after being established (Motin et al, 2016). In order to emulate this effect in the model, we increased 10 times the removal rate of Nav1.7 inactivation ( a h in Equation 4).…”

“…In this study, we performed to our knowledge the first test of the scorpion toxin OD1 in hiPSC-derived DRG neurons. This toxin enhances the recovery from fast inactivation of the threshold current Nav1.7 (Motin et al, 2016). Our extracellular recordings also confirmed previous findings of Cao et al (2016) with patch clamp regarding the increased spontaneous firing of erythromelalgia DRG cells and the analgesic effects of PF-05089771.…”

“…The effect of OD1 (and other synthetic toxin analogs) on the gating properties of the Nav1.7 sodium channels was studied by Motin et al (2016) using voltage clamp whole cell and single channel recordings in Chinese hamster ovary (CHO) cells expressing human Nav1.7 channels. They found that the decay phase of the Nav1.7 channel opening slows down in a concentration-dependent manner in the presence of these toxins.…”

“…Wells contained 200 µl of growing medium and 5 µl drops were added to apply the treatments. The experimental doses were selected to be in a near saturation range to ensure a strong effect, based on dose response curves published previously (Cao et al, 2016 for PF-05089771; Motin et al, 2016 for OD1). Both compounds were purchased from Tocris (Bio-Techne, Abingdon, UK).…”

“…In this study, we have used extracellular recordings of spontaneous activity in DRG neuron cultures derived from human induced pluripotent stem cells (hiPSCs) obtained from an erythromelalgia patient and a control subject to study the voltage dependent gating properties of Nav1.7 channels. To start, the effects on the neuronal firing of two different pharmacological compounds -a pain eliciting scorpion toxin (OD1, Motin et al, 2016) and an analgesic drug (PF-05089771, Cao et al, 2016)- were assessed in these cultures using multi electrode array (MEA) recordings. We then present a simple conductance-based computational model of the DRG neuron to explain our findings in terms of the Nav1.7 gating process, focusing on the channel activation (opening) and repriming (i.e., recovery from inactivation).…”