Abstract
BackgroundBmK IT2 is regarded as a receptor site-4 modulator of sodium channels with depressant insect toxicity. It also displays anti-nociceptive and anti-convulsant activities in rat models. In this study, the potency and efficacy of BmK IT2 were for the first time assessed and compared among four sodium channel isoforms expressed in Xenopus oocytes. Combined with molecular approach, the receptor site of BmK IT2 was further localized.Principal Findings2 µM BmK IT2 strongly shifted the activation of DmNav1, the sodium channel from Drosophila, to more hyperpolarized potentials; whereas it hardly affected the gating properties of rNav1.2, rNav1.3 and mNav1.6, three mammalian central neuronal sodium channel subtypes. (1) Mutations of Glu896, Leu899, Gly904 in extracellular loop Domain II S3–S4 of DmNav1 abolished the functional action of BmK IT2. (2) BmK IT2-preference for DmNav1 could be conferred by Domain III. Analysis of subsequent DmNav1 mutants highlighted the residues in Domain III pore loop, esp. Ile1529 was critical for recognition and binding of BmK IT2.Conclusions/SignificanceIn this study, BmK IT2 displayed total insect-selectivity. Two binding regions, comprising domains II and III of DmNav1, play separated but indispensable roles in the interaction with BmK IT2. The insensitivity of Nav1.2, Nav1.3 and Nav1.6 to BmK IT2 suggests other isoforms or mechanism might be involved in the suppressive activity of BmK IT2 in rat pathological models.
Highlights
Voltage-gated sodium channels (VGSC) are key membrane proteins responsible for neuron excitability, consisting of an ionconducting a-subunit accompanied by one or more auxiliary subunits [1]
Efficacy of BmK IT2 on VGSC isoforms from insect and mammalian central neuronal system Using the two-electrode voltage clamp recording, BmK IT2 was subjected to a comparative study for the effects on four VGSC subtypes, rNav1.2/b1, rNav1.3/b1, mNav1.6/b1 and DmNav1/ TipE expressed in Xenopus oocytes (Fig. 1)
Whether or not b1 subunit was coexpressed with these mammalian VGSC subtypes did not influence the action of BmK IT2
Summary
Voltage-gated sodium channels (VGSC) are key membrane proteins responsible for neuron excitability, consisting of an ionconducting a-subunit accompanied by one or more auxiliary subunits [1]. Despite the high structure similarity, various VGSC subtypes display distinct distribution, gating properties and function activities. Amongst the neurotoxins purified from scorpions, b-toxins shift the voltage dependence of VGSC activation to cause subthreshold channel opening, which can be enhanced when channels are preactivated by a depolarizing prepulse [4]. BmK IT2 is regarded as a receptor site-4 modulator of sodium channels with depressant insect toxicity. It displays anti-nociceptive and anti-convulsant activities in rat models. The receptor site of BmK IT2 was further localized
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