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Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current.

ABSTRACT: The assertion that large-diameter nerve fibers have low thresholds and small-diameter fibers have high thresholds in response to electrical stimulation has been held in a nearly axiomatic regard in the field of neuromodulation and neuroprosthetics. In contrast to the short pulses used to evoke action potentials, long-duration ionic direct current has been shown to block neural activity. We propose that the main determinant of the neural sensitivity to direct current block is not the size of the axon but the types of voltage-gated sodium channels prevalent in its neural membrane. On the basis of the variants of voltage-gated sodium channels expressed in different types of neurons in the peripheral nerves, we hypothesized that the small-diameter nociceptive fibers could be preferentially blocked. We show the results of a computational model and in vivo neurophysiology experiments that offer experimental validation of this novel phenomenon.

SUBMITTER: Yang F

PROVIDER: S-EPMC5895440 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current.

Yang Fei F Anderson Michael M He Shaoqiu S Stephens Kimberly K Zheng Yu Y Chen Zhiyong Z Raja Srinivasa N SN Aplin Felix F Guan Yun Y Fridman Gene G

Science advances 20180411 4

The assertion that large-diameter nerve fibers have low thresholds and small-diameter fibers have high thresholds in response to electrical stimulation has been held in a nearly axiomatic regard in the field of neuromodulation and neuroprosthetics. In contrast to the short pulses used to evoke action potentials, long-duration ionic direct current has been shown to block neural activity. We propose that the main determinant of the neural sensitivity to direct current block is not the size of the ...[more]

PMID: 29651458

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Project description:In the preparation of synthetic conotoxins containing multiple disulfide bonds, oxidative folding can produce numerous permutations of disulfide bond connectivities. Establishing the native disulfide connectivities thus presents a significant challenge when the venom-derived peptide is not available, as is increasingly the case when conotoxins are identified from cDNA sequences. Here, we investigate the disulfide connectivity of ?-conotoxin KIIIA, which was predicted originally to have a [C1-C9,C2-C15,C4-C16] disulfide pattern based on homology with closely related ?-conotoxins. The two major isomers of synthetic ?-KIIIA formed during oxidative folding were purified and their disulfide connectivities mapped by direct mass spectrometric collision-induced dissociation fragmentation of the disulfide-bonded polypeptides. Our results show that the major oxidative folding product adopts a [C1-C15,C2-C9,C4-C16] disulfide connectivity, while the minor product adopts a [C1-C16,C2-C9,C4-C15] connectivity. Both of these peptides were potent blockers of Na(V)1.2 (K(d) values of 5 and 230 nM, respectively). The solution structure for ?-KIIIA based on nuclear magnetic resonance data was recalculated with the [C1-C15,C2-C9,C4-C16] disulfide pattern; its structure was very similar to the ?-KIIIA structure calculated with the incorrect [C1-C9,C2-C15,C4-C16] disulfide pattern, with an ?-helix spanning residues 7-12. In addition, the major folding isomers of ?-KIIIB, an N-terminally extended isoform of ?-KIIIA identified from its cDNA sequence, were isolated. These folding products had the same disulfide connectivities as ?-KIIIA, and both blocked Na(V)1.2 (K(d) values of 470 and 26 nM, respectively). Our results establish that the preferred disulfide pattern of synthetic ?-KIIIA and ?-KIIIB folded in vitro is 1-5/2-4/3-6 but that other disulfide isomers are also potent sodium channel blockers. These findings raise questions about the disulfide pattern(s) of ?-KIIIA in the venom of Conus kinoshitai; indeed, the presence of multiple disulfide isomers in the venom could provide a means of further expanding the snail's repertoire of active peptides.

Dataset Information

Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current.

Publications

Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current.

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