The β3-subunit modulates the effect of venom peptides ProTx-II and OD1 on NaV1.7 gating

7Citations
Citations of this article
8Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

The voltage-gated sodium channel NaV1.7 is involved in various pain phenotypes and is physiologically regulated by the NaV-β3-subunit. Venom toxins ProTx-II and OD1 modulate NaV1.7 channel function and may be useful as therapeutic agents and/or research tools. Here, we use patch-clamp recordings to investigate how the β3-subunit can influence and modulate the toxin-mediated effects on NaV1.7 function, and we propose a putative binding mode of OD1 on NaV1.7 to rationalise its activating effects. The inhibitor ProTx-II slowed the rate of NaV1.7 activation, whilst the activator OD1 reduced the rate of fast inactivation and accelerated recovery from inactivation. The β3-subunit partially abrogated these effects. OD1 induced a hyperpolarising shift in the V1/2 of steady-state activation, which was not observed in the presence of β3. Consequently, OD1-treated NaV1.7 exhibited an enhanced window current compared with OD1-treated NaV1.7-β3 complex. We identify candidate OD1 residues that are likely to prevent the upward movement of the DIV S4 helix and thus impede fast inactivation. The binding sites for each of the toxins and the predicted location of the β3-subunit on the NaV1.7 channel are distinct. Therefore, we infer that the β3-subunit influences the interaction of toxins with NaV1.7 via indirect allosteric mechanisms. The enhanced window current shown by OD1-treated NaV1.7 compared with OD1-treated NaV1.7-β3 is discussed in the context of differing cellular expressions of NaV1.7 and the β3-subunit in dorsal root ganglion (DRG) neurons. We propose that β3, as the native binding partner for NaV1.7 in DRG neurons, should be included during screening of molecules against NaV1.7 in relevant analgesic discovery campaigns.

Cite

CITATION STYLE

APA

Salvage, S. C., Rahman, T., Eagles, D. A., Rees, J. S., King, G. F., Huang, C. L. H., & Jackson, A. P. (2023). The β3-subunit modulates the effect of venom peptides ProTx-II and OD1 on NaV1.7 gating. Journal of Cellular Physiology, 238(6), 1354–1367. https://doi.org/10.1002/jcp.31018

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free