Sodium Channel β Subunits-An Additional Element in Animal Tetrodotoxin Resistance?

Abstract

Tetrodotoxin (TTX) is a neurotoxic molecule used by many animals for defense and/or predation, as well as an important biomedical tool. Its ubiquity as a defensive agent has led to repeated independent evolution of tetrodotoxin resistance in animals. TTX binds to voltage-gated sodium channels (VGSC) consisting of α and β subunits. Virtually all studies investigating the mechanisms behind TTX resistance have focused on the α subunit of voltage-gated sodium channels, where tetrodotoxin binds. However, the possibility of β subunits also contributing to tetrodotoxin resistance was never explored, though these subunits act in concert. In this study, we present preliminary evidence suggesting a potential role of β subunits in the evolution of TTX resistance. We gathered mRNA sequences for all β subunit types found in vertebrates across 12 species (three TTX-resistant and nine TTX-sensitive) and tested for signatures of positive selection with a maximum likelihood approach. Our results revealed several sites experiencing positive selection in TTX-resistant taxa, though none were exclusive to those species in subunit β1, which forms a complex with the main physiological target of TTX (VGSC Na_v1.4). While experimental data validating these findings would be necessary, this work suggests that deeper investigation into β subunits as potential players in tetrodotoxin resistance may be worthwhile.

Keywords: resistance; sodium channels; subunit beta; tetrodotoxin.

Figure 1

SCN1B sequences showing the positively selected G33N substitution in T. rubripes and the location of the residue on the protein (in red).

Figure 2

Crystal structure of the human Na_v1.4 VGSC (orange) in complex with subunit β1 (cyan). TM = Transmembrane domain, Ig = Immunoglobulin domain. Residue G33 (mutated to N33 in the TTX-resistant T. rubripes) is highlighted in red. Structure retrieved from the Protein Data Bank following Pan et al. [15].

Figure 3

SCN2B sequences showing the positively selected P35X substitution in TTX-resistant taxa and E. electricus and the location of the residue on the protein (in red).

Figure 4

SCN3B sequences showing the positively selected Q93X and D197X substitutions in TTX-resistant taxa as well as P. textilis and D. rerio. The location of the residues on the protein is highlighted in red.