Ancient Origin of Four-Domain Voltage-gated Na+ Channels Predates the Divergence of Animals and Fungi

The four-domain voltage-gated Na+ channels are believed to have arisen in multicellular animals, possibly during the evolution of the nervous system. Recent genomic studies reveal that many ion channels, including Na+ channels and Ca2+ channels previously thought to be restricted to animals, can be traced back to one of the unicellular ancestors of animals, Monosiga brevicollis. The eukaryotic supergroup Opisthokonta contains animals, fungi, and a diverse group of their unicellular relatives including M. brevicollis. Here, we demonstrate the presence of a putative voltage-gated Na+ channel homolog (TtrNa(V)) in the apusozoan protist Thecamonas trahens, which belongs to the unicellular sister group to Opisthokonta. TtrNa(V) displays a unique selectivity motif distinct from most animal voltage-gated Na+ channels. The identification of TtrNa(V) suggests that voltage-gated Na+ channels might have evolved before the divergence of animals and fungi. Furthermore, our analyses reveal that Na-V channels have been lost independently in the amoeboid holozoan Capsaspora owczarzaki of the animal lineage and in several basal fungi. These findings provide novel insights into the evolution of four-domain voltage-gated ion channels, ion selectivity, and membrane excitability in the Opisthokonta lineage.