8.A.19 The Sodium Channel Auxiliary Subunit TipE (SCAT) Family

The SCAT family is a relatively small family of insect homologues (Feng et al. 1995). Homologues of TipE possess two transmembrane segments. Five sites of glycosylation were found in TipE. TipE may be involved in the biogenesis of sodium channels but also affect channel activity. Highly negatively charged extracellular regions are found in these proteins with unknown function (Gurnett and Campbell 1996). TipE-like genes form a remarkably conserved genomic cluster across all examined insect genomes (Li et al. 2011). The insect Nav auxiliary subunits share functional features with their mammalian counterparts, although structurally and phylogenetically distant (Bourdin et al. 2015).

TipE is an auxiliary subunit of the Drosophila Para sodium channel. Derst et al. 2006 described four sequences, TEH1-4, homologous to TipE in the Drosophila melanogaster genome, harboring all typical structures of both TipE and the beta-subunit family of big-conductance Ca²⁺-activated potassium channels: short cytosolic N- and C-terminal stretches, two transmembrane domains, and a large extracellular loop with two disulfide bonds. Whereas TEH1 and TEH2 lack the TipE-specific extension in the extracellular loop, both TEH3 and TEH4 possess two extracellular EGF-like domains. A CNS-specific expression was found for TEH1, while TEH2-4 were more widely expressed. The genes for TEH2-4 are localized close to the tipE gene on chromosome 3L. Coexpression of TEH subunits with Para in Xenopus oocytes showed a strong (30-fold, TEH1), medium (5- to 10-fold, TEH2 and TEH3), or no (TEH4) increase in sodium current amplitude, while TipE increased the current 20-fold. In addition, steady-state inactivation and the recovery from fast inactivation were altered by coexpression of Para with TEH1. Derst et al. 2006 concluded that members of the TEH-family are auxiliary subunits for Para sodium channels and possibly for other ion channels. TipE and its homologs affect Na+ channel gating (Wang et al. 2013) and differently affect Na+ channel TipE splice variants (Wang et al. 2015).