8.A.115. The Transmembrane Protein 223 (TMEM223) Family
TMEM223 regulates the activity of CaV2.2 (Mallmann et al. 2019). It lowers the average current density, accelerates the kinetics of cumulative current inactivation and slows the kinetics of recovery from inactivation. TMEM223 interacts directly with Cav2.2 and negatively modulate Ca2+ entry via this channel protein, and this interaction is required for proper transmitter release and/or for dendritic plasticity under physiological conditions (Mallmann et al. 2019). Pain-causing stinging nettle toxins target TMEM233, and this interaction modulates NaV1.7 function (Jami et al. 2023). Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived Na(V) channel modulating peptide toxin. Jami et al. 2023 showed that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for the pharmacological activity of ExTxA at NaV channels, and that co-expression of TMEM233 modulates the gating properties of NaV1.7. This family may be distantly related to TC family 8.A.58.