Recharging the Phylogenetic Analysis of Voltage Sensor Domains

Abstract

Sequence and phylogenetic analysis of voltage-gated ion channels has famously resulted in the discovery of novel ion channels in previously unexplored phyla, and has provided insight into the molecular underpinnings of ion channel function. Because of their crucial role in human health, most current evolutionary analysis has quite reasonably centered on ‘traditional’ pore-forming channels (e.g., Yu, et al, 2005, Pharmacol. Rev., 57:387-395, among many others). Earlier phylogenetic analyses of voltage sensor domain (VSD) modules (e.g., Komanovics et al, 2002, FASEB J., 16:1623-1629, among others) were undertaken before the discovery and characterization of the genes for voltage sensitive phosphatases (VSP) and voltage gated proton channels (HV1), which contain VSDs but do not contain traditional ion pores. We recently reported two new discoveries: in one line of inquiry we found and characterized a dinoflagellate HV1, supporting the prediction of its existence in bioluminescent dinoflagellates by Fogel and Hastings in 1972 (PNAS, 3:690-693); and in the other we uncovered the universal selectivity filter of HV1's. Both of these studies were informed by large-scale sequence and phylogenetic analyses that focused on homologs of VSDs themselves, separate from their N- or C-terminal appendages. Here we present a full sequence and phylogenetic analysis that updates earlier work and reveals that VSDs may have taken a different evolutionary path from associated ion channel pore domains, which has mechanistic and physiological implications.