Evolutionary Origins of the Shaker Family of Voltage-Gated Potassium Channels

Abstract

The Shaker family of voltage-gated K+ channels in bilaterians consists of four closely related gene subfamilies (Shaker, Shab, Shaw and Shal) that regulate neuronal excitability in diverse ways. We examined the evolutionary origins of the gene family by characterizing Shaker channels in early branching metazoan lineages. Shaker family channels can be definitively identified by the combination of a voltage-dependent potassium channel core and a cytosolic domain (T1) that mediates subfamily-specific tetrameric assembly. The Shaker, Shab, Shaw and Shal subfamilies are present in cnidarians, a close sister group to the bilaterians. We show that all four subfamilies are highly conserved on a functional level in the sea anemone Nematostella vectensis, an emerging cnidarian model organism. The Nematostella Shaker, Shal and Shaw subfamilies include cnidarian-specific expansions of regulatory subunits that extend functional diversity through the formation of heteromeric channels. We were unable to identify Shaker family genes in choanoflagellates or sponges, but found over 40 Shaker family genes in a ctenophore (Mnemiopsis leidyi). Ctenophores are the earliest branching metazoans with a nervous system. Phylogenetic analysis indicates that the ctenophore Shaker family expanded independently and diverged prior to emergence of the Shaker, Shab, Shal and Shaw subfamilies. The phylogeny and functional analysis support Shaker as the oldest of these subfamilies. Two Mnemiopsis Shaker family subunits heteromerize with Nematostella and mouse Shaker subfamily channels, but not with Shab, Shaw or Shal. Thus the subunit interface of Shaker subfamily may retain ancestral features. Our results indicate that the Shaker family is metazoan-specific and was present by the time neurons evolved. However, the Shaker, Shab, Shal and Shaw subfamilies evolved in the cnidarian/bilaterian lineage long after the evolution of the first nervous systems.