Functional evolution of Erg potassium channel gating reveals an ancient origin for I _Kr

Abstract

Mammalian Ether-a-go-go related gene (Erg) family voltage-gated K + channels possess an unusual gating phenotype that specializes them for a role in delayed repolarization. Mammalian Erg currents rectify during depolarization due to rapid, voltage-dependent inactivation, but rebound during repolarization due to a combination of rapid recovery from inactivation and slow deactivation. This is exemplified by the mammalian Erg1 channel, which is responsible for I Kr , a current that repolarizes cardiac action potential plateaus. The Drosophila Erg channel does not inactivate and closes rapidly upon repolarization. The dramatically different properties observed in mammalian and Drosophila Erg homologs bring into question the evolutionary origins of distinct Erg K + channel functions. Erg channels are highly conserved in eumetazoans and first evolved in a common ancestor of the placozoans, cnidarians, and bilaterians. To address the ancestral function of Erg channels, we identified and characterized Erg channel paralogs in the sea anemone Nematostella vectensis. N. vectensis Erg1 (NvErg1) is highly conserved with respect to bilaterian homologs and shares the I Kr -like gating phenotype with mammalian Erg channels. Thus, the I Kr phenotype predates the divergence of cnidarians and bilaterians. NvErg4 and Caenorhabditis elegans Erg (unc-103) share the divergent Drosophila Erg gating phenotype. Phylogenetic and sequence analysis surprisingly indicates that this alternate gating phenotype arose independently in protosomes and cnidarians. Conversion from an ancestral I Kr -like gating phenotype to a Drosophila Erg-like phenotype correlates with loss of the cytoplasmic Ether-a-go-go domain. This domain is required for slow deactivation in mammalian Erg1 channels, and thus its loss may partially explain the change in gating phenotype.sei | CNBHD | Anopheles | PAS

Evolution of voltage-gated ion channels at the emergence of Metazoa

“…Phylogeny reveals that NvErg1 and the mammalian channels represent the ancestral electrical behavior, whereas NvErg4 evolved in a convergent manner to the Drosophila channel. Surprisingly, it seems that nematode Erg channels also acquired this feature independently, suggesting that this electrical behavior evolved at least three times during animal evolution (Martinson et al, 2014).…”

“…Moreover, the Shaker gene in the genome of a deuterostome -the sea urchin Strongylocentrotus purpuratus -is intron-less as well (Sodergren et al, 2006), suggesting that chordate and most cnidarian Shaker genes may have evolved from a common intron-less ancestor (Jegla et al, 2012). A recent study of the functional properties of another family of cnidarian K V channels uncovered the properties of ancestral channels: in the study, Martinson et al (Martinson et al, 2014) functionally expressed the Nematostella homologs of the bilaterian Ether-a-go-go related channel (Erg, also known as K V 11.1). One of the Nematostella homologs (NvErg1) exhibits similar electrical characteristics to those of the human channels, whereas another (NvErg4) behaves similarly to the Drosophila channel.…”

“…Phylogeny reveals that NvErg1 and the mammalian channels represent the ancestral electrical behavior, whereas NvErg4 evolved in a convergent manner to the Drosophila channel. Surprisingly, it seems that nematode Erg channels also acquired this feature independently, suggesting that this electrical behavior evolved at least three times during animal evolution (Martinson et al, 2014).Voltage-gated calcium channels: a widely, yet sparsely, distributed channel family Ca 2+ currents are associated with locomotion via flagellar movements in paramecium (Plattner, 2014) and algae (Chlamydomonas) (Wakabayashi et al, 2009;Fujiu et al, 2009), stress responses in diatoms (Vardi et al, 2006), protein secretion, motility differentiation and infection in parasitic protozoa (Moreno and Docampo, 2003;Nagamune et al, 2007) and light emission in dinoflagellates (von Dassow and Latz, 2002). Hence, it would seem that four-domain Ca V s would be widespread in protozoa.…”

Ether-à-go-go family voltage-gated K+ channels evolved in an ancestral metazoan and functionally diversified in a cnidarian–bilaterian ancestor

“…The EAG gene family is comprised of three separate subfamilies classified by high intra-family sequence conservation: Eag, Erg and Elk Jegla et al, 2009). Each subfamily is present in vertebrates and protostome invertebrates, and members of each family have been identified in the genome of the starlet sea anemone Nematostella vectensis Martinson et al, 2014;Putnam et al, 2007), pointing to an origin prior to the cnidarian-bilaterian divergence.…”

“…Evidence that the Eag, Elk and Erg subfamilies are functionally independent includes the finding that although voltage-gated K + channels are tetrameric, co-assembly of subunits from distinct subfamilies does not occur (Wimmers et al, 2001;Zou et al, 2003). We have previously expressed Nematostella (sea anemone) Erg channel paralogs and demonstrated that an inactivating I Kr -like phenotype of Ether-à-go-go family voltage-gated K + channels evolved in an ancestral metazoan and functionally diversified in a cnidarianbilaterian ancestor mammalian Erg channels is the likely functional phenotype of Erg channels in the cnidarian-bilaterian ancestor (Martinson et al, 2014). Erg channels are specialized for delayed repolarization of broad action potentials and/or regulation of excitation threshold (Garcia and Sternberg, 2003;LeBoeuf and Garcia, 2012;Martinson et al, 2014;Sanguinetti and Tristani-Firouzi, 2006;Titus et al, 1997).…”