Abstract
Four-domain voltage-gated cation channels (FVCCs) represent a large family of pseudo-tetrameric ion channels which includes voltage-gated calcium (Cav) and sodium (Nav) channels, as well as their homologues. These transmembrane proteins are involved in a wide range of physiological processes, such as membrane excitability, rhythmical activity, intracellular signalling, etc. Information about actual diversity and phylogenetic relationships of FVCCs across the eukaryotic tree of life is scarce. We for the first time performed a taxonomically broad phylogenetic analysis of 277 FVCC sequences from a variety of eukaryotes and showed that many groups of eukaryotic organisms have their own clades of FVCCs. Moreover, the number of FVCC lineages in several groups of unicellular eukaryotes is comparable to that in animals. Based on the primary structure of FVCC sequences, we characterised their functional determinants (selectivity filter, voltage sensor, Nav-like inactivation gates, Cavβ-interaction motif, and calmodulin-binding region) and mapped them on the obtained phylogeny. This allowed uncovering of lineage-specific structural gains and losses in the course of FVCC evolution and identification of ancient structural features of these channels. Our results indicate that the ancestral FVCC was voltage-sensitive, possessed a Cav-like selectivity filter, Nav-like inactivation gates, calmodulin-binding motifs and did not bear the structure for Cavβ-binding.
Highlights
Four-domain voltage-gated cation channels (FVCCs) represent a family of ion channels of eukaryotes which belongs to the large and ancient voltage-gated cation channel superfamily[1]
Phylogenetic analysis showed that actual diversity of FVCCs is very complex and not limited to five conventional genetic subfamilies
The results indicate that many groups of eukaryotes possess their own clades of four-domain channels which do not cluster with Nav, HVA Cav, LVA Cav, NALCN, or Cch
Summary
Four-domain voltage-gated cation channels (FVCCs) represent a family of ion channels of eukaryotes which belongs to the large and ancient voltage-gated cation channel superfamily[1]. It should be noted that characterised channels from all these subfamilies, except fungal Cch, are Metazoa-specific, and little is known about FVCCs of other eukaryotic groups. Metazoan HVA and LVA Cav channels are thought to be more ancient than Nav, since four-domain voltage-gated calcium channels are present in eukaryotic lineages distant from Metazoa, such as green algae and ciliates[7]. There is no evidence of a close phylogenetic relationship between metazoan Cav and voltage-gated calcium channels of protists, with the only exception of FVCCs of choanoflagellates (the sister group to Metazoa) which are closely related to metazoan HVA Cav[8]. Phylogenetic analysis of two other subfamilies of FVCCs – NALCN of metazoans and Cch of fungi – revealed that both subfamilies form a single clade of opisthokont voltage-insensitive channels[8]. Many structures of FVCCs, such as segments S4, selectivity filter, inactivation gates, etc., are critical determinants of their functional activity, but the order of acquisition and evolution of these structures still have to be elucidated
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