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, 108 (22), 9154-9

Evolution of Sodium Channels Predates the Origin of Nervous Systems in Animals

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Evolution of Sodium Channels Predates the Origin of Nervous Systems in Animals

Benjamin J Liebeskind et al. Proc Natl Acad Sci U S A.

Abstract

Voltage-dependent sodium channels are believed to have evolved from calcium channels at the origin of the nervous system. A search of the genome of a single-celled choanoflagellate (the sister group of animals) identified a gene that is homologous to animal sodium channels and has a putative ion selectivity filter intermediate between calcium and sodium channels. Searches of a wide variety of animal genomes, including representatives of each basal lineage, revealed that similar homologs were retained in most lineages. One of these, the Placozoa, does not possess a nervous system. We cloned and sequenced the full choanoflagellate channel and parts of two placozoan channels from mRNA, showing that they are expressed. Phylogenetic analysis clusters the genes for these channels with other known sodium channels. From this phylogeny we infer ancestral states of the ion selectivity filter and show that this state has been retained in the choanoflagellate and placozoan channels. We also identify key gene duplications and losses and show convergent amino acid replacements at important points along the animal lineage.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Hypothetical secondary structure of a sodium-channel protein. (Top) Transmembrane domains (DI–DIV), their component segments (S1–S6), and their connecting loops (in white). The pore loops (P loop), which dip down into the membrane, form the ion-selectivity filter. The inactivation gate resides on the long loop between DIII/S6 and DIV/S1. (Middle) How the domains cluster to form the protein and its pore. (Bottom) Fine structure of one of the domains with the pore loop in the foreground. The black dots on the pore loops in the Top and Bottom represent the location of the amino acids, which makes up the pore motif.
Fig. 2.
Fig. 2.
Maximum likelihood phylogeny of Nav and Cav channels. Bootstrap scores are indicated on branches, with stars indicating scores of 100%. Clades corresponding to major ion channel groups are detailed on the Right.
Fig. 3.
Fig. 3.
Phylogeny of Nav channels with key amino acid sequences mapped to their corresponding taxa. Taxa are color coded the same as in Fig. 2. The amino acids are alignments of the pore loops of all four domains (DI–DIV) and the critical inactivation particle on the inactivation gate. The critical amino acids in the pore are indicated by the vertical lines, and there are red stars next to convergent lysines (red K). Note the functional conservation of the hydrophobic triplet called the “inactivation particle” (first three amino acids on the inactivation gate).
Fig. 4.
Fig. 4.
Simplified gene tree of the Nav family showing inferred ancestral states of the pore motifs. The gene duplication leading to the bilaterian Nav 1 and Nav 2 clades is noted, as are the points where we reconstruct fixation of lysines (K) in pore loops. Taxonomic information and information about the nervous system is also given. The Nematostella β and Trichoplax β genes have been left out for simplicity, but their addition would not change the proposed ancestral states. Pore states for both Mnemiopsis genes are shown because neither has a complete pore motif.

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