Differential evolution of voltage-gated sodium channels in tetrapods and teleost fishes
Open accessAbstract
The voltage-gated sodium channel (SCN) alpha subunits are large proteins with central roles in the generation of action potentials. They consist of approximately 2,000 amino acids encoded by 24-27 exons. Previous evolutionary studies have been unable to reconcile the proposed gene duplication schemes with the species distribution and molecular phylogeny of the genes. We have carefully annotated the complete SCN gene sequences, correcting numerous database errors, for a broad range of vertebrate species and analyzed their phylogenetic relationships. We have also compared the chromosomal positions of the SCN genes relative to adjacent gene families. Our studies show that the ancestor of the vertebrates probably had a single sodium channel gene with two characteristic AT-AC introns, the second of which is unique to vertebrate SCN genes. This ancestral gene, located close to a HOX gene cluster, was quadrupled along with HOX in the two rounds of basal vertebrate tetraploidizations to generate the ancestors of the four channels SCN1A, SCN4A, SCN5A, and SCN8A. The third tetraploidization in the teleost fish ancestor doubled this set of genes and all eight are still present in at least three of four investigated teleost fish genomes. In tetrapods, the gene family expanded by local duplications before the radiation of amniotes, generating the cluster SCN5A, SCN10A, and SCN11A on one chromosome and the cluster SCN1A, SCN2A, SCN3A, and SCN9A on a different chromosome. In eutherian mammals, a tenth gene, SCN7A, arose in a local duplication in the SCN1A gene cluster. The SCN7A gene has undergone rapid evolution and has lost the ability to cause action potentials-instead, it functions as a sodium sensor. The three genes in the SCN5A cluster were translocated from the HOX-bearing chromosome in a mammalian ancestor along with several adjacent genes. This evolutionary scenario is supported by the adjacent TGF-β receptor superfamily (comprised of five distinct families) and the cysteine-serine-rich nuclear protein gene family as well as the HOX clusters. The independent expansions of the SCN repertoires in tetrapods and teleosts suggest that the functional diversification may differ between the two lineages.
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The ten human voltage-gated sodium channels derive from this ancestral NaV1 channel, and different model organisms reflect stages in this differentiation.
“The ten voltage-gated sodium channels in humans are derived from this NaV1 channel (Figure 3) [45–47] with different model organisms reflecting stages in this differentiation (Table 3).”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [45]
The Abstract and Discussion (pages unavailable) trace the human SCN gene family to a single ancestral vertebrate gene and compare duplications across vertebrate lineages, supporting the evolutionary account. But the Introduction says the tenth human gene, SCN7A, produces Naₓ, which is not voltage-gated; the source therefore does not support calling all ten human channels voltage-gated. (LLM, conf=0.88)
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Progress in Understanding and Treating SCN2A-Mediated Disorders
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“A series of gene duplication and differentiation events give rise to the ten channels seen in humans and reflected in the proximity of similar channels in the genome [45,46].”
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- Authors
- Widmark, J., Sundstrom, G., Ocampo Daza, D., & Larhammar, D.
- Affiliations
- Uppsala University (SE)
- Corresponding author
- Larhammar, D.
- ORCID
- Larhammar, D.
- Venue
- Molecular Biology and Evolution
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-10-05
- Volume
- 28
- Issue
- 1
- Pages
- 859-871
- ISSN
- 0737-4038 (ISSN-L)
- 1537-1719
- OpenAlex
- W2106355394
- Cited by
- 88
- References
- 53
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 7 · 2022: 8 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 7 · 2017: 6 · 2016: 3 · 2015: 9 · 2014: 7 · 2013: 11 · 2012: 12
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Biology and Evolution (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Carl Tryggers Stiftelse för Vetenskaplig Forskning
- Vetenskapsrådet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- voltage-gated sodium channels, gene family evolution, gene duplication, tetrapod evolution, teleost evolution, vertebrate genome evolution, tetraploidization, action potential, Hox gene clusters, chromosomal translocation, SCN1A, SCN5A, SCN8A, SCN10A, SCN11A, SCN2A, SCN3A, SCN9A, SCN4A
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Biological Evolution, Fishes, Multigene Family, Humans, Models, Molecular, Molecular Sequence Data, Phylogeny, Protein Conformation, Sodium Channels, Sequence Alignment, Evolution, Molecular, Protein Isoforms, Protein Subunits
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