Abstract
BackgroundAction potential generation in excitable cells such as myocytes and neurons critically depends on voltage-gated sodium channels. In mammals, sodium channels exist as macromolecular complexes that include a pore-forming alpha subunit and 1 or more modulatory beta subunits. Although alpha subunit genes have been cloned from diverse metazoans including flies, jellyfish, and humans, beta subunits have not previously been identified in any non-mammalian species. To gain further insight into the evolution of electrical signaling in vertebrates, we investigated beta subunit genes in the teleost Danio rerio (zebrafish).ResultsWe identified and cloned single zebrafish gene homologs for beta1-beta3 (zbeta1-zbeta3) and duplicate genes for beta4 (zbeta4.1, zbeta4.2). Sodium channel beta subunit loci are similarly organized in fish and mammalian genomes. Unlike their mammalian counterparts, zbeta1 and zbeta2 subunit genes display extensive alternative splicing. Zebrafish beta subunit genes and their splice variants are differentially-expressed in excitable tissues, indicating tissue-specific regulation of zbeta1-4 expression and splicing. Co-expression of the genes encoding zbeta1 and the zebrafish sodium channel alpha subunit Nav1.5 in Chinese Hamster Ovary cells increased sodium current and altered channel gating, demonstrating functional interactions between zebrafish alpha and beta subunits. Analysis of the synteny and phylogeny of mammalian, teleost, amphibian, and avian beta subunit and related genes indicated that all extant vertebrate beta subunits are orthologous, that beta2/beta4 and beta1/beta3 share common ancestry, and that beta subunits are closely related to other proteins sharing the V-type immunoglobulin domain structure. Vertebrate sodium channel beta subunit genes were not identified in the genomes of invertebrate chordates and are unrelated to known subunits of the para sodium channel in Drosophila.ConclusionThe identification of conserved orthologs to all 4 voltage-gated sodium channel beta subunit genes in zebrafish and the lack of evidence for beta subunit genes in invertebrate chordates together indicate that this gene family emerged early in vertebrate evolution, prior to the divergence of teleosts and tetrapods. The evolutionary history of sodium channel beta subunits suggests that these genes may have played a key role in the diversification and specialization of electrical signaling in early vertebrates.
Highlights
Action potential generation in excitable cells such as myocytes and neurons critically depends on voltage-gated sodium channels
Coordinated electrical signals in the metazoan nervous system, heart, and skeletal muscle depend on the generation of action potentials, rapid changes in membrane potential mediated by the passage of ions through voltage-gated ion channels [1]
Zebrafish β subunit genes and their splice variants are differentially-expressed in excitable tissues, and co-expression of zβ1 with the zebrafish sodium channel α subunit gene zscn5a in Chinese Hamster Ovary (CHO) cells demonstrated functional α-β interactions that we predict may occur in native tissues
Summary
Action potential generation in excitable cells such as myocytes and neurons critically depends on voltage-gated sodium channels. Sodium channels exist as macromolecular complexes that include a pore-forming alpha subunit and 1 or more modulatory beta subunits. Coordinated electrical signals in the metazoan nervous system, heart, and skeletal muscle depend on the generation of action potentials, rapid changes in membrane potential mediated by the passage of ions through voltage-gated ion channels [1]. Voltage-gated sodium channels are multiprotein complexes that include a pore-forming α subunit and 1 or more modulatory β subunits [5,6,7,8,9]. The unique expression profiles of each β subunit gene and their variable effects on α subunit function, expression, and localization suggest that different subunit combinations in heart, brain, and muscle may contribute to diversity and specialization in electrical signaling [18,19]
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