Evolution of voltage-gated Na+ channels
Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697-4025, USA
*e-mail: agoldin{at}uci.edu
Accepted 14 December 2001
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Summary |
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Key words: Na+ channel, cloning, phylogeny, evolution, diversity.
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Introduction |
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The Na+ channel consists of a highly processed subunit of approximately 260 kDa and contains four homologous domains termed IIV. Within each domain, there are six transmembrane segments called S1S6, and a hairpin-like P loop between S5 and S6 that comprises part of the channel pore (Fig. 1). The
subunit is associated with accessory subunits in the tissues of certain species, such as the ß subunits in mammals (Catterall, 1993
) and the tipE subunits in flies (Feng et al., 1995
). The purpose of this review is to examine the phylogenetic relationships among the different voltage-gated Na+ channels that have been identified thus far. The structure and functional characteristics of the isoforms will not be discussed in detail as these topics have recently been reviewed (Catterall, 2000
; Goldin, 2001
).
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More invertebrate Na+ channel genes have been identified, with 13 full-length sequences representing 11 species. However, more than one full-length sequence has been determined for only two invertebrate species, Blattella germanica and Halocynthia roretzi. Two sequences have been determined from Drosophila melanogaster, with one full-length (DmNav1) and one that is almost complete (DmNav2). Blackshaw et al. (1999) have attempted to identify all the Na+ channel genes in an invertebrate species, Hirudo medicinalis. They determined partial sequences for four distinct genes, and these sequences have been included in the analysis.
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Phylogeny of Na+ channels |
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It is likely that the Ca2+ channels evolved from the K+ channels during the evolution of the stem eukaryotes (Hille, 1989). Protozoans generally use Ca2+ as the inward charge carrier, and purely Na+-dependent action potentials are not common until the cnidarians (Hille, 1989
; Anderson and Greenberg, 2001
). Na+ channels have not been detected in protozoa, algae or higher plants (Hille, 1989
). According to this scenario, the Na+ channels evolved early in the metazoan era from an ancestral channel resembling the T-type (Cav3 family) Ca2+ channels, before the separation of diploblasts and triploblasts (Spafford et al., 1999
).
The four domains of the Na+ channel have more similarity to the four domains of the Ca2+ channels than to each other, further supporting the argument that Na+ channels evolved after the subunit duplications leading to the Ca2+ channels (Hille, 1989; Strong et al., 1993
). On the basis of sequence similarities, Strong et al. (1993
) suggested that the original duplication event resulted in a two-domain channel consisting of domains I/III and II/IV, each of which then duplicated to result in the first four-domain Ca2+ channel. In this context, it is interesting to note that no channels consisting of two homologous domains have been observed. In addition, no K+ channels with multiple homologous domains have been observed, suggesting either that there was strong selective pressure against this form of channel or that the selectivity change from K+ to Ca2+ occurred before the gene duplication event (Anderson and Greenberg, 2001
). The primordial Na+ channel then evolved from the Ca2+ channels, and this primordial Na+ channel subsequently evolved independently in vertebrates and invertebrates (Fig. 2) (Strong et al., 1993
).
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Evolution of vertebrate Na+ channels |
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The other mammalian Na+ channel genes that are clustered together are those encoding the Nav1.5, Nav1.8 and Nav1.9 isoforms. These genes are clustered on chromosome 9 in humans and the orthologous region of chromosome 3 in mice (Table 1). These isoforms also share functional characteristics, including the fact that they are all considered TTX-resistant Na+ channels, requiring micromolar concentrations of TTX before they are blocked. Although the gene for Nav1.9 is clustered on the chromosome with the other two genes, this channel appears to represent a distinct branch of the tree, and it may have evolved from a distinct ancestral Na+ channel gene (Plummer and Meisler, 1999).
The final two isoforms, Nav1.4 and Nav1.6, each represent a separate branch of the tree, and the genes encoding these channels are located on separate chromosomes. The gene for Nav1.4 is located on chromosome 11 in humans and chromosome 17 in mice, and the gene for Nav1.6 is located on chromosome 15 in humans and chromosome 12 in mice (Table 1). The properties of these two channels are generally similar to those of the channels expressed in the nervous system, including block by nanomolar concentrations of TTX. Nav1.6 is the most closely related channel to the branch containing the nervous system Na+ channels, and this isoform is also expressed in the nervous system. Nav1.4 is the primary channel expressed in adult skeletal muscle, and is unique in this regard.
Plummer et al. (1999) observed that each of the chromosome segments containing the Na+ channel genes represents one of the Hox gene clusters. They suggested that the initial expansion of the Na+ channel genes was associated with the genomic duplications that occurred after the divergence of prevertebrates from invertebrate chordates and resulted in the four mammalian Hox gene clusters. Later tandem duplications of the Na+ channel genes on chromosomes 2 and 9 in humans (chromosomes 2 and 3 in mice) resulted in the two clusters of Na+ channel genes. Nav1.9 was more distantly related to Nav1.5 and Nav1.8 in the analysis of Plummer et al. (1999), and it appears on a separate branch in the current analysis (Fig. 2). Plummer et al. (1999) hypothesized that the ancestral chromosome might have had two Na+ channel genes, one that represented the ancestor of Nav1.9 and a second that represented the ancestor of the other mammalian Na+ channels. This model assumes that the ancestor of Nav1.9 was subsequently lost from three of the four chromosome segments.
The analysis of the non-mammalian vertebrate Na+ channels that have been characterized thus far is consistent with that of the mammalian channels and provides further information about the timing of the duplication events. The most informative data were obtained by Lopreato et al. (2001), who cloned partial sequences for six separate isoforms from the teleost fish Sternopygus macrurus. These sequences probably represent all the Na+ channels in that species. As pointed out by Lopreato et al. (2001
), these isoforms align well with the branches of the mammalian channels (Fig. 2). SmNav3 and SmNav4 are in the branch with Nav1.1, SmNav5 aligns with Nav1.6, and SmNav1 and SmNav6 are in the branch with Nav1.4. SmNav2 forms a distinct branch of its own, although it is more closely related to Nav1.5 and Nav1.8 than to the other Na+ channel isoforms. SmNav2 was located on a branch with Nav1.5, Nav1.8 and Nav1.9 in the analysis of Lopreato et al. (2001
). This branching pattern is not as robust as that for the other vertebrate channels though, because it is based on partial sequence data. Lopreato et al. (2001
) suggested that the initial Na+ channel duplication into four genes occurred early in vertebrate history close to the emergence of the first vertebrates, so that a common ancestor of mammals and teleost fish already had four distinct genes. This hypothesis is consistent with the conclusions of Plummer et al. (1999). The duplications occurred as an initial event leading to two pairs of Hox genes, each of which then duplicated to result in the four clusters that are now present. These initial chromosomal duplications were then followed by tandem duplications, as suggested by Plummer et al. (1999), and these duplications were independent in teleosts and mammals. The relationships between the mammalian and teleost genes shown in Fig. 2 are supported by the corresponding tissue expression patterns of the mammalian and teleost channels encoded within each cluster (Lopreato et al., 2001
).
An additional means of generating diversity in Na+ channels is through post-transcriptional processing, including alternative splicing and RNA editing. Alternative splicing has been demonstrated for five isoforms present in the mammalian nervous system, Nav1.1, Nav1.2, Nav1.3, Nav1.6 and Nav1.7 (Ahmed et al., 1990; Sarao et al., 1991
; Schaller et al., 1992
; Gustafson et al., 1993
; Belcher et al., 1995
; Plummer et al., 1997
, 1998
; Dietrich et al., 1998
; Oh and Waxman, 1998
). The proportion of differentially spliced transcripts depends on various factors, including age of development, the tissue of origin and the presence of modulatory agents such as dibutyryl cyclic AMP (Gustafson et al., 1993
; Plummer et al., 1997
; Dietrich et al., 1998
; Oh and Waxman, 1998
). However, electrophysiological differences resulting from alternative splicing have only been demonstrated for two alternatively spliced forms of Nav1.6 (Dietrich et al., 1998
), so it is not clear how much functional diversity in mammalian Na+ channels results from alternative splicing. No alternative splicing has been demonstrated for non-mammalian vertebrate Na+ channels, and no RNA editing has been demonstrated for any vertebrate Na+ channels. This is in contrast to the situation with the invertebrate Na+ channels, which will be discussed below.
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Evolution of invertebrate Na+ channels |
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It is difficult to evaluate the functional significance of the two branches of invertebrate Na+ channels. Functional expression has been reported for only three channels, DmNav1 (Feng et al., 1995), MdNav1 (Smith et al., 1997
) and BgNav1 (Tan et al., 2001
; Liu et al., 2001b
), and all these channels are in the same branch of the phylogenetic tree. However, K. Dong and colleagues have preliminary evidence for functional expression of the BgNav2 channel (K. Dong, personal communication). They suggest that the properties of this channel are so unique that it is questionable whether it should be considered a voltage-gated Na+ channel. If BgNav2 does not represent a true voltage-gated Na+ channel, it would suggest that there is only one branch of voltage-gated Na+ channels in invertebrates and that the second branch has diverged to the point that these channels carry out unique functions. If this is the case, then the functional diversity of Na+ channels in many, if not most, invertebrate species would have to result from post-transcriptional regulatory events, as suggested by Liu et al. (2001a
), unless additional Na+ channel genes remain to be discovered in these species.
The two major post-transcriptional processes that would increase Na+ channel diversity are alternative splicing and RNA editing. Alternative splicing of Na+ channels has been shown to occur in two invertebrate species, Drosophila melanogaster (Loughney et al., 1989; Thackeray and Ganetzky, 1995
) and Blattella germanica (Liu et al., 2001a
). Spafford et al. (1999
) pointed out that 85 % of the intron splice junctions in a jellyfish Na+ channel (PpNav1) are also found in mammalian Na+ channels with similar locations, suggesting that the positions of the introns within the coding regions have been retained from a common ancestor. However, no alternatively spliced variants were detected in PpNav1, suggesting that alternative splicing was not a primordial means of generating diversity in Na+ channels. RNA editing has been demonstrated for some invertebrate Na+ channels, including DmNav1 from Drosophila melanogaster (Hanrahan et al., 2000
; Reenan, 2001
). Hanrahan et al. (2000
) observed that two of the three characterized RNA editing sites in Drosophila melanogaster are also conserved in Drosophila virilis, suggesting that this process has been maintained throughout the 6165 million years of divergence between these two species.
Considering the fact that invertebrate species appear to have only 24 Na+ channel genes, in contrast to the nine mammalian genes, it is likely that invertebrates and vertebrates use fundamentally different means of generating diversity in Na+ channel function. The major means of generating diversity in invertebrate Na+ channels may involve alternative splicing and RNA editing, whereas vertebrate Na+ channel diversity may result primarily from the presence of multiple genes.
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Concluding remarks |
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Acknowledgments |
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References |
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