Evolution of Voltage Gated Sodium Channels

Added 3/25/06: Jason Rosenhouse has an excellent summary and discussion of the PNAS paper this refers to over at The Panda’s Thumb. Just for kicks here is a link to ID the Future’s grotesque caricature of the paper…
Science Daily has an interesting story on the convergent evolution of electric organs in African and South American species of fish. The electric organs evolved via mutations of genes for sodium channel proteins. According to the article, the electric organs arose via duplication of one of the genes for sodium channels:

“The spare gene gave [the electric fish] a little bit of evolutionary leeway,” says Zakon, professor of neurobiology. “This is really one of the first cases that the ancestral gene duplication in fish has actually been linked to a gene that has been freed up and evolving in accordance with a ‘new lifestyle.'”
Zakon and colleagues looked at two sodium channel genes in the electric organs and muscles in electric and non-electric fish. Electric fish use their electric organs, which are modified muscles, to communicate with each other and sense their environment.
The researchers found that electric fishes expressed one of the sodium channel genes in their electric organs only, while non-electric fish express both genes in their muscles.

This is actually an outgrowth of previous research on the subject. But before going further a little background is in order. Cell membranes can allow small nonpolar – such as O2 – and uncharged polar molecules – urea, for example – to diffuse across the lipid bilayer.
On the other hand, they are relatively impermeable to charged molecules such as sodium, potassium and calcium. Consequently, some other method of getting across the bilayer is needed. This is accompliched through to main classes of transport proteins. Carrier proteins and channel proteins. Here we are concerned with channel proteins in two main ways. First, they show ion selectivity, that is they permit some ions to pass but not others. Second, ion channels are not continuously open, rather they have gates at one end that open and close as a response to specific stimuli. There are several different classes of gated channels, voltage gated, mechanically gated and ligand gated for example. The sodium channel is part of a larger superfamily that includes K+, Ca2+, and cyclic nucleotide gated channels. There is some evidence that the Ca2+ channels evolved from the K+ channels (via two rounds of gene duplication) and that the sodium (Na+) channels evolved from the Ca2+ channels. Interestingly enough, the appearance of Na+ channels coincides with the appearance metazoans with specialized neurons. I should mention at this point that channel proteins allow ions to cross the lipid bilayer at rates about 1,000 times higher than carrier proteins. Sodium channels are composed of two subunits – the alpha and beta.
Each channel, as you can see from the picture above, is composed of four repeating alpha units and a variable number of beta units. You will also note the lines, on top, connecting each alpha unit which go through an orange colored ball (which I will get back to later). Whearas, invertebrates have only a few genes for sodium channels, ten have been identified in mammals. In humans all ten sodium channel genes reside in clusters on four chromosomes. Below is a phylogenetic analysis of sodium channel genes in humans, rats and the elctric fish Sternopygus macrurus
(Legend: Mammalian Na+ channel genes are in colored blocks; genes on the same chromosome are the same color. Sternopygus Na+ channel genes are underlined with the color used for their mammalian orthologs. To the right of the tree are boxes indicating the Hox gene cluster with which each mammalian Na+ channel gene is linked as well as the main tissue in which these genes are expressed.)
Note there are four clusters. In each cluster rat, human and electric fish genes all share similar function (are orthologues). Coincidently, there are four clusters of Hox genes in mammals and since sodium channel genes seem to be linked to Hox gene clusters they can be used to test various scenarios for their evolution (that, however, would take a post of its own so I won’t go into here. Consult the paper linked to above and references therein for more – especially Amores et al).
I mentioned the orange ball in the diagram of the sodium channel (see above). This is the binding site for TTX (and related toxins) most famously found in puffer fish. Here is another view:
Tetrodotoxin binds to this site and closes the channel causing respiratory paralysis and death. If you look at the phylogentic analysis above, you will notice a cluster (the very top) with “rNav1.5, rNav1.9 and hNav1.9”. These genes confer a certain amount of resistence to tetrodotoxin. In Nav1.5, for example, a single amino acid change (from phenylalanine to cysteine in domain one, see pict above for location of domain one) confers a 200 fold reduction in sensitivity to TTX. At the corresponding positions in Nav1.8 and Nav1.9 phenylalanine is replaced with serine confering even greater resistance (both of which provide great counterexamples to Dembskis’ obfusticatory and misleading Searching Large Spaces paper, and incidently confirm that, contra ID, increase in information can be generated via mutation and selection). More on the subject of toxin resistance here.


5 Responses

  1. Thanks for a very cool and informative post. I’m currently attempting to get the hang of this sort of stuff (am considering applying for a computational biology MPhil) – can you recommend a textbook?

  2. I wish I could…I’m still trying to get the hang of it myself. For the evo-devo parts I would Wolpert et als’ Principles of Development. For the genomics and metazoan evolution parts I’m stumped…for cellular biology you can do no better than Alberts et al’s Molecular Biology of the Cell…

  3. Cheers, will get book-hunting (and I’ll bring to your attention any other good ones I come across :))

  4. You should also check out the definitive book in ion channel electrophysiology: Ion Channels of Excitable Membranes by Bertil Hille.

  5. Looks like there are some affordable used editions so I may have to buy me a copy…

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