Cover Image


View/Hide Left Panel

(electric fish), in protection against lethal Nav channel toxins (snakes, newts, pufferfish, insects), and in specialized habitats (naked mole rats).

Multicellular animals evolved >650 million years ago (Love et al., 2009). The nervous system and muscles evolved shortly thereafter. The phylogeny of basal metazoans is poorly resolved, likely because of the rapid radiation of these then-new life-forms (Rokas et al., 2005), so depending on the phylogeny one embraces, the nervous system evolved once with a loss in sponges, or twice independently in ctenophora and bilateria + cnidaria or bilateria and cnidaria + ctenophora (Moroz, 2009; Schierwater et al., 2009). However, in all animals with nervous systems, neurons generate action potentials (APs), release excitatory and inhibitory neurotransmitters, form circuits, receive sensory input, innervate muscle, and direct behavior.

The history of brain evolution and its key neural genes would fill volumes. I will use voltage-dependent Na+ (Nav, Na-permeable voltage-dependent = protein; scn, sodium channel = gene) channels as an exemplar to tell this story because all neuronal excitability depends on Nav channels, there is a good understanding of their function and regulation from biophysical, biochemical, and modeling studies, and there are fascinating examples of ecologically relevant adaptations. An additional rationale is that although many proteins, such as immunoglobins, sperm and egg receptors, olfactory receptors, opsins, and surface proteins of pathogens, are routinely studied in the field of molecular evolution, only recently have ion channels begun to receive greater attention (Lopreato et al., 2001; Geffeney et al., 2005; Zakon et al., 2006, 2011; Arnegard et al., 2010; Liu et al., 2011); of these studies, the majority are on Nav channels.


Voltage-gated ion channels are the basis of electrical excitability of all animals and many single-celled eukaryotes. Potassium leak and voltage-dependent K+ (Kv) channels appeared 3 billion years ago in bacteria and occur in all organisms (Anderson and Greenberg, 2001) (Fig. 2.1). They establish resting potentials and repolarize membranes after excitatory events. Kv channels are the “founding members” of the family of ion-permeating channels whose basic structure is a protein of six transmembrane helices (6TM) that associate as tetramers to form a channel. At some point early in eukaryote evolution, the gene for a 6TM channel likely duplicated, giving rise to a protein with two domains. These proteins then dimerized to form a complete channel (Strong et al., 1993). Such a channel still exists in the two-pore channel family of Ca2+-permeable channels

The National Academies of Sciences, Engineering, and Medicine
500 Fifth St. N.W. | Washington, D.C. 20001

Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement