For instance, knockout of the EAG family K + channel Kv12.2 in mice reduces sub-threshold K + current and lowers action potential threshold in hippocampal pyramidal neurons ( Zhang et al., 2010). Genetic deletion or pharmacological block of various EAG family channels demonstrates that they have significant influence on excitation threshold. Ether-à-go-go (EAG) family K + channels make significant contributions to sub-threshold K + currents in mammalian neurons, but their specific physiological roles are not yet fully understood. Therefore, the responsiveness of a neuron to incoming stimuli can be tuned by regulation of sub-threshold K + conductance. Inward currents produced by excitatory stimuli must overcome outward K + flux through these channels to effectively excite a neuron. Sub-threshold voltage-gated K + channels have a strong influence on neuronal excitability because they prevent small stimuli from eliciting action potentials. Most notable is the expression of NvEag in cnidocytes, a cnidarian-specific stinging cell thought to be a neuronal subtype. mRNA in situ hybridization of EAG channels in Nematostella suggests that they are differentially expressed in distinct cell types. This mutation may preserve sub-threshold activation of Nematostella Eag and Erg channels in a high divalent cation environment. However, characteristic inhibition of voltage activation by Mg 2+ in Eag channels and Ca 2+ in Erg channels is reduced in Nematostella because of mutation of a highly conserved aspartate residue in the voltage sensor. Potent inhibition of voltage activation by extracellular protons is conserved between mammalian and Nematostella EAG channels. NvEag, like bilaterian Eag channels, has rapid kinetics, whereas NvElk activates at extremely hyperpolarized voltages, which is characteristic of Elk channels.

Here we show that Eag and Elk channels from the sea anemone Nematostella vectensis (NvEag and NvElk) also share high functional conservation with mammalian channels. Erg channel function is highly conserved between cnidarians and mammals.

However, phylogenetic analysis including two EAG family channels from the ctenophore Mnemiopsis leidyi indicates that the diversification of the Eag, Erg and Elk gene subfamilies occurred in a cnidarian/bilaterian ancestor after divergence from ctenophores. Searches of genome sequence indicate that EAG channels are metazoan specific, appearing first in ctenophores. The bilaterian EAG family comprises three gene subfamilies (Eag, Erg and Elk) distinguished by sequence conservation and functional properties. We examined the evolutionary origins of the ether-à-go-go (EAG) family of voltage-gated K + channels, which have a strong influence on the excitability of neurons.

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