The first member of the Eag family was cloned in Drosophila melanogaster in 19915, 6. The mutants in its gene, ether-a-go-go, were characterized by a leg-shaking behavior when the flies were anesthetized with ether. Since then, several mammalian homologs of Eag channel have been cloned1, 20. Structurally, Eag family channels belong to the family of Shaker-related K+ channels, containing 6 TM domains and K+ -selective pore. In addition, the members of this family contain cyclic nucleotide binding domain, characteristic to cyclic nucleotide-activated protein kinases, as well as to cyclic nucleotide gated cation channels (CNG) and HCN channels. In contrast to the latter two groups, however, Eag family channels are specific to K+. At the N-terminus, all members of Eag family contain a unique conservative domain, called “eag domain”. The 3-D structure of eag domain, revealed by X-ray crystallography, showed that it belongs to so-called “PAS domain” family10. PAS domains are involved in the interaction with other proteins11, however, the counterparts of the interaction with Eag family channels are yet unknown.
On basis of structural homologies, the Eag family can be subdivided into three subfamilies: ether-a-go-go (Eag), Eag-like (Elk), and Eag-related (Erg).
The proper ties of different mammalian Eag channels are summarized in Table 1. This review will concentrate on Erg channels.
Erg channels provide very distinct current characteristics (see reviewed in 20).
In contrast to the classical Kv channels, a large depolarization potential induces a small transient outward current that quickly declines to a steady state.
However, a large transient outward current is elicited upon repolarization. This phenomenon has been explained by the inverse gating kinetic compared to classical Kv channels: inactivation faster then the activation rate and recovery from inactivation faster then deactivation15.
Erg channels can be selectively blocked by class III antiarrhythmic drugs such as the methanesulfanylamides E-4031 and WAY-123, 398. An Erg-specific toxin from a scorpion Centruroides noxius has been recently described5, 23.
During the plateau phase of the cardiac action potential, two different outward currents are activated, the rapidly (IKr) and slowly (IKs) activating delayed rectifying K+ channels. IKs is mediated by KvLQT1 channel, assembled with its auxiliary subunit, IsK (minK) . IKr is mediated by Erg1 (HERG) channel. Mutations in Erg1 gene (KCNH2) are characterized by a prolongation of the heart action potential. The inherited disease is characterized by a prolonged Q-T interval (LQT2 syndrome)8. The functional consequence of this mutation is an increased tendency to cardiac arrhythmias and torsade de pointes, which eventually lead to sudden death. Similar symptoms occur as side effects during treatment of heart disease with type III antiarrhythmic drugs, or as cardiac side effects of some neuroleptics, like haloperidol or histamine-receptor antagonists like terfenadine. All these agents have been shown to block Erg channels (reviewed in 7).
Besides its cardiac function, other functions have been suggested for Erg channels. Erg1 channel is expressed in tumors of different histogenesis, providing the inward rectifier current, responsible for keeping the resting potential within the depolarized value, necessary for unlimited tumor growth19. Erg1-3 are expressed in nervous system, providing some role for them in neurons. In Drosophila, the mutations in HERG homolog, seizure, lead to temperature-sensitive hyperexcitability21,22. In humans, the homozygous truncation of Erg1 channel did not lead to detectable malfunction in any other organ except heart18.
Recently, a new group of IsK-related auxiliary subunits, called MiRP1-3, has been cloned2,3. One of them, MiRP1, assembles with Erg1, thus forming the channels that resemble IKr channels more than with Erg1 alone3. Mutations in MiRP1 gene (KCNE2) lead to different forms of cardiac arrhythmia (LQT6 syndrome)3.
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