The ether-a-go-go gene (EAG) family is a relative novel group of K+– channels, which belong to an increasing number of cloned KV channels. Its first member was cloned in 1991 from a mutant of Drosophila melanogaster, and was characterized by a leg-shaking behavior when the fruitflies were anesthetized with ether1,2. Since 1994, different mammalian homologs of the Drosophila EAG channels have been cloned3,4.
EAG channels belong to the family of Shaker-related K+-channels, composed of four subunits, each of which consists of six putative transmembrane-spanning domains and K+-selective pore (P region). Two unique characteristics typical of the EAG channels family are: a signature sequence (GFGN) in the P region, that is different from that of other K+-channels (GYGD) and the presence of a cyclic nucleotide binding domain (cNBD) within the cytoplasmic part of the carboxyl terminal4.
On the basis of structural homologies, three different EAG subfamilies have been distinguished: ether-a-go-go gene (Eag), eag-like (Elk), and eag-related gene (Erg) K+ channels. Studies clearly demonstrated that the gating kinetics, as well as other properties are distinct from those of other K+ currents4.
The functions of Erg-mediated K+ currents have best been characterized in various native cells and found unusual insofar as its current shows a form of inward rectification apparently similar to that of inward rectifier K+-channels (two transmembrane segments), but has six putative transmembrane segments typical of depolarization-activated K+-channels5. ERG currents that are induced by a large depolarization potential are highly voltage dependent in their activation and inactivation kinetics and are followed (upon termination of the depolarization pulse) by a large slowly deactivating tail current.
Tail outward current is functionally important for the fast repolarization of the cardiac action potential4. The Erg channels can be selectively blocked by class III antiarrhythrmic substances such as the methanesulfonanildes E-4031 (#E-500) and WAY-123,398. The Erg currents are also blocked by some antipsychotics (such as Haloperidol, Sertindole and Pimozide) and also by histamine-receptor antagonists (such as Terfenadine), tricyclic depressants and some antibiotics4,6. Recently, two peptides were discovered to be specific blockers of the Erg channels. Ergtoxin-1 (#STE-450) from the Centruroides noxius Hoffmann scorpion, which specifically blocks the ERG channels in nerve, heart and endocrine cells, and is unable to block other K+-channels, including the most closely related EAG channel5,6,7 and BeKm-1 (#STB-470) from the Buthus eupeus scorpion, which specifically blocks the hERG1 channel with potency 5 times higher than that of the previously reported Ergtoxin9,10.
The ether-a-go-go gene (EAG) K+-channel was initially suggested to contribute to the mammalian M-channel underlying the native M-current in neurons. Later, heteromeric KCNQ2/KCNQ3 channels were demonstrated to contribute to the native M-current. The M-like current described in NG108-15 cells has been reported to contain “slow” and a “fast” component, and postulated to be carried by KCNQ2/KCNQ3 and channels encoded by the mouse ether-a-go-go-related gene (mERG1), respectively10,11.
In heart, both KCNQ1 (KvLQT1) channels (Iks, slow Ik) and KCNH2 (ERG1) channels (Ikr, rapid Ik) play significant roles in the repolarization of the cardiac action potential. Mutations in either channel gene result in a prolongation of the QT-interval on the electrocardiogram and give rise to long QT (LQT) syndrome. LQT syndrome is a disorder that may cause syncope and sudden death resulting from episodic ventricular arrhythmias of the torsades de pointes-types and ventricular fibrillation. Inherited LQT type 2 results from mutations in the human ERG1 (KCNH2)10,12, and they are the most common known cause of the LQT Syndrome13.
Several indications suggest that hERG channel has regulatory β subunits. The first came from a study on mouse atrial cell line (AT-1 cell), in which the major outward current is Ikr. Treating the cells with anti-sense oligonucleotides against minK (IsK), reduces the Ikr current amplitude. Furthermore, in homozygous minK knockout mouse myocytes, the Ikr amplitude and the deactivation rate are significantly smaller14. In 1999, three gene families that encode minK-related peptides (MiRPs) were identified (known also as IsK-related auxiliary subunits). These MiRPs, along with minK, constitute four KCNE families (KCNE1 to KCNE4, encoding minK and MiRP1 to MiRP3)3.
MiRP1 mutations that are linked to congenital (LQT6) or aquired LQT syndrome have been identified. However, currently there is no biochemical evidence supporting an association between native MiRP1 and hERG proteins in cardiac myocytes15. MiRP2 has been shown to decrease the single channel conductance and accelerates the rate of HERG channel deactivation13 and to suppress the expression of hERG in oocytes, suggesting another β subunit that can potentially modulate the hERG channel function14.
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