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The ether-a-go-go Related Gene (erg) Voltage-Gated K+ Channels: A Common Structure With Uncommon Characteristics

The erg or KV11 (according to the new nomenclature) is a subfamily of the voltage dependent K+ channel superfamily and includes three members: KV11.1 (erg1), KV11.2 (erg2) and KV11.3 (erg3) channels. The most studied member of this subfamily is KV11.1 that regulates the duration of the cardiac action potential. Mutations in this channel have been associated with cardiac arrhythmias and sudden death. The physiological functions of KV11.2 and KV11.3 are less well understood. A brief description of the characteristics of the three channels will follow below.


K+ channels are the largest and most diverse group of ion channels and include about 70 different genes. Among them, the voltage-gated K+ group stands out with 40 different genes.

The ether-a-go-go (eag) K+ channel family was identified in Drosophila melanogaster in mutagenesis experiments.1 The search for mammalian homologues lead to the identification of three structurally similar K+ channel families: the eag (KV10) with two members, the eag-related channels (erg or KV11) and the eag-like K+ channels (elk or KV12) with three members each.2

The KV11 channels share a sequence homology of about 60% at the amino acid level and a higher degree of conservation between species (i.e. the rat KV11 isoform is 95% identical to the human counterpart).

The KV11 erg channel subfamily is by far the most studied of the three eag families. This is due in large part to the discovery that KV11.1 is the molecular underlay of some forms of cardiac arrhythmias associated with sudden death (see below).3,4

This article summarizes findings regarding structure and function of the three members of the erg K+ channel subfamily including the less studied KV11.2 (erg2) and KV11.3 (erg3) channels (see Table 1).

Table 1. KV11 Channel Subfamily Nomenclature and Tissue Distribution

Structural Characteristics

The KV11 subfamily channels possess the signature structure of the voltage-dependent K+ channels: six membrane-spanning domains with intracellular N and C termini and a voltage sensor in the 4thtransmembrane domain.

Despite the structural similarity with the voltage-gated K+ superfamily the KV11 subfamily has some distinct characteristics. For example, the cytosolic N-terminus of all KV11 subfamily members includes a Per-Arnt-Sim (PAS) domain.5 The PAS domain has been identified in a large number of proteins expressed in plant, bacteria and eukaryotic cells. The PAS domain is involved in several transduction mechanisms triggered in response to environmental clues such as oxygen, light and redox potential. A protein with a PAS domain relays the stimulus input by binding to another protein that similarly expresses a PAS domain and inducing a conformational change in this second protein. Aside from the KV11 subfamily members, proteins that express the PAS domain include the mammalian CLOCK and Per proteins that are transcription factors involved in circadian regulation and the HIF transcription factors that regulate the cellular response to hypoxia, among others.6

The functional significance of the presence of a PAS domain in the N-terminus of the KV11 subfamily members is not clear. However, in the case of the KV11.1 channel mutations in the PAS domain region have been associated with defective channel deactivation and intracellular trafficking defects (see also below). Whether the PAS-expressing KV11 proteins can bind to other proteins expressing PAS domains remains to be established.

Another distinct characteristic of the KV11 channel subfamily is the presence of a cyclic nucleotidebinding domain (CNBD) in their intracellular C-terminus domain.2 CNBD domains have been identified in other ion channels such as cyclic nucleotide-gated (CNG) cation channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels. However, as opposed to the CNG and HCN channels, cyclic nucleotide binding does not have an effect on KV11 channel activation. On the other hand, several studies have shown that the activity of the KV11.1 channel can be regulated by cAMP in either direct or indirect (via the cAMP downstream effector PKA) pathways.7 In addition, mutations in the CNBD domain of KV11.1 and KV11.3 have been implicated in trafficking defects of both subunits.8

As with all voltage-dependent K+ channels, the functional channel formed by the KV11 subunits is a tetramer composed of four subunits. The functional multimeric channel can be homomeric, (i.e. four identical KV11.1 subunits) but functional heteromeric complexes of KV11 subunits have also been described.9 Whether KV11 subunit multimerization occurs also in vivo, is not clear at the moment.

Biophysical Properties

The biophysical properties of the KV11 subfamily channels also sets them apart from the voltagegated K+ channel superfamily. The KV11 channels are characterized by very slow activation kinetics compared to the classical KV channel. This is accompanied by rapid inactivation kinetics resulting in currents that show strong inward rectification.

There are some differences between the different KV11 channels regarding their biophysical properties. The current of the KV11.1 and KV11.2 channels is that of a strong inward rectifier with slow activating kinetics. The KV11.3 channel has different properties: it is a weak inward rectifier that is activated at negative potentials and has rapid activating kinetics.10

From a pharmacological point of view, most studies concentrated on the KV11.1 channel. The KV11 channels can be blocked by well characterized organic blockers such as the anti-arrhythmic E-4031 drug. KV11.1 can also be blocked by the peptide toxins Ergtoxin-1BeKm-1 and APETx-1. APETx-1 is unable to block KV11.2 or KV11.3, while Ergtoxin-1 and BeKm-1 block them with different potencies.11

In the last few years, it has been recognized that drugs causing ventricular arrhythmia as an unintended side effect, do so by blocking the cardiac KV11.1 channel. This phenomenon has been termed acquired long QT syndrome (as opposed to the congenital syndrome, see below). Drugs including terfenadine and astemizole (antihistamines), sertindole (a psychoactive agent) and grepafloxacin (an antimicrobial) have all been found to cause ventricular arrhythmias in patients prompting regulatory drug agencies to issue recommendations for the testing of new drugs for their potential KV11.1 blocking effect.12,13

Physiological Significance

The prototypical and most studied KV11 current is that of the KV11.1 channel that underlies the cardiac Ikrcurrent.14 In cardiac ventricular myocytes, Na+ channels initiate an action potential and produce a rapid depolarization of the membrane. This is followed by a much slower repolarization with several molecular components. The last phase of this repolarization is responsible for ending the action potential and bringing the cardiac myocyte membrane potential to the resting level. The KV11.1 channel is the most important component of this last repolarization phase. As mentioned above, mutations in the KV11.1 channel cause inherited long QT syndrome (LQTS) or abnormalities in the repolarization of the heart that are associated with life-threatening arrhythmias and sudden death. About 200 different mutations in the KV11.1 channel have been identified today that cause either loss of function of the channel or defects in the trafficking of the channel to the cell membrane.14 In addition, the KV11.1 channel has proven to be very susceptible to inhibition by several unrelated compounds inducing the so-called acquired LQTS.

Besides its function in the heart, the KV11.1 channel has other physiological functions in other tissues. For example in smooth muscle cells of the stomach and colon the KV11.1 channel probably has a function in the maintenance of the membrane resting potential. In these cells blocking of the channel induces a membrane depolarization that is associated with muscle contraction.10

The KV11.1 channel has also been implicated in pathological conditions such as cancer.15

Indeed, KV11.1 expression was found to be upregulated in several tumor cell lines of different histogenesis, suggesting that it confers the cells some advantage in cell proliferation. In several studies it has been shown that inhibition of the KV11.1 current leads to a decrease in tumor cell proliferation while in colon cancer cell lines it blocked cell invasiveness. In addition, KV11.1 expression has been detected in primary tumors such as colon cancer and also in leukemias.16,17

The physiological function of the KV11.2 and KV11.3 channels has been difficult to assess in large part because of the lack of discerning pharmacological and biochemical tools. However, KV11 currents have been located in the brain that could possibly underlie homomeric or heteromeric channels of the three KV11 subunits.10

KV11.2 (erg2) Expression in Rat Hippocampus
Immunohistochemical staining of KV11.2 in rat hippocampus. Frozen sections of rat hippocampus were visualized with Anti-KCNH6 (erg2) Antibody (#APC-114 ) (1:100).(A) KV11.2 appears as diffuse staining (green) that defines the boundary of the reticular nucleus of thalamus (arrow). (B) Staining with mouse anti-parvalbumin (PV, red) demonstrates both neuronal and diffuse staining. (C) Confocal merge of KV11.2 and PV demonstrates overlap of the two markers labeling the reticular nucleus of the thalamus (orange).
KV11.3 (erg3) Expression in Rat Hippocampus
Immunohistochemical staining of KV11.3 in rat cerebellum. Frozen sections of rat cerebellum were visualized with Anti-KCNH7 (erg3) Antibody (#APC-112) (1:100).(A) KV11.3 channel appears in glial processes (red). (B) Staining of astrocytic fibers with mouse anti-glial fibrillary acidic protein (GFAP, green). (C) Confocal merge of KV11.3 channel and GFAP demonstrates colocalization in molecular layer but separate localization of these proteins at the Purkinje cell layer.


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