Kv11.2

Description: potassium voltage-gated channel, subfamily H (eag-related), member 6
Gene: Kcnh6 Synonyms: Kv11.2, ERG2, HERG2, KCNH6

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Introduction

The voltage-gated K+ channels of the EAG (ether-à-go-go) family consist of three subfamilies: eag, elk (eag-like) and erg (eag-related gene). Erg channels play critical roles in regulating the resting membrane potential [780], [781], action potential duration [782], spike frequency adaptation [797] and hormone secretion [797]. Due to a Per-Arnt-Sim domain in the N-terminus of erg channel subunits, even a role in O2-sensing has been discussed [783]. The different physiological roles of erg channels are enabled by their peculiar gating [325]. The erg subfamily consists of three members: erg1, erg2 (aka. Kv11.2) and erg3 [789], [790], [791]. These subunits may form homomultimeric channels, but they are also able to form heteromultimers within their subfamily [792].

Experimental data

Rat Kv11.2 gene in CHO host cell datasheet
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Gene

RGD ID	Chromosome	Position	Species
620304	10	95400862-95421678	Rat
1332067	11	105869517-105895378	Mouse
737542	17	61600695-61626338	Human

Kcnh6 : potassium voltage-gated channel, subfamily H (eag-related), member 6

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Transcript

Acc No	Sequence	Length	Source
NM_053937	n/A	n/A	NCBI
NM_001037712	n/A	n/A	NCBI
NM_173092	n/A	n/A	NCBI
NM_030779	n/A	n/A	NCBI

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Ontology

Accession		Name			Definition					Evidence
GO:0005887		integral to plasma membrane			Penetrating at least one phospholipid bilayer of a plasma membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer.					IDA
GO:0016020		membrane			Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins.					IEA

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Interaction

Cytosolic Ca2+

Like eag1 currents, eag2 currents are blocked by low concentrations of cytosolic Ca2+ [327], [800].

Erg1 and Erg3

In the central nervous system of mammals, two other ERG channel genes are expressed (ERG2 and ERG3)11, and here heteromultimeric channel complexes of all three subunits can be formed [792]

RPR regulates hERG1 and rERG2 differentially

RPR260243 (RPR) induces voltage-dependent slowing of hERG1 deactivation. A study using site-directed mutagenesis proposed the C-linker domain as key component of slow deactivation in ERG channels and found that residues in the C-linker and the adjacent cyclic nucleotide-binding homology domains are sufficient to explain the different sensitivities of hERG1 and rERG2 to RPR.[2091]

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Protein

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Structure

Schematic diagram of Kv11.2

Schematic diagram of a Kv11 subunit containing six alpha-helical transmembrane segments S1–S6 (in gray) and the pore P. The locations of the N-terminal PAS- domain and the C-terminal cyclic nucleotide binding domain (CNBD) are highlighted in dark and light blue, respectively. [796]

The ether-a-go-go gene K+ channel alpha-subunits consist of six membrane-spanning domains (S1–S6). A Per-Arnt-Sim (PAS) domain is located at the N-terminus and a cyclic nucleotide-binding domain (cNBD) in the C-terminus. This, and the tetrameric structure of a K+ channel can be seen in fig1 of Bauer [778]. The pore region P and S6 may form the inner core of the channel, S1–S5 the outer parts of the channel with S4 as the voltage sensor. [778]

Drug Binding Site to hERG channel

The side chains of all four residues are orientated towards the large central cavity of the channel, which is consistent with the observation that hERG channels are only blocked by these drugs after the channel has opened. The two pore helix residues (Thr 623 and Ser 624) are highly conserved in Kv channels and thus cannot easily explain the promiscuous blocking by drugs of hERG. However, the two S6 residues (Tyr 652 and Phe 656) are not conserved — most Kv channels have an Ile and a Val in homologous positions. Further mutagenesis identified the most relevant physicochemical properties of these two S6 residues [1738]

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Distribution

Kv11.2 Distribution in Neuronal Retina

In contrast to this postsynaptic distribution of Kv11.1 subunits in the OPL, Kv11.2 seemed to be expressed presynaptically in this layer (see Fig. 2B). The additional occurrence of Kv11.2 in dense packages in the IPL indicates the expression of Kv11.2 subunits presynaptically in ribbon synapses of both, photoreceptors and bipolar cells. As these synapses are glutamatergic, we performed double-labeling experiments with Kv11.2- and vGluT1-specific antibodies [1734]

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Expression

Expression in CNS

Kv11.2 and Kv11.3 are thought, contrary to Kv11.1, to be found exclusively in the nervous system [790]. However, recently, Kv11.2 and Kv11.3 transcripts were shown in rat pancreatic islets [798]. In rodent brain, the three channel subtypes display a widespread expression pattern although one study did detect Kv11.2 almost exclusively in the olfactory bulb [327]

Herg channel expression in Brain

All three Kv11 channels are expressed in the olfactory bulb, and erg1 and erg3 are co-expressed in the reticular thalamic nucleus, cerebral cortex, cerebellum and hippocampus [327]. Single cell RT-PCR experiments have shown that the erg subunits can be expressed in different combinations in individual rat lactotroph cells [781]. In addition, transcripts for more than one erg subunit have been detected in various cell lines: NG108-15 (neuroblastoma, erg1–3, [793]), PC12 (sympathetic ganglia neuron, erg1 and erg2, [327]), MMQ (lactotroph, erg1–3, [794]) and GH3/B6 (somatomammotroph, erg1 and erg2, [789]).

Expression in Rat

Kv11.2 and Kv11.3 are thought, contrary to Kv11.1, to be found exclusively in the nervous system [790]. However Kv11.2 and Kv11.3 transcripts were shown in rat pancreatic islets [798]. In rodent brain, the three channel subtypes display a widespread expression pattern [799], [326], [327]. although one study [327] did detect Kv11.2 almost exclusively in the olfactory bulb. (From [796])

Mouse Retina

By real-time PCR experiments we were able to show that Kv11.1 and Kv11.2 are expressed in a comparable level in the mouse retina while Kv11.3 expression was significantly lower [1734]

Pre vertebral Sympathetic Ganglia

The erg2 gene is expressed abundantly in the two prevertebral sympathetic ganglia examined: the celiac ganglia (CG) and the superior mesenteric ganglia (SMG) [790]

Tissue distribution of herg2

Neither erg2 nor erg3 mRNA is expressed at detectable levels in atrial or ventricular (Vent) muscle, [790]

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Functional

Retina

Kv11.2 channels are expressed presynaptically in glutamatergic synapses of the retina, suggesting their contribution to the synaptic release of glutamate in photoreceptors and bipolar cells. The axons of OFF bipolar cells terminate in the outer half of the IPL, whereas those of ON and rod bipolar cells terminate in the inner half of the IPL. Accordingly, the co-localization of Kv11.2 and vGluT1 throughout the IPL strongly suggests that Kv11.2 subunits are expressed in all types of bipolar cells, but not in amacrine cells which is supported by the absence of Kv11.2 and GAD65 co-staining [1734]

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Kinetics

Kinetics of human fetal Kv11.2 in X. oocytes

[796] Voltage dependence of channel activation (-80mV) to Peak (60mV). The activation rate was voltage dependent for all three Kv11 channels, the activation rate being faster at more depolarized potentials. Kv11.2 activated more than twofold slower than hKv11.1.

Like eag1 currents, eag2 currents exhibit a pronounced Cole-Moore shift and they are blocked by low concentrations of cytosolic Ca2+ [327], [800]. However, the activation threshold of eag2 channels is much more negative (−100 mV) than that of rat eag1 channels (−50 mV)[800], and eag2 channels exhibit only a weak potential dependence. [778]

Rat Kv11.2 (erg2) Expressed in CHO cells

The different erg subunits vary considerably in their expression levels (compare erg1 and erg2 in the figure where erg2 cDNA was injected in a ten-fold concentration compared with erg1). Therefore, we concatenated two erg subunits by cloning the 5'-end of one cDNA to the 3'-end of the other one to obtain homogeneous channel populations with a defined subunit composition. The strongest inward rectifier were erg2 channels when compared to erg1 and erg3 [325]

Activation curves of Erg1a, Erg1b, Erg2 (Kv11.2) and Erg3 channels

Voltage dependence of Erg current activation and inactivation in Purkinje cells compared to currents of Erg1a, Erg1b, Erg2 and Erg3 channels heterologously expresssed in HEK293 cells. Activation curves of erg1b and erg2 were shifted to more positive potentials by ∼20 and >40 mV, respectively, compared to erg1a and erg3 currents.[1737]

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