Kv11.3

Description: potassium voltage-gated channel, subfamily H (eag-related), member 7
Gene: Kcnh7 Synonyms: Kv11.3, erg3, kcnh7, HERG3

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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 Kv11.3 gene in CHO host cell datasheet
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Gene

RGD ID	Chromosome	Position	Species
621112	3	44657361-45153509	Rat
734397	2	62541003-63022344	Mouse
734396	2	163227917-163695240	Human

Kcnh7 : potassium voltage-gated channel, subfamily H (eag-related), member 7

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Transcript

Acc No	Sequence	Length	Source
NM_131912	n/A	n/A	NCBI
NM_133207	n/A	n/A	NCBI
NM_033272	n/A	n/A	NCBI
NM_173162	n/A	n/A	NCBI

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Ontology

Accession		Name			Definition					Evidence
GO:0016021		integral to membrane			Penetrating at least one phospholipid bilayer of a membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer. When used to describe a protein, indicates that all or part of the peptide sequence is embedded in the membrane.					IEA
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

BeKm-1 and APETx1

The toxins BeKm-1 and APETx1 reduced the currents mediated by erg1a and erg1a/erg3 concatemers to a similar degree as the erg current of Purkinje cells. A–D, BeKm-1 (100 nM) or APETx1 (1 μM) were applied to HEK 293 cells stably expressing erg1a, erg2, erg3, or concatemeric erg1a/erg3 channels.

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Protein

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Structure

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]

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Distribution

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Expression

Herg3 Expression in the Brain in Rats

HERG2 and HERG3 are expressed exclusively in brain [1743] 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]).

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])

The erg3 gene is broadly expressed throughout the nervous system, similar to erg1. In addition to brain,erg3 mRNA is expressed in all of the sympathetic ganglia tested and also is expressed at low levels in retina [790]

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Functional

Association of Kv11.3 with bipolar spectrum disorders

Several mutations of Kv11.3 potassium channels were associated with the pathophysiology of bipolar spectrum disorders, particularly with bipolar 1 disorder, in genome-wide association studies. [2089] [2090]

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Kinetics

Human Kv11.3 inactivation in X oocytes

It can be seen from these data that the appearance of a transient waveform at positive potentials in the erg3 currents, but not the erg1 and erg2 currents, is attributable to differences in the relative rates of activation and inactivation. The ratio between the inactivation and activation rates of theerg3 channel was close to two at positive potentials, whereas inactivation rates were at least 10-fold faster than activation rates for both the erg1 and erg2 channels in this potential range. For the erg1 and erg2 channels, the inactivation process is in quasi-steady-state relative to the much slower activation process. The transient waveform of theerg3 current is produced by much the same mechanism as for a typical “A current,” which has an inactivation rate that is similar or somewhat slower than the activation rate. The primary difference between the erg3 current and a typical A current is the persistence of a maintained plateau current, which is attributable to the very shallow steady-state inactivation curve of the erg3 channel [790]

As expected, hKv11.3 inactivation was considerably slower than hKv11.1 and hKv11.2, which display similar inactivation rate [796].

Rat Herg3 (rKv11.3) expressed in CHO cells

NS1643 is one of the small molecule HERG (Kv11.1) channel activators and has also been found to increase erg2 (Kv11.2) currents. We now investigated whether NS1643 is also able to act as an activator of Kv11.3 (erg3) channels expressed in CHO cells. Activation of rat Kv11.3 current occurred in a dose-dependent manner and maximal current increasing effects were obtained with 10 µM NS1643. At this concentration, steady-state outward current increased by about 80% and the current increase was associated with a significant shift in the voltage dependence of activation to more negative potentials by about 15 mV [1797]