Channelpedia

Kv7.4

Description: potassium voltage-gated channel, KQT-like subfamily, member 4
Gene: Kcnq4     Synonyms: KV7.4, DFNA2, KV7.4, DFNA2A, KCNQ4

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Introduction

The KCNQ gene family encodes Kv7 channel subunits that form homo- or heteromeric Kv7 channels (also termed M-channels) which represent the molecular correlate to the M-current [695]. Brown and colleagues were the first to describe a neuronal K+ current in bullfrog sympathetic cells that they named ‘M current’ due to its suppression by stimulation of muscarinic acetylcholine receptors (mAChRs) [465]. This time- and voltage-dependent K+ current has a threshold for activation at typical neuronal resting potentials, with greater activity upon depolarization. This characteristic and its lack of inactivation give M current a major impact on neuronal excitability. Suppression of M current by the activation of appropriate receptors or by pharmacological blockade allows neurons to fire more rapidly due to the reduction in accommodation or spike frequency adaptation [758], [695], [759]. Underlain by the KCNQ family of genes [695], M channels, also known as Kv7 [760], are localized throughout the nervous system [695],[702], where the channels are inhibited by stimulation of a variety of Gq/11 -coupled neurotransmitter receptors. [751] The gene KCNQ4 (also known as DFNA2; KV7.4; DFNA2A) encodes a potassium voltage-gated channel, KQT-like subfamily, member 4, with the same name. It is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene


Experimental data


Rat Kv7.4 gene in CHO host cell

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Gene

The gene KCNQ4 that encodes the channel Kv7.4 is also known as DFNA2 or DFNA2A.

RGD ID Chromosome Position Species
61799 5 141289211-141339803 Rat
62091 4 120370078-120419781 Mouse
736263 1 41249684-41306124 Human

Kcnq4 : potassium voltage-gated channel, KQT-like subfamily, member 4


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Transcript

Acc No Sequence Length Source
NM_001081142 n/A n/A NCBI
NM_004700 n/A n/A NCBI
NM_172163 n/A n/A NCBI

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Ontology

Accession Name Definition Evidence
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
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:0009925 basal plasma membrane The region of the plasma membrane located at the basal end of the cell. Often used in reference to animal polarized epithelial membranes, where the basal membrane is the part attached to the extracellular matrix, or in plant cells, where the basal membrane is defined with respect to the zygotic axis. IEA
GO:0005737 cytoplasm All of the contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures. IDA
GO:0005886 plasma membrane The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. IDA
GO:0043005 neuron projection A prolongation or process extending from a nerve cell, e.g. an axon or dendrite. IDA

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Interaction

Kv7.3/Kv7.2

The Kv7.4 subunit coassembles with the Kv7.3, but not the Kv7.2, subunit, which produces larger currents than homomeric Kv7.4 channels per se [763].

KCNE Subunits

Coexpression of the KCNE- Beta-subunits with human KCNQ4 in the Xenopus laevis oocyte expression system revealed that all KCNEs modulate KCNQ4 voltage dependence, protein stability and ion selectivity of hKCNQ4 in Xenopus oocytes. The deafness-associated Jervell and Lange- Nielsen syndrome (JLNS) mutation KCNE1(D76N) impairs KCNQ4-function whereas the Romano-Ward syndrome (RWS) mutant KCNE1(S74L), which shows normal hearing in patients, does not impair KCNQ4 channel function. In conclusion, KCNEs are presumably coexpressed with KCNQ4 in hair cells from the organ of Corti and might regulate KCNQ4 functional properties, effects that could be important under physiological and pathophysiological conditions [1817]

Linopirdine

When Kv7.4 forms a heteromer with Kv7.3, the resulting potassium channel conductance is more sensitive to linopirdine [763]

Retigabine

The principal Kv7 channel opener, retigabine, is able to produces a hyperpolarizing shift of the activation curve of the channel by 14–43 mV (depending on the Kv7 channel subtype) at 10 μm. KCNQ4 channels, stably expressed in HEK293 cells, were activated by retigabine and BMS-204352 in a reversible and concentration-dependent manner in the concentration range 0.1–10 μM. Both compounds shifted the KCNQ4 channel activation curves towards more negative potentials by about 10 mV. Further, the maximal current obtainable at large positive voltages was also increased concentration-dependently by both compounds. (Schroder [136])

[764].

Mepyramine

Mepyramine inhibits the individual homomeric KCNQ1-4 channels. (Liu [72])

Ca2+

M currents in mammalian neuron are inhibited but in amphibian are enhanced by [Ca2+]. (Su [137])

Ionomycin

Ionomycin enhances the KCNQ4 current which is expressed in Xenopus oocytes. The enhanced effect is reversed by the application of BAPTA-AM, a fast calcium chelator. Surprisingly, the intracellular injection of calcium (0.01–1 mM) into the cytoplasm directly did not change the KCNQ4 currents. These data demonstrated that the effect of ionomycin acts on intramembrane site of KCNQ4 protein and without relation to cytoplasmic calcium concentration. (Su [137])

ML213 and NS15370

Recently, two novel Kv7 channel enhancers have been identified, ML213 and NS15370, that show increased potency, particularly on Kv7.4 channels. This study identifies and characterises ML213 and NS15370 as potent vasorelaxants in different blood vessels, thereby highlighting these new compounds as potential therapeutics for various smooth muscle disorders.

Janus kinase 2

Janus kinase-2 (JAK2) participates in the signaling of several hormones, growth factors and cytokines. JAK2 downregulates KCNQ4 activity and thus counteracts K(+) exit, an effect which may contribute to cell volume regulation [1812]


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Protein


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Structure

Structural Model of Kv7.4

Kv7.1 structure (A) Stereoview of the KCNQ4 α-carbon frame model (yellow) superimposed onto that of Kv1.2 (cyan). The position of Tyr270 is indicated with a yellow arrow. The α-helices, the PH, and the P-loop are also identified. (B) Part of the wild-type KCNQ4 model, and (C) the Tyr270His model overlaid with their corresponding electrostatic surface potentials. The side chains of Tyr270 (B) and His270 (C) are indicated by arrows. Negatively and positively charged residues are depicted respectively in red and blue in the electrostatic potential surface representations. (D) Stereoview of a portion of the ribbon model of the Tyr270His pore region [1814] [1823]


KCNQ4 Structure with DFNA2 MUTATION

KCNQ4 channel belongs to the family of voltage-gated K+ channels, which consists of six transmembrane domains (S1–S6) and a K+ selective pore. Most of missense mutations associated with DFNA2 affect the pore structure of the channels, exerting strong dominant negative effects on the channel function. Deletions, on the other hand, cause a frame-shift, resulting in the truncated channels that are nonfunctional. Clinically, patients with deletions have milder hearing loss than that observed in the patients with missense mutations [11]. Further study of KCNQ4 mutations will improve our understanding of the molecular mechanisms of progressive hearing loss [1684]


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Distribution

KCNQ4 Cellular Distribution in Neuron

Kv7.4 channels are expressed only in mesencephalic dopaminergic neurons at somatodendritic sites (see fig 1 in [752]).


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Expression

Expression in the Brain

While the Kv7.2 and Kv7.3 subunits are present in almost all brain regions examined so far [724] the Kv7.4 subunit is expressed only in discrete nuclei of brainstem, including the mid- brain [762], [761].

KCNQ4 is found only in a few nuclei and tracts mainly in the brainstem [762]

Kv7.4 can be found in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), [762].

The M type K+ channel, whose molecular basis is considered to be KCNQ2-5, has been characterized in many typesof peripheral and central neurons, including superior cervical ganglion (SCG), dorsal root ganglion (DRG), hippocampal and cortical neurons (Owen et al., 1990 [1088]; Passmore et al., 2003 [1089]; Peretz et al., 2005 [78]; Shah et al., 2002 [700]).

Expression In Body

KCNQ4 current is a low-threshold, non-inactivating K+ current, which is expressed in the outer hair cell of cochlea, brain, heart, and skeletal muscle. (Su [137])

Hair Cells

KCNQ4 can also associate with KCNQ3 and yield M-type currents, but its expression pattern is much more restricted. It is prominently expressed in sensory hair cells in the inner ear8, and in certain tracts and nuclei of the central auditory pathway [464]

BDNF Increases expression of Kv7.4

BDNF profoundly and specifically increases KCNQ4 expression in neurons derived from embryonic stem cells [1813]


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Functional

Stablizing membrane potential

The M current plays a key role in regulating various central and peripheral neuron excitabilities and stabilizing membrane potential (Delmas and Brown, 2005 [1090], [1091]).

Deafness

Mutations in KCNQ4 channel produce inherited syndrome of deafness Kubisch ([763]). The deficit of KCNQ4 function might result in a chronic potassium overload of outer hair cells, causing their slow degeneration. (Su [137])

Mutations in KCNQ4 lead to a slowly progressive, dominant hearing loss [464]

KCNQ4 K(+) Channels Tune Mechanoreceptors

Mutations inactivating the potassium channel KCNQ4 (K(v)7.4) lead to deafness in humans and mice. In addition to its expression in mechanosensitive hair cells of the inner ear, KCNQ4 is found in the auditory pathway and in trigeminal nuclei that convey somatosensory information. We have now detected KCNQ4 in the peripheral nerve endings of cutaneous rapidly adapting hair follicle and Meissner corpuscle mechanoreceptors from mice and humans.

Down regulation of Kv7.4 in Hypertension

In 2 different rat and mouse models of hypertension, the functional impact of Kv7 channels was dramatically downregulated.

Modulation of KCNQ4 channel activity by changes in cell volume

KCNQ4 channels expressed in HEK 293 cells are sensitive to cell volume changes, being activated by swelling and inhibited by shrinkage, respectively. The KCNQ4 channels contribute significantly to the regulatory volume decrease (RVD) process following cell swelling. Under isoosmotic conditions, the KCNQ4 channel activity is modulated by protein kinases A and C, G protein activation, and a reduction in the intracellular Ca2+ concentration, but these signalling pathways are not responsible for the increased channel activity during cell swelling [1818]


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Kinetics

KCNQ General Kinetics

Kv7 subtypes start opening at around −60 mV (although the voltage dependency of Kv7 channels differ between heterologous and native cells), thus being functionally active close to the resting membrane potential. In addition, Kv7 channels may be considered as being non-inactivating (‘leaky’) K+ channels at physiologically relevant resting potentials, although a proportion of Kv7 channels may undergo steady-state inactivation [712]. These characteristics enable the Kv7 channels to produce the underlying subthreshold M-current, which stabilizes the neuronal resting potential. Consequently, the Kv7 channels are thought to inhibit neuronal excitability and put a ‘brake’ on action potential firing when the neuron is exposed to an excitatory stimulus. [752]

KCNQ4 Kinetics in CHO cells

Using the whole-cell configuration of the patch-clamp technique, we have investigated the characteristics of these transfected cells. The average cell capacitance of the CHO cells was 22.2 ± 8.7 pF (mean ± S.D., n = 21). The outward current showed properties of KCNQ4. The current activated with a time constant of 110 ± 46 ms when the potential was stepped to 0 mV. At 0 mV the current was 2.64 ± 1.46 nA in amplitude. The current was half activated at a potential of -28.8 ± 8.0 mV. In eight cells, outward current was almost completely blocked by 200 µM linopirdine (mean inhibition 82 %). The anti-arrhythmic bepridil, a blocker of KCNQ1, applied at 10 µM, also blocked 49 % (n = 3) of the CHO outward currents (University College London (2003) J Physiol 547P, PC21)

KCNQ4 expressed in CHO cells+ Various Channel Openers

Kv7.1 structure Representative recordings from CHO cells transiently transfected with wt KCNQ4 under control conditions and after application of flupirtine, retigabine, BMS-204352, zinc pyrithione (ZnP) or a combination of zinc pyrithione and retigabine (ZnP/Ret) (10 µM each, voltage command as indicated). Dashed lines indicate zero currents, and scale bar applies to all recordings [1811]












Kv7.4 Expressed in HEK and CHO cells Comparison

Kv7.1 structure Here we show that (+/-)BMS-204352 also induces a voltage-independent KCNQ4 current. The channels were stably expressed in human embryonic kidney cells (HEK293), and investigated by use of the whole-cell mode of the patch-clamp technique. The voltage-independent current reversed at the equilibrium potential for potassium (EK), hence was carried by a K+ conductance, and was blocked by the selective KCNQ channel blockers XE991 and linopirdine. Similar results were obtained with KCNQ4 channels transiently transfected into Chinese hamster ovary cells (CHO) [1819]


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Model


References

750

de Heer AM. et al. Audioprofile-directed successful mutation analysis in a DFNA2/KCNQ4 (p.Leu274His) family.
Ann. Otol. Rhinol. Laryngol., 2011 Apr , 120 (243-8).

751

Shapiro MS. et al. Regulation of neural KCNQ channels: signalling pathways, structural motifs and functional implications.
J. Physiol. (Lond.), 2008 Apr 1 , 586 (1811-21).

752

Jentsch TJ. et al. Kv7 channels: interaction with dopaminergic and serotonergic neurotransmission in the CNS.
J. Physiol. (Lond.), 2008 Apr 1 , 586 (1823-32).

753

Yang Y. et al. [KCNQ4 gene mutations affected a pedigree with autosomal dominant hereditary hearing loss]
Zhonghua Er Bi Yan Hou Ke Za Zhi, 2002 Oct , 37 (343-7).

754

756

Chambard JM. et al. Regulation of the voltage-gated potassium channel KCNQ4 in the auditory pathway.
Pflugers Arch., 2005 Apr , 450 (34-44).

757

Scuvée-Moreau J. et al. The KCNQ channel opener retigabine inhibits the activity of mesencephalic dopaminergic systems of the rat.
J. Pharmacol. Exp. Ther., 2006 Sep , 318 (1006-19).

724

Jentsch TJ. et al. KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents.
J. Biol. Chem., 2000 Aug 4 , 275 (24089-95).

761

Hansen HH. et al. K(v)7 channels: function, pharmacology and channel modulators.
, 2006 , 6 (999-1023).

712

Grunnet M. et al. Inactivation as a new regulatory mechanism for neuronal Kv7 channels.
Biophys. J., 2007 Apr 15 , 92 (2747-56).

135

Grunnet M. et al. hKCNE4 inhibits the hKCNQ1 potassium current without affecting the activation kinetics.
Biochem. Biophys. Res. Commun., 2005 Mar 25 , 328 (1146-53).

137

Su CC. et al. Studies of the effect of ionomycin on the KCNQ4 channel expressed in Xenopus oocytes.
Biochem. Biophys. Res. Commun., 2006 Sep 15 , 348 (295-300).

Brown DA. et al. M-current noise and putative M-channels in cultured rat sympathetic ganglion cells.
J. Physiol. (Lond.), 1990 Dec , 431 (269-90).

Brown DA. et al. KCNQ/M currents in sensory neurons: significance for pain therapy.
J. Neurosci., 2003 Aug 6 , 23 (7227-36).

700

Delmas P. et al. Molecular correlates of the M-current in cultured rat hippocampal neurons.
J. Physiol. (Lond.), 2002 Oct 1 , 544 (29-37).

Crest M. et al. Functional organization of PLC signaling microdomains in neurons.
Trends Neurosci., 2004 Jan , 27 (41-7).

Delmas P. et al. Pathways modulating neural KCNQ/M (Kv7) potassium channels.
Nat. Rev. Neurosci., 2005 Nov , 6 (850-62).

464

Jentsch TJ. et al. Neuronal KCNQ potassium channels: physiology and role in disease.
Nat. Rev. Neurosci., 2000 Oct , 1 (21-30).

1810

Greenwood IA. et al. Vasorelaxant effects of novel Kv7.4 channel enhancers ML213 and NS15370.
Br. J. Pharmacol., 2014 Jun 9 , ().

Lang F. et al. Downregulation of KCNQ4 by Janus kinase 2.
J. Membr. Biol., 2013 Apr , 246 (335-41).

1815

Jentsch TJ. et al. KCNQ4 K(+) channels tune mechanoreceptors for normal touch sensation in mouse and man.
Nat. Neurosci., 2012 Jan , 15 (138-45).

1816

Olesen SP. et al. Downregulation of Kv7.4 channel activity in primary and secondary hypertension.
Circulation, 2011 Aug 2 , 124 (602-11).

Fedorenko O. et al. Functional coassembly of KCNQ4 with KCNE-beta- subunits in Xenopus oocytes.
Cell. Physiol. Biochem., 2006 , 18 (57-66).

Olesen SP. et al. Modulation of KCNQ4 channel activity by changes in cell volume.
Biochim. Biophys. Acta, 2004 Jan 28 , 1660 (1-6).

Olesen SP. et al. Voltage-independent KCNQ4 currents induced by (+/-)BMS-204352.
Pflugers Arch., 2003 Aug , 446 (607-16).

136

Schrøder RL. et al. KCNQ4 channel activation by BMS-204352 and retigabine.
Neuropharmacology, 2001 Jun , 40 (888-98).

Minor DL. et al. Structural insight into KCNQ (Kv7) channel assembly and channelopathy.
Neuron, 2007 Mar 1 , 53 (663-75).


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Credits

Editor : Admin.

Contributors : Rajnish Ranjan, Michael Schartner

To cite : [Editor], [Contributors]. Accessed on [Date] Channelpedia , http://channelpedia.epfl.ch/ionchannels/26