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potassium voltage-gated channel, KQT-like subfamily, member 4
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 . 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) . 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 , , . Underlain by the KCNQ family of genes , M channels, also known as Kv7 , are localized throughout the nervous system ,, where the channels are inhibited by stimulation of a variety of Gq/11 -coupled neurotransmitter receptors.  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
The gene KCNQ4 that encodes the channel Kv7.4 is also known as DFNA2 or DFNA2A.
Kcnq4 : potassium voltage-gated channel, KQT-like subfamily, member 4
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 .
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 
When Kv7.4 forms a heteromer with Kv7.3, the resulting potassium channel conductance is more sensitive to linopirdine 
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 )
Mepyramine inhibits the individual homomeric KCNQ1-4 channels. (Liu )
M currents in mammalian neuron are inhibited but in amphibian are enhanced by [Ca2+]. (Su )
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 )
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 
Structural Model of Kv7.4
(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  
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 . Further study of KCNQ4 mutations will improve our understanding of the molecular mechanisms of progressive hearing loss 
KCNQ4 Cellular Distribution in Neuron
Kv7.4 channels are expressed only in mesencephalic dopaminergic neurons at somatodendritic sites (see fig 1 in ).
Expression in the Brain
While the Kv7.2 and Kv7.3 subunits are present in almost all brain regions examined so far  the Kv7.4 subunit is expressed only in discrete nuclei of brainstem, including the mid- brain , .
KCNQ4 is found only in a few nuclei and tracts mainly in the brainstem 
Kv7.4 can be found in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), .
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 ; Passmore et al., 2003 ; Peretz et al., 2005 ; Shah et al., 2002 ).
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 )
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 
BDNF Increases expression of Kv7.4
BDNF profoundly and specifically increases KCNQ4 expression in neurons derived from embryonic stem cells 
Stablizing membrane potential
Mutations in KCNQ4 channel produce inherited syndrome of deafness Kubisch (). The deficit of KCNQ4 function might result in a chronic potassium overload of outer hair cells, causing their slow degeneration. (Su )
Mutations in KCNQ4 lead to a slowly progressive, dominant hearing loss 
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 
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 . 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. 
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
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 
Kv7.4 Expressed in HEK and CHO cells Comparison
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) 
Editor : Admin.
Contributors : Rajnish Ranjan, Michael Schartner
To cite : [Editor], [Contributors]. Accessed on [Date] Channelpedia , http://channelpedia.epfl.ch/ionchannels/26