Channelpedia

Kv7.1

Description: potassium voltage-gated channel, KQT-like subfamily, member 1
Gene: Kcnq1
Alias: KV7.1, LQT, RWS, WRS, LQT1, SQT2, ATFB1, ATFB3, JLNS1, KCNA8, KCNA9, Kv1.9, KVLQT1, KCNQ1

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Introduction

Kv7.1, encoded by the gene KCNQ1, is a member of the potassium voltage-gated channel KQT-like subfamily. These channels, which transport positively charged atoms (ions) of potassium into and out of cells, play a key role in a cell's ability to generate and transmit electrical signals[248] Kv7.1, is also known as: LQT; RWS; WRS; LQT1; SQT2; ATFB1; ATFB3; JLNS1; KCNA8; KCNA9; KVLQT1; FLJ26167.

Experimental data

Rat Kv7.1 gene in CHO host cells       datasheet

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Gene

The gene is located in a region of chromosome 11 that contains a number of contiguous genes, which are abnormally imprinted in cancer and the Beckwith-Wiedemann syndrome. This gene is also imprinted, with preferential expression from the maternal allele in some tissues, excluding cardiac muscle. Alternatively spliced transcripts encoding distinct isoforms have been described. NCBI

Species NCBI gene ID Chromosome Position
Human 3784 11 404097
Mouse 16535 7 320173
Rat 84020 1 332972
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Transcript

Species NCBI accession Length (nt)
Human NM_000218.3 3224
Mouse NM_008434.2 3052
Rat NM_032073.2 3017
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Protein Isoforms

Species Uniprot ID Length (aa)
Human P51787 676
Mouse P97414 668
Rat Q9Z0N7 669

Isoforms

Transcript
Length (nt)
Protein
Length (aa)
Variant
Isoform
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Post-Translational Modifications

PTM
Position
Type
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Structure

Kv7.1
Visual Representation of Kv7.1 Structure
Methodology for visual representation of structure available here

KV7.1 STRUCTURE

Kv7.1 structure


KCNQ1, previously named KvLQT1, was first identified in a linkage study looking at some of the genetic causes of sudden death from cardiac arrhythmia. To date, five genes of this family (KCNQ1-5), all encoding K+ channel subunits with the ‘‘shaker-like’’ motif of 6TMD and a single P-loop, have been identified. The proteins share between 30 and 65% amino acid identity, with particularly high homology in the transmembrane regions. The S4 TMD, as other shaker- like K + channels, has been suggested to form the voltage sensor. A regular distribution of positively charged amino acids is seen. All KCNQ subunits have a regular distribution of six positively charged amino acids in the S4 region, except KCNQ1, which has four. The P- loop contains the K+ pore signature sequence TxxTxGYG. All five proteins display a highly homolo- gous region on their intracellular C-terminus termed the ‘‘A-domain’’ [722]

The α-subunit of KvLQT1 has the domain structure composed of six membrane-spanning segments (S1–S6) containing a pore region localized at cell membrane and the N-terminal and C-terminal regions that are localized in the cytoplasm. The KvLQT1 channel consists of four α-subunits [688] and two β-subunits (MinK) encoded by KCNE1 [689], which generates slow component of delayed rectifier potassium current (IKs).

Crystal Structure of Open and CLosed State

Kv7.1 structure Rosetta homology and de novo methods were employed to construct KCNQ1 models in the open and closed states using the open and closed state hybrid experimental/model structures of Kv1.2 as templates. This approach assumes that both KCNQ1 states are similar to the corresponding states of Kv1.2. In the open state model, all residues fell within favored (90%), allowed (9%), or generously allowed (1%) regions of the Ramachandran plot. In the closed model, only 5 residues (0.6%) fell into disallowed regions, with the remaining 99.4% being in favored (87%), allowed (11%), or generously allowed (1.5%) regions. Analysis of side chain conformations further confirmed the quality of these models with 99.7% (open) and 99.2% (closed) of χ1 and χ2 rotamers inhabiting favorable conformations. This is well within the expected bandwidth of precision for high-resolution structural models and represents a positive indicator of the reliability of these models [1705]

CRYSTAL STRUCTURE

Kv7.1 structure

Top-down (extracellular) view of the all atom system. Each of the 4 channel subunits (consisting of S1–S6 segments) is color coded. Pore regions (S5–S6) of one subunit interact with the adjacent subunit voltage-sensing region (S1–S4). (C) Voltage-sensing region with lipid of the 4 channel subunits (consisting of S1–S6 segments) (gray) and water (light blue) solvent molecules.[1676]

Kv7.1 structure (D) 4 translation and rotation. β-carbon of R4 labeled with red beads shows motion. Arrows indicate stable configurations (labeled). S1, Yellow; S2, Red; S3, White; S4, Green; S5, Blue. (E) Implicit membrane. Isocontours at dielectric constant ε = 78 (blue) and ε = 2 (transparent) show the transition region representing the lipid esters. Water (blue) can penetrate the protein as in C and is represented by ε = 78. (F) Energy landscape at Vm = 0 mV and associated conformations. [1676]

Kv7.1 predicted AlphaFold size

Species Area (Å2) Reference
Human 6848.73 source
Mouse 6802.32 source
Rat 8278.33 source

Methodology for AlphaFold size prediction and disclaimer are available here

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Kinetics

KV7.1 kinetics

Kv7.1 kinetics [1670] The Kv7 family of voltage-activated K+ channels is encoded by five genes (KCNQ1–5). Unlike other classes of voltage-activated K+ channels, Kv7 channels are known to activate at very negative voltages (around −60 mV) and function to stabilize resting membrane voltages in many types of excitable cells [1677]

Oocytes injected with KVLQT1 cRNA exhibited robust outward currents that activated at potentials positive to −60 mV and exceeded 5 μA at +40 mV (less than 150 nA at +40 mV in the water-injected oocytes). KvLQT1 currents exhibited a delayed rectifier current phenotype and rectified weakly at positive voltages. Tail currents, elicited upon repolarization to −80 mV, exhibited an initial rise in amplitude before deactivation. The initial increase in tail current amplitude may be due to fast recovery from inactivation, similar to that observed with HERG currents expressed in oocytes [688]

KV7.1 Single Channel Current

Kv7.1 kinetics [1676]

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Biophysics

HODGKIN AND HUXLEY MODEL

Kv7.1 kinetics Mean ± SEM values of τact determined from a fit of the activating current based on the Hodgkin and Huxley model for a voltage-dependent potassium channel activation of PIP-2 dependent KCNQ1/KCNE1 channel [1683]


MARKOV MODEL Kv7.1

Kv7.1 kinetics [1676]

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Expression and Distribution

HEART

KCNQ1 has a high level of expression in the heart where it co-assembles with minK (KCNE1) channels to give a slow delayed rectifier type current, IK,s. (Barhanin et al. 1996 [1074]; Sanguinetti et al. 1996 [1075]; Yang et al. 1997 [688]).

UTERUS

KCNQ expression has also been shown in the mouse and human uterus where KCNQ1 expression predominates throughout the oestrous cycle. KCNQ expression has also been found to change during pregnancy with the majority of KCNQ isoform expression decreases initially in early pregnancy before returning to robust levels at late pregnancy. Kv7 activators (flupirtine and retigabine) relaxed the human and mouse uterus ex vivo, but were more effective on the uteri of late pregnant mice and humans.

OTHER TISSUE

Kv7.1 is expressed in the stomach, small and large intestine, kidney and pancreas [722]

Smooth Muscle

Although Kv7.1 has been readily shown to be expressed in rodent and human vascular smooth muscle, the functional impact of this channel has remained enigmatic [1675]

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CNS Sub-cellular Distribution

DISTRIBUTION OF KV7.1 in NEURON

Staining of Kv7.1 in stratum lucidum could be attributable to granule cell mossy fiber axons or CA3 pyramidal cell apical dendrites.

KCNQ1 antibody also labeled most somata in the neocortex and thalamus, as well as glia-like processes in subcortical white matter tracts and the dentate granule cell layer [1682]

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Function

CARDIAC REPLOARIZATION

The role that IKs (the current which is mediated partly by KCNQ1) plays in cardiac repolarization is particularly important for its ability to counterbalance the depolarizing effect of enhanced L-type Ca2+ current during sympathetic stimulation of the heart (Bosch [1078], Burashnikov [1079], Farges [1080], Jost [1081]). This is highlighted by the finding that LQT1 mutations are usually symptomatically silent in many carriers until sudden exertion or emotional upset triggers cardiac events (Chen [1082], Zagotta [1083]). The properties of IKs constitute an important cardiac repolarization reserve invoked especially during elevated sympathetic tone (Nakashima [1086]).

BRAIN

They were first identified in the brain, where they modulate neuronal excitation [1677]

Arrythmia in Brain and Heart

That long QT syndrome mutations in KCNQ1 cause epilepsy reveals the dual arrhythmogenic potential of an ion channelopathy coexpressed in heart and brain and motivates a search for genetic diagnostic strategies to improve risk prediction and prevention of early mortality in persons with seizure disorders of unknown origin [1682]

Lange-Nielsen syndrome

Recent genetic analyses have revealed that most of the Jervell and Lange-Nielsen syndrome patients carried mutations in KCNQ1 that encodes the α-subunit of a voltage-gated cardiac potassium channel, KvLQT1 (a.k.a. Kv1.7). [682]

Romano Ward Syndrome

Romano Ward syndrome can be caused by mutations in genes for potassium channels, including KvLQT1 and HERG, sodium channels, a calcium channel, and other molecules associated with cardiac ion channels [683], [684], [685], [686], [687].

INSULIN

Kv7.1 is also present in pancreatic β-cells, where it is thought to be implicated in the regulation of insulin secretion [1671].

SALT& WATER TRANSPORT

In addition, Kv7.1 is expressed in several epithelia, where it is involved in salt and water transport [1672] Most importantly, the channel regulates gastric acid secretion and contributes to the release of potassium to the endolymph in the inner ear [1671]

KNOCKOUT MICE

Kv7.1 knock-out mice show gastric hyperplasia and are completely deaf [1673]

MUTATION

Mutations in the KCNQ1 gene are furthermore associated with long QT (LQT)4 syndrome, an inherited form of cardiac arrhythmia that can lead to cardiac arrest. In its recessive form, the Jervell and Lange-Nielsen syndrome, the disease additionally leads to hearing loss due to disturbances in the flow of potassium in the inner ear. The mechanism underlying the LQT syndrome is reflected in a loss of Kv7.1 function, frequently originating from trafficking disorders, and hence a decrease in number of channels in the plasma membrane [1670]

Airway Diseases (Asthma)

In airway smooth muscle, expression of KCNQ1, KCNQ4 and KCNQ5 appears to predominate in humans; however, KCNQ2 predominates in guinea pig with KCNQ1 being undetectable. This study found that both human and guinea pig airways were modulated by application of Kv7 activators and blockers, suggesting that Kv7 channels can regulate airway diameter and are likely to be responsible for maintaining the resting tone in the airways. Moreover, this study suggests that Kv7 enhancers may be useful bronchodilators in the treatment of airway diseases such as asthma [1677]

Gastric Juices

The cardiac K+ channel KCNQ1 is essential for gastric acid secretion [1752]

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Interaction

Ca2+/calmodulin (CaM) and PIP2

M-type channels can be variously composed of KCNQ1-5 subunits, and M current is known to be regulated by Ca2+/calmodulin (CaM) and PIP2. [249]

Antiarrythmic agent (clofilium)

Clofilium, a class III antiarrhythmic agent with the propensity to induce torsades de pointes, substantially inhibits the current [688]

KCNQ SUBUNITS

Stimulation of M1 receptors by 10 micro mol oxotremorine-M (Oxo-M) strongly reduced (to 0—10%) currents produced by KCNQ1—4 subunits expressed individually and also those produced by KCNQ2+KCNQ3 and KCNQ1+KCNE1 heteromers, which are thought to generate neuronal M currents (IK,M) and cardiac slow delayed rectifier currents (IK,s), respectively. (Selyanko [70])

Beta-adrenergic stimulation

IKs is distinguished from the rapidly activating delayed rectifier K+ current (IKr) by its gating kinetics, pharmacological sensitivity, and other properties, notably its considerable enhancement by beta-adrenergic stimulation (Han [1084], Sanguinetti [1085]).

Kv7.1 activators/blockers effect blood vessels

In several smooth muscle studies, Kv7.1-specific blockers such as chromanol 293B, HMR1556, L-768 673 and JNJ39490282 have had no contractile effect. However, recently Kv7.1 activators, such as R-L3 (L-364373) and mefenamic acid, relax precontracted rat blood vessels, which is abolished by application of Kv7.1-specific blockers. These findings suggest that Kv7.1 channels are functional in vascular smooth muscle but, because the Kv7.1-specific blockers have no effect, do not appear to contribute to resting vascular tone [1679]

INSULIN

insulin, a known activator of PI3K, also antagonizes Nedd4-2-mediated reductions in Kv7.1 currents [1670]

Linopirdine and XE991

linopirdine and XE991, produce membrane depolarization, and concomitant vasoconstriction by enhancing calcium influx through voltage-dependent calcium channels [1092]

KCNNE1

The potassium channel Kv7.1 (KCNQ1, KvLQT) plays an important role in a number of tissues where it associates with the auxiliary KCNE β-subunits. In the heart, Kv7.1, together with KCNE1, forms the delayed rectifier potassium current IKs, which is an important contributor to the repolarization of the cardiac action potential [689]

Whereas KCNQ1, which belongs to the Kv family of voltage-gated K+ channels, reconstitutes a rapidly activating voltage-dependent K+ conductance, cotransfection of the KCNE1 regulatory subunit confers the characteristic delayed slowly activating gating kinetics as well as the cAMP/protein kinase A (PKA) pathway-dependent modulation of the native current, IKs (Barhani [10], Kurokawa [1076], Marx [1077], Sanguinetti [689]).

KCNE3

In epithelia, Kv7.1 associates with the KCNE3 expression product to generate a constitutively active, voltage-independent channel crucial for fluid secretion/accumulation [1675]

293B

Kv7.1 structure To examine whether KCNQ1 channel proteins form functional channels at the plasma membrane, a selective inhibitor of the channel chromanols 293B is often used. 293B maximally inhibited 60% of the outward current at 100 lM with a half maximal concentration (IC50) of 37 umol/l [1674]

Retigabine

Additionally, Leu-272 in S5, Leu-314 within the inner pore loop, and Leu-338 in S6 of the neighbouring subunit are of importance for the binding of retigabine. These four amino acids are not found in Kv7.1, thus explaining why this subtype is insensitive to retigabine-induced enhancement [1675]

E-4031, 4-aminopurine, tetraethylammonium, and clofilium

Kv7.1 structure Effects of E-4031, 4-aminopurine, tetraethylammonium, and clofilium on KvLQT1 current. Superimposed currents were recorded during 500-ms steps to +30 mV, from −80 mV, during the same experiment. Compounds were applied via bath perfusion in order from top to bottom. The bath was perfused with control solution for 5 min, or until effects reversed completely, between compounds [688]


MinK

Coexpression of Kv1.7 with MinK induces the cardiac current IKs. [689]

Nedd4-2

Kv7.1 structure PI3K pathway stabilizes cell surface expression of Kv7.1 channels in both polarizing and polarized cells. We find that PI3K primarily acts through SGK1 and demonstrate that SGK1 controls Kv7.1 localization by inhibiting Nedd4-2-dependent endocytosis of the channel [1670]

References

70

Selyanko AA et al. Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors.
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130

Imredy JP et al. Modeling of the adrenergic response of the human IKs current (hKCNQ1/hKCNE1) stably expressed in HEK-293 cells.
Am. J. Physiol. Heart Circ. Physiol., 2008 Nov , 295 (H1867-81).

132

Boulet IR et al. Role of the S6 C-terminus in KCNQ1 channel gating.
J. Physiol. (Lond.), 2007 Dec 1 , 585 (325-37).

133

Tinel N et al. KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel.
EMBO J., 2000 Dec 1 , 19 (6326-30).

134

Seebohm G et al. A kinetic study on the stereospecific inhibition of KCNQ1 and I(Ks) by the chromanol 293B.
Br. J. Pharmacol., 2001 Dec , 134 (1647-54).

248

Sato A et al. Novel mechanisms of trafficking defect caused by KCNQ1 mutations found in long QT syndrome.
J. Biol. Chem., 2009 Dec 11 , 284 (35122-33).

249

Bal M et al. Ca2+/calmodulin disrupts AKAP79/150 interactions with KCNQ (M-Type) K+ channels.
J. Neurosci., 2010 Feb 10 , 30 (2311-23).

335

Peroz D et al. Kv7.1 (KCNQ1) properties and channelopathies.
J. Physiol. (Lond.), 2008 Apr 1 , 586 (1785-9).

464

Jentsch TJ Neuronal KCNQ potassium channels: physiology and role in disease.
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684

Goldenberg I et al. Long QT syndrome.
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686

Curran ME et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
Cell, 1995 Mar 10 , 80 (795-803).

688

Yang WP et al. KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias.
Proc. Natl. Acad. Sci. U.S.A., 1997 Apr 15 , 94 (4017-21).

689

Sanguinetti MC et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel.
Nature, 1996 Nov 7 , 384 (80-3).

722

Robbins J KCNQ potassium channels: physiology, pathophysiology, and pharmacology.
Pharmacol. Ther., 2001 Apr , 90 (1-19).

1074

Barhanin J et al. K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current.
Nature, 1996 Nov 7 , 384 (78-80).

1075

Sanguinetti MC Dysfunction of delayed rectifier potassium channels in an inherited cardiac arrhythmia.
Ann. N. Y. Acad. Sci., 1999 Apr 30 , 868 (406-13).

1076

Kurokawa J et al. Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel.
Proc. Natl. Acad. Sci. U.S.A., 2003 Feb 18 , 100 (2122-7).

1083

Zagotta WN et al. Shaker potassium channel gating. III: Evaluation of kinetic models for activation.
J. Gen. Physiol., 1994 Feb , 103 (321-62).

1084

Han W et al. Slow delayed rectifier current and repolarization in canine cardiac Purkinje cells.
Am. J. Physiol. Heart Circ. Physiol., 2001 Mar , 280 (H1075-80).

1671

Yamagata K et al. Voltage-gated K+ channel KCNQ1 regulates insulin secretion in MIN6 β-cell line.
Biochem. Biophys. Res. Commun., 2011 Apr 15 , 407 (620-5).

1672

Dedek K et al. Colocalization of KCNQ1/KCNE channel subunits in the mouse gastrointestinal tract.
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1673

Lee MP et al. Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice.
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1674

Ullrich S et al. Effects of I(Ks) channel inhibitors in insulin-secreting INS-1 cells.
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1676

Silva JR et al. A multiscale model linking ion-channel molecular dynamics and electrostatics to the cardiac action potential.
Proc. Natl. Acad. Sci. U.S.A., 2009 Jul 7 , 106 (11102-6).

1677

Brueggemann LI et al. Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy.
Am. J. Physiol. Lung Cell Mol. Physiol., 2012 Jan , 302 (L120-32).

1678

McCallum LA et al. The contribution of Kv7 channels to pregnant mouse and human myometrial contractility.
J. Cell. Mol. Med., 2011 Mar , 15 (577-86).

1682

Goldman AM et al. Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death.
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1705

Smith JA et al. Structural models for the KCNQ1 voltage-gated potassium channel.
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1752

Grahammer F et al. The cardiac K+ channel KCNQ1 is essential for gastric acid secretion.
Gastroenterology, 2001 May , 120 (1363-71).

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Credits

Contributors: Rajnish Ranjan, Michael Schartner, Nitin Khanna, Katherine Johnston

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/23/ , accessed on 2024 Dec 21