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
Click for details 15 °C show 104 cells	Click for details 25 °C show 45 cells	Click for details 35 °C show 88 cells

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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

Known

NM_001406837.1

3316

NP_001393766.1

586

transcript variant 4

isoform 4

NM_000218.3

3224

NP_000209.2

676

transcript variant 1

isoform 1

NM_001406836.1

3128

NP_001393765.1

644

transcript variant 3

isoform 3

NM_001406838.1

2684

NP_001393767.1

496

transcript variant 5

isoform 5

NM_181798.2

3021

NP_861463.1

549

transcript variant 2

isoform 2 precursor

NM_001406839.1

1652

NP_001393768.1

180

transcript variant 6

isoform 6

Known

NM_008434.2

3052

NP_032460.2

668

isoform 1

NM_001412611.1

2806

NP_001399540.1

557

isoform 2

NM_001412612.1

2746

NP_001399541.1

511

isoform 3

Predicted

XM_006508492.3

2611

XP_006508555.1

556

transcript variant X6

isoform X6

XM_006508490.4

1990

XP_006508553.3

558

transcript variant X4

isoform X4

XM_006508491.4

1778

XP_006508554.3

558

transcript variant X5

isoform X5

XM_006508488.4

3104

XP_006508551.2

688

transcript variant X1

isoform X1

XM_011241982.3

2105

XP_011240284.2

634

transcript variant X2

isoform X2

XM_006508489.5

1737

XP_006508552.2

524

transcript variant X3

isoform X3

XM_017321998.1

2786

XP_017177487.1

511

transcript variant X8

isoform X8

XM_036152718.1

2655

XP_036008611.1

536

transcript variant X7

isoform X7

Known

NM_032073.2

3017

NP_114462.2

669

Predicted

XM_039092713.1

4342

XP_038948641.1

490

transcript variant X3

isoform X3

XM_039092720.1

5184

XP_038948648.1

488

transcript variant X4

isoform X4

XM_039092702.1

3248

XP_038948630.1

641

transcript variant X1

isoform X1

XM_039092725.1

5178

XP_038948653.1

467

transcript variant X5

isoform X5

XM_039092705.1

3025

XP_038948633.1

614

transcript variant X2

isoform X2

XM_039092732.1

2105

XP_038948660.1

366

transcript variant X6

isoform X6

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Post-Translational Modifications

PTM

Position

Type

Modified residue

Phosphoserine; by PKA

Modified residue

407

Phosphoserine

Modified residue

409

Phosphoserine

Glycosylation

289

N-linked (GlcNAc...) asparagine

Modified residue

Phosphoserine; by PKA

Modified residue

406

Phosphoserine

Modified residue

408

Phosphoserine

Glycosylation

288

N-linked (GlcNAc...) asparagine

Modified residue

Phosphoserine; by PKA

Modified residue

407

Phosphoserine

Modified residue

409

Phosphoserine

Glycosylation

289

N-linked (GlcNAc...) asparagine

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Structure

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

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

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

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]

(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

[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

[1676]

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Biophysics

HODGKIN AND HUXLEY MODEL

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

[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

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

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

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]