KvLQT1

Last updated

KCNQ1
Protein CD44 PDB 1poz.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases KCNQ1 , ATFB1, ATFB3, JLNS1, KCNA8, KCNA9, KVLQT1, Kv1.9, Kv7.1, LQT, LQT1, RWS, SQT2, WRS, potassium voltage-gated channel subfamily Q member 1
External IDs OMIM: 607542; MGI: 108083; HomoloGene: 85014; GeneCards: KCNQ1; OMA:KCNQ1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3784

16535

Ensembl

ENSG00000282076
ENSG00000053918

ENSMUSG00000009545

UniProt

P51787

P97414

RefSeq (mRNA)

NM_181798
NM_000218
NM_181797

NM_008434

RefSeq (protein)

NP_000209
NP_861463

NP_032460

Location (UCSC) Chr 11: 2.44 – 2.85 Mb Chr 7: 142.66 – 142.98 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Kv7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the KCNQ1 gene. [5] It's mutation causes Long QT syndrome, Kv7.1 is a voltage and lipid-gated potassium channel present in the cell membranes of cardiac tissue and in inner ear neurons among other tissues. In the cardiac cells, Kv7.1 mediates the IKs (or slow delayed rectifying K+) current that contributes to the repolarization of the cell, terminating the cardiac action potential and thereby the heart's contraction. It is a member of the KCNQ family of potassium channels.

Contents

Structure

KvLQT1 is made of six membrane-spanning domains S1-S6, two intracellular domains, and a pore loop. [6] The KvLQT1 channel is made of four KCNQ1 subunits, which form the actual ion channel.

Function

This gene encodes a protein for a voltage-gated potassium channel required for the repolarization phase of the cardiac action potential. The gene product can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. The gene is located in a region of chromosome 11 that contains a large number of contiguous genes that are abnormally imprinted in cancer and the Beckwith-Wiedemann syndrome. Two alternative transcripts encoding distinct isoforms have been described. [7]

Clinical significance

Mutations in the gene can lead to a defective protein and several forms of inherited arrhythmias as Long QT syndrome [8] which is a prolongation of the QT interval of heart repolarization, Short QT syndrome, [8] and Familial Atrial Fibrillation. KvLQT1 are also expressed in the pancreas, and KvLQT1 Long QT syndrome patients has been shown to have hyperinsulinemic hypoglycaemia following an oral glucose load. [9] Currents arising from Kv7.1 in over-expression systems have never been recapitulated in native tissues - Kv7.1 is always found in native tissues with a modulatory subunit. In cardiac tissue, these subunits comprise KCNE1 and yotiao. Though physiologically irrelevant, homotetrameric Kv7.1 channels also display a unique form of C-type inactivation that reaches equilibrium quickly, allowing KvLQT1 currents to plateau. This is different from the inactivation seen in A-type currents, which causes rapid current decay.

Ligands

Interactions

KvLQT1 has been shown to interact with PRKACA, [11] PPP1CA [11] and AKAP9. [11]

KvLQT1 can also associate with any of the five members of the KCNE family of proteins, but interactions with KCNE1, KCNE2, KCNE3 are the only interactions within this protein family that affect the human heart. KCNE2, KCNE4, and KCNE5 have been shown to have an inhibitory effect on the functionality of KvLQT1, while KCNE1 and KCNE3 are activators of KvLQT1. [6] KvLQT1 can associate with KCNE1 and KCNE4 with the activation effects of KCNE1 overriding the inhibitory effects of KCNE4 on the KvLQT1 channel, and KvLQT1 will commonly associate with anywhere from two to four different KCNE proteins in order to be functional. [6] However, KvLQT1 most commonly associates with KCNE1 and forms the KvLQT1/KCNE1 complex since it has only been seen to function in vivo when associated with another protein. [6] KCNQ1 will form a heteromer with KCNE1 in order to slow its activation and enhance the current density at the plasma membrane of the neuron. [6] [12] In addition to associating with KCNE proteins, the N-terminal juxtamembranous domain of KvLQT1 can also associate with SGK1, which stimulates the slow delayed potassium rectifier current. Since SGK1 requires structural integrity to stimulate KvLQT1/KCNE1, any mutations present in the KvLQT1 protein can result in reduced stimulation of this channel by SGK1. [13] General mutations in KvLQT1 have been known to cause a decrease in this slow delayed potassium rectifier current, longer cardiac action potentials, and a tendency to have tachyarrhythmias. [12]

KvLQT1/KCNE1

KCNE1 (minK), can assemble with KvLQT1 to form a slow delayed potassium rectifier channel. KCNE1 slows the inactivation of KvLQT1 when the two proteins form a heteromeric complex, and the current amplitude is greatly increased compared to WT-KvLQT1 homotetrameric channels. KCNE1 associates with the pore region of KvLQT1, and its transmembrane domain contributes to the selectivity filter of this heteromeric channel complex. [12] The alpha helix of the KCNE1 protein interacts with the pore domain S5/S6 and with the S4 domain of the KvLQT1 channel. This results in structural modifications of the voltage sensor and the selectivity filter of the KvLQT1 channel. [14] Mutations in either the alpha subunit of this complex, KvLQT1 or the beta subunit, KCNE1, can lead to Long QT Syndrome or other cardiac rhythmic deformities. [13] When associated with KCNE1, the KvLQT1 channel activates much more slowly and at a more positive membrane potential. It is believed that two KCNE1 proteins interact with a tetrameric KvLQT1 channel, since experimental data suggests that there are 4 alpha subunits and 2 beta subunits in this complex. [14] KVLQT1/KCNE1 channels are taken up from the plasma membrane through a RAB5 dependent mechanism, but inserted into the membrane by RAB11, a GTPase. [15]

See also

Related Research Articles

<span class="mw-page-title-main">Ion channel</span> Pore-forming membrane protein

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

<span class="mw-page-title-main">Long QT syndrome</span> Medical condition

Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, drowning, seizures, or sudden death. These episodes can be triggered by exercise or stress. Some rare forms of LQTS are associated with other symptoms and signs including deafness and periods of muscle weakness.

<span class="mw-page-title-main">Repolarization</span> Change in membrane potential

In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarization phase usually returns the membrane potential back to the resting membrane potential. The efflux of potassium (K+) ions results in the falling phase of an action potential. The ions pass through the selectivity filter of the K+ channel pore.

<span class="mw-page-title-main">Romano–Ward syndrome</span> Medical condition

Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death. Romano–Ward syndrome can be distinguished clinically from other forms of inherited LQTS as it affects only the electrical properties of the heart, while other forms of LQTS can also affect other parts of the body.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g. muscle, glial cells, neurons) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

hERG Mammalian protein found in humans

hERG is a gene that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart's beating.

<span class="mw-page-title-main">Inward-rectifier potassium channel</span> Group of transmembrane proteins that passively transport potassium ions

Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are activated by phosphatidylinositol 4,5-bisphosphate (PIP2). The malfunction of the channels has been implicated in several diseases. IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export. The process of inward-rectification was discovered by Denis Noble in cardiac muscle cells in 1960s and by Richard Adrian and Alan Hodgkin in 1970 in skeletal muscle cells.

<span class="mw-page-title-main">Voltage-gated potassium channel</span> Class of transport proteins

Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state.

<span class="mw-page-title-main">KCNE1</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the KCNE1 gene.

<span class="mw-page-title-main">KCNE2</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a protein that in humans is encoded by the KCNE2 gene on chromosome 21. MiRP1 is a voltage-gated potassium channel accessory subunit associated with Long QT syndrome. It is ubiquitously expressed in many tissues and cell types. Because of this and its ability to regulate multiple different ion channels, KCNE2 exerts considerable influence on a number of cell types and tissues. Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain a single membrane-spanning region, extracellular N-terminal and intracellular C-terminal. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited cardiac arrhythmias. The KCNE2 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored.

<span class="mw-page-title-main">KvLQT2</span> Protein-coding gene in humans

Kv7.2 (KvLQT2) is a voltage- and lipid-gated potassium channel protein coded for by the gene KCNQ2.

<span class="mw-page-title-main">KvLQT3</span> Protein-coding gene in the species Homo sapiens

Kv7.3 (KvLQT3) is a potassium channel protein coded for by the gene KCNQ3.

<span class="mw-page-title-main">KCNA4</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily A member 4 also known as Kv1.4 is a protein that in humans is encoded by the KCNA4 gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.

<span class="mw-page-title-main">KCNE3</span> Protein-coding gene in humans

Potassium voltage-gated channel, Isk-related family, member 3 (KCNE3), also known as MinK-related peptide 2(MiRP2) is a protein that in humans is encoded by the KCNE3 gene.

<span class="mw-page-title-main">KCND3</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily D member 3 also known as Kv4.3 is a protein that in humans is encoded by the KCND3 gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.

<span class="mw-page-title-main">KCNQ4</span> Mammalian protein found in Homo sapiens

Potassium voltage-gated channel subfamily KQT member 4, also known as voltage-gated potassium channel subunit Kv7.4, is a protein that in humans is encoded by the KCNQ4 gene.

<span class="mw-page-title-main">KCNE4</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily E member 4, originally named MinK-related peptide 3 or MiRP3 when it was discovered, is a protein that in humans is encoded by the KCNE4 gene.

<span class="mw-page-title-main">KCNE5</span> Protein-coding gene in the species Homo sapiens

KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.

<span class="mw-page-title-main">SGK1</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase Sgk1 also known as serum and glucocorticoid-regulated kinase 1 is an enzyme that in humans is encoded by the SGK1 gene.

KCNQ genes encode family members of the Kv7 potassium channel family. These include Kv7.1 (KCNQ1) - KvLQT1, Kv7.2 (KCNQ2), Kv7.3 (KCNQ3), Kv7.4 (KCNQ4), and Kv7.5 (KCNQ5). Four of these (KCNQ2-5) are expressed in the nervous system. They constitute a group of low-threshold voltage-gated K+ channels originally termed the ‘M-channel’ (see M-current). The M-channel name comes from the classically described mechanism wherein the activation of the muscarinic acetylcholine receptor deactivated this channel.

References

  1. 1 2 3 ENSG00000053918 GRCh38: Ensembl release 89: ENSG00000282076, ENSG00000053918 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000009545 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Jespersen T, Grunnet M, Olesen SP (2005). "The KCNQ1 potassium channel: from gene to physiological function". Physiology. 20 (6): 408–416. doi:10.1152/physiol.00031.2005. PMID   16287990.
  6. 1 2 3 4 5 Bendahhou S, Marionneau C, Haurogne K, Larroque MM, Derand R, Szuts V, Escande D, Demolombe S, Barhanin J (August 2005). "In vitro molecular interactions and distribution of KCNE family with KCNQ1 in the human heart". Cardiovascular Research. 67 (3): 529–538. doi: 10.1016/j.cardiores.2005.02.014 . PMID   16039274.
  7. ↑ "Entrez Gene: KCNQ1 potassium voltage-gated channel, KQT-like subfamily, member 1".
  8. 1 2 Hedley PL, Jørgensen P, Schlamowitz S, Wangari R, Moolman-Smook J, Brink PA, Kanters JK, Corfield VA, Christiansen M (November 2009). "The genetic basis of long QT and short QT syndromes: a mutation update". Human Mutation. 30 (11): 1486–1511. doi: 10.1002/humu.21106 . PMID   19862833. S2CID   19122696.
  9. ↑ Torekov SS, Iepsen E, Christiansen M, Linneberg A, Pedersen O, Holst JJ, Kanters JK, Hansen T (2014). "KCNQ1 Long QT syndrome patients have hyperinsulinemia and symptomatic hypoglycemia.)". Diabetes. 63 (4): 1315–1325. doi: 10.2337/db13-1454 . PMID   24357532.
  10. ↑ Mattmann ME, Yu H, Lin Z, Xu K, Huang X, Long S, Wu M, McManus OB, Engers DW, Le UM, Li M, Lindsley CW, Hopkins CR (2012). "Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K(v)7.1 (KCNQ1) potassium channel activator". Bioorganic & Medicinal Chemistry Letters. 22 (18): 5936–5941. doi:10.1016/j.bmcl.2012.07.060. PMC   3433560 . PMID   22910039.
  11. 1 2 3 Marx SO, Kurokawa J, Reiken S, Motoike H, D'Armiento J, Marks AR, Kass RS (January 2002). "Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel". Science. 295 (5554): 496–499. Bibcode:2002Sci...295..496M. doi:10.1126/science.1066843. PMID   11799244. S2CID   6153394.
  12. 1 2 3 Tristani-Firouzi M, Sanguinetti MC (1998). "Voltage-dependent inactivation of the human K+ channel KvLQT1 is eliminated by association with minimal K+ channel (minK) subunits". The Journal of Physiology. 510 (Pt 1): 37–45. doi:10.1111/j.1469-7793.1998.037bz.x. PMC   2231024 . PMID   9625865.
  13. 1 2 Seebohm G, Strutz-Seebohm N, Ureche ON, Henrion U, Baltaev R, Mack AF, Korniychuk G, Steinke K, Tapken D, Pfeufer A, Kääb S, Bucci C, Attali B, Merot J, Tavare JM, Hoppe UC, Sanguinetti MC, Lang F (December 2008). "Long QT syndrome-associated mutations in KCNQ1 and KCNE1 subunits disrupt normal endosomal recycling of IKs channels". Circulation Research. 103 (12): 1451–1457. doi:10.1161/CIRCRESAHA.108.177360. PMID   19008479. S2CID   21497142.
  14. 1 2 Strutz-Seebohm N, Pusch M, Wolf S, Stoll R, Tapken D, Gerwert K, Attali B, Seebohm G (2011). "Structural basis of slow activation gating in the cardiac I Ks channel complex". Cellular Physiology and Biochemistry. 27 (5): 443–452. doi: 10.1159/000329965 . PMID   21691061.
  15. ↑ Seebohm G, Strutz-Seebohm N, Birkin R, Dell G, Bucci C, Spinosa MR, Baltaev R, Mack AF, Korniychuk G, Choudhury A, Marks D, Pagano RE, Attali B, Pfeufer A, Kass RS, Sanguinetti MC, Tavare JM, Lang F (March 2007). "Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels". Circulation Research. 100 (5): 686–692. doi: 10.1161/01.RES.0000260250.83824.8f . PMID   17293474.

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