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Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''KCNE2''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
on
chromosome 21 Chromosome 21 is one of the 23 pairs of chromosomes in humans. Chromosome 21 is both the smallest human autosome and chromosome, with 46.7 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cell ...
. MiRP1 is a
voltage-gated potassium channel Voltage-gated potassium channels (VGKCs) are potassium channel, transmembrane channels specific for potassium and Voltage-gated ion channel, sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a ...
accessory subunit (beta subunit) associated with
Long QT syndrome 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 fainti ...
. It is ubiquitously expressed in many tissues and cell types. Because of this and its ability to regulate multiple different
ion channel 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 (electrophysiol ...
s, 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 The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
and intracellular
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...
. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited
cardiac arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beat ...
s. The ''KCNE2'' gene also contains one of 27
SNPs In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
associated with increased risk of
coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...
. More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored.


Discovery

Steve Goldstein (then at Yale University) used a BLAST search strategy, focusing on KCNE1 sequence stretches known to be important for function, to identify related expressed sequence tags (ESTs) in the NCBI database. Using sequences from these ESTs, KCNE2, 3 and 4 were cloned.


Tissue distribution

KCNE2 protein is most readily detected in the
choroid plexus The choroid plexus, or plica choroidea, is a plexus of cells that arises from the tela choroidea in each of the ventricles of the brain. Regions of the choroid plexus produce and secrete most of the cerebrospinal fluid (CSF) of the central ...
epithelium, gastric
parietal cell Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions o ...
s, and thyroid epithelial cells. KCNE2 is also expressed in atrial and ventricular cardiomyocytes, the pancreas, pituitary gland, and lung epithelium. In situ hybridization data suggest that KCNE2 transcript may also be expressed in various neuronal populations.


Structure


Gene

The ''KCNE2'' gene resides on chromosome 21 at the band 21q22.11 and contains 2
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
s. Since human ''KCNE2'' is located ~79 kb from ''KCNE1'' and in the opposite direction, KCNE2 is proposed to originate from a
gene duplication Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene ...
event.


Protein

This protein belongs to the potassium channel KCNE family and is one five single
transmembrane domain A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...
voltage-gated potassium (Kv) channel ancillary subunits. KCNE2 is composed of three major domains: the
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
domain, the transmembrane domain, and the
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...
domain. The N-terminal domain protrudes out of the
extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
side of the
cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
and is, thus,
soluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubi ...
in the aqueous environment. Meanwhile, the transmembrane and C-terminal domains are lipid-soluble to enable the protein to incorporate into the cell membrane. The C-terminal faces the
intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
side of the membrane and may share a putative PKC
phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...
site with other KCNE proteins. Like other KCNEs, KCNE2 forms a
heteromer A heteromer is something that consists of different parts; the antonym of homomeric. Examples are: Biology * Spinal neurons that pass over to the opposite side of the spinal cord. * A protein complex that contains two or more different polypeptide ...
ic
complex Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...
with the Kv α subunits.


Function


Choroid plexus epithelium

KCNE2 protein is most readily detected in the
choroid plexus The choroid plexus, or plica choroidea, is a plexus of cells that arises from the tela choroidea in each of the ventricles of the brain. Regions of the choroid plexus produce and secrete most of the cerebrospinal fluid (CSF) of the central ...
epithelium, at the apical side. KCNE2 forms complexes there with the voltage-gated potassium channel α subunit, Kv1.3. In addition, KCNE2 forms reciprocally regulating tripartite complexes in the choroid plexus epithelium with the
KCNQ1 Kv7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the ''KCNQ1'' gene. Its mutation causes Long QT syndrome, Kv7.1 is a voltage and lipid-gated potassium channel present in the cell membranes of cardi ...
α subunit and the sodium-dependent ''myo''-inositol transporter, SMIT1. ''Kcne2''-/- mice exhibit increased seizure susceptibility, reduced immobility time in the tail suspension test, and reduced cerebrospinal fluid ''myo''-inositol content, compared to wild-type littermates. Mega-dosing of ''myo''-inositol reverses all these phenotypes, suggesting a link between ''myo''-inositol and the seizure susceptibility and behavioral alterations in ''Kcne2''-/- mice.


Gastric epithelium

KCNE2 is also highly expressed in parietal cells of the gastric epithelium, also at the apical side. In these cells,
KCNQ1 Kv7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the ''KCNQ1'' gene. Its mutation causes Long QT syndrome, Kv7.1 is a voltage and lipid-gated potassium channel present in the cell membranes of cardi ...
-KCNE2 K+ channels, which are constitutively active, provide a conduit to return K+ ions back to the stomach lumen. The K+ ions enter the parietal cell through the gastric H+/K+-ATPase, which swaps them for protons as it acidifies the stomach. While KCNQ1 channels are inhibited by low extracellular pH, KCNQ1-KCNE2 channels activity is augmented by extracellular protons, an ideal characteristic for their role in parietal cells.


Thyroid epithelium

KCNE2 forms constitutively active K+ channels with KCNQ1 in the basolateral membrane of thyroid epithelial cells. ''Kcne2''-/- mice exhibit
hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...
, particularly apparent during
gestation Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregn ...
or
lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process ...
. KCNQ1-KCNE2 is required for optimal iodide uptake into the thyroid by the basolateral sodium iodide symporter (NIS). Iodide is required for biosynthesis of
thyroid hormone File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones triiodothyronine, T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus r ...
s.


Heart

KCNE2 was originally discovered to regulate
hERG hERG (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution t ...
channel function. KCNE2 decreases macroscopic and unitary current through hERG, and speeds hERG deactivation. hERG generates IKr, the most prominent repolarizing current in human ventricular
cardiomyocyte Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
s. hERG, and IKr, are highly susceptible to block by a range of structurally diverse pharmacological agents. This property means that many drugs or potential drugs have the capacity to impair human ventricular repolarization, leading to drug-induced
long QT syndrome 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 fainti ...
. KCNE2 may also regulate hyperpolarization-activated, cyclic-nucleotide-gated (HCN) pacemaker channels in human heart and in the hearts of other species, as well as the Cav1.2 voltage-gated calcium channel. In mice, mERG and KCNQ1, another Kv α subunit regulated by KCNE2, are neither influential nor highly expressed in adult ventricles. However, ''Kcne2''-/- mice exhibit QT prolongation at baseline at 7 months of age, or earlier if provoked with a QT-prolonging agent such as
sevoflurane Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflu ...
. This is because KCNE2 is a promiscuous regulatory subunit that forms complexes with Kv1.5 and with Kv4.2 in adult mouse ventricular myocytes. KCNE2 increases currents though Kv4.2 channels and slows their inactivation. KCNE2 is required for Kv1.5 to localize to the intercalated discs of mouse ventricular myocytes. ''Kcne2'' deletion in mice reduces the native currents generated in ventricular myocytes by Kv4.2 and Kv1.5, namely Ito and IKslow, respectively.


Clinical significance


Gastric epithelium

''Kcne2''-/- mice exhibit
achlorhydria Achlorhydria and hypochlorhydria are states where the production of hydrochloric acid in gastric secretions of the stomach is absent or low, respectively. Achlorhydria is commonly a complication of some other disease, such as chronic '' Helicobac ...
, gastric
hyperplasia Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of Tissue (biology), organic tissue that results from ...
, and mis-trafficking of KCNQ1 to the parietal cell basal membrane. The mis-trafficking occurs because
KCNE3 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. Function Voltage-gated potassium channels (Kv) represent the mos ...
is upregulated in the parietal cells of ''Kcne2''-/- mice, and hijacks KCNQ1, taking it to the
basolateral membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extra ...
. When both ''Kcne2'' and ''Kcne3'' are germline-deleted in mice, KCNQ1 traffics to the parietal cell apical membrane but the gastric phenotype is even worse than for ''Kcne2''-/- mice, emphasizing that KCNQ1 requires KCNE2 co-assembly for functional attributes other than targeting in parietal cells. ''Kcne2''-/- mice also develop gastritis cystica profunda and gastric
neoplasia A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
. Human KCNE2 downregulation is also observed in sites of gastritis cystica profunda and gastric adenocarcinoma.


Thyroid epithelium

Positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...
data show that with KCNE2, 124I uptake by the thyroid is impaired. ''Kcne2'' deletion does not impair organification of iodide once it has been taken up by NIS. Pups raised by ''Kcne2''-/- dams are particularly severely affected becauset they receive less milk (hypothyroidism of the dams impairs milk ejection), the milk they receive is deficient in T4, and they themselves cannot adequately transport iodide into the thyroid. ''Kcne2''-/- pups exhibit stunted growth,
alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...
,
cardiomegaly Cardiomegaly (sometimes megacardia or megalocardia) is a medical condition in which the heart becomes enlarged. It is more commonly referred to simply as "having an enlarged heart". It is usually the result of underlying conditions that make the h ...
and reduced cardiac
ejection fraction An ejection fraction (EF) is the volumetric fraction (or portion of the total) of fluid (usually blood) ejected from a chamber (usually the heart) with each contraction (or heartbeat). It can refer to the cardiac atrium, cardiac ventricle, gall ...
, all of which are alleviated by thyroid hormone supplementation of pups or dams. Surrogating ''Kcne2''-/- pups with ''Kcne2''+/+ dams also alleviates these phenotypes, highlighting the influence of maternal genotype in this case.


Heart

As observed for hERG mutations, KCNE2 loss-of-function mutations are associated with inherited long QT syndrome, and hERG-KCNE2 channels carrying the mutations show reduced activity compared to wild-type channels. In addition, some KCNE2 mutations and also more common polymorphisms are associated with drug-induced long QT syndrome. In several cases, specific KCNE2 sequence variants increase the susceptibility to hERG-KCNE2 channel inhibition by the drug that precipitated the QT prolongation in the patient from which the gene variant was isolated. Long QT syndrome predisposes to potentially lethal ventricular
cardiac arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beat ...
s including torsades de pointe, which can degenerate into
ventricular fibrillation Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the Ventricle (heart), ventricles of the heart Fibrillation, quiver. It is due to disorganized electrical conduction system of the heart, electrical activity. Ventricula ...
and
sudden cardiac death Cardiac arrest (also known as sudden cardiac arrest ''SCA is when the heart suddenly and unexpectedly stops beating. When the heart stops beating, blood cannot properly circulate around the body and the blood flow to the brain and other org ...
. Moreover, KCNE2 gene variation can disrupt HCN1-KCNE2 channel function and this may potentially contribute to cardiac arrhythmogenesis. KCNE2 is also associated with familial atrial fibrillation, which may involve excessive KCNQ1-KCNE2 current caused by KCNE2 gain-of-function mutations. Recently, a battery of extracardiac effects were discovered in ''Kcne2''-/- mice that may contribute to cardiac arrhythmogenesis in ''Kcne2''-/- mice and could potentially contribute to human cardiac arrhythmias if similar effects are observed in human populations. ''Kcne2'' deletion in mice causes anemia, glucose intolerance, dyslipidemia, hyperkalemia and elevated serum angiotensin II. Some or all of these might contribute to predisposition to sudden cardiac death in ''Kcne2''-/- mice in the context of myocardial ischemia and post-ischemic arrhythmogenesis.


Clinical marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the ''KCNE2'' gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from
statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...
therapy. The study was based on a community
cohort study A cohort study is a particular form of longitudinal study that samples a Cohort (statistics), cohort (a group of people who share a defining characteristic, typically those who experienced a common event in a selected period, such as birth or gra ...
(the Malmo Diet and Cancer study) and four additional
randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...
s of
primary prevention Preventive healthcare, or prophylaxis, is the application of healthcare measures to prevent diseases.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental health a ...
cohorts (JUPITER and ASCOT) and
secondary prevention Preventive healthcare, or prophylaxis, is the application of healthcare measures to prevent diseases.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental health a ...
cohorts (CARE and PROVE IT-TIMI 22).


See also

*
Voltage-gated potassium channel Voltage-gated potassium channels (VGKCs) are potassium channel, transmembrane channels specific for potassium and Voltage-gated ion channel, sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a ...
*
KCNE1 Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the ''KCNE1'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence ...
*
KCNE3 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. Function Voltage-gated potassium channels (Kv) represent the mos ...
*
KCNQ1 Kv7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the ''KCNQ1'' gene. Its mutation causes Long QT syndrome, Kv7.1 is a voltage and lipid-gated potassium channel present in the cell membranes of cardi ...


Notes


References


Further reading

* * * * * * * * * * * * * * * * * *


External links


GeneReviews/NIH/NCBI/UW entry on Romano-Ward Syndrome
* * * * {{DEFAULTSORT:Kcne2 Ion channels Articles containing video clips