KCNE5

KCNE5
Identifiers
Aliases	KCNE5, KCNE1L, potassium voltage-gated channel subfamily E regulatory subunit 5
External IDs	OMIM: 300328; MGI: 1913490; HomoloGene: 8177; GeneCards: KCNE5; OMA:KCNE5 - orthologs
Gene location (Human) Chr. X chromosome (human)[1] Band Xq23 Start 109,623,700 bp[1] End 109,625,172 bp[1]
Gene location (Mouse) Chr. X chromosome (mouse)[2] Band X|X F2 Start 141,087,748 bp[2] End 141,089,290 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gonad substantia nigra nucleus accumbens hypothalamus putamen caudate nucleus amygdala hippocampus proper right hemisphere of cerebellum primary visual cortex Top expressed in ankle ventricular zone neural tube embryo internal carotid artery tail of embryo embryo Gonadal ridge medial ganglionic eminence optic nerve More reference expression data BioGPS n/a
Gene ontology Molecular function transmembrane transporter binding voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization potassium channel regulator activity protein binding voltage-gated potassium channel activity delayed rectifier potassium channel activity voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization Cellular component integral component of membrane membrane voltage-gated potassium channel complex plasma membrane Biological process regulation of atrial cardiac muscle cell membrane repolarization regulation of heart contraction cardiac muscle contraction ventricular cardiac muscle cell action potential ion transport regulation of cation channel activity atrial cardiac muscle cell action potential potassium ion transmembrane transport positive regulation of potassium ion transmembrane transport negative regulation of potassium ion transmembrane transport regulation of membrane repolarization regulation of heart rate by cardiac conduction regulation of potassium ion transmembrane transport regulation of ventricular cardiac muscle cell membrane repolarization membrane repolarization during cardiac muscle cell action potential membrane repolarization during action potential membrane repolarization during ventricular cardiac muscle cell action potential negative regulation of delayed rectifier potassium channel activity potassium ion export across plasma membrane negative regulation of potassium ion export across plasma membrane Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23630 66240 Ensembl ENSG00000176076 ENSMUSG00000090122 UniProt Q9UJ90 Q9QZ26 RefSeq (mRNA) NM_012282 NM_021487 RefSeq (protein) NP_036414 NP_067462 Location (UCSC) Chr X: 109.62 – 109.63 Mb Chr X: 141.09 – 141.09 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.^[5][6]

Voltage-gated potassium (K_v) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. KCNE5 encodes a membrane protein, KCNE5 (originally named KCNE1-L) that has sequence similarity to the KCNE1 gene product, a member of the potassium channel, voltage-gated, isk-related subfamily.^[6]

The KCNE gene family comprises five genes in the human genome, each encoding a type I membrane protein. The KCNE subunits are potassium channel regulatory subunits that do not pass currents themselves but alter the properties of potassium channel pore-forming alpha subunits. KCNE5 is thus far the least-studied member of the KCNE family, but it is known to regulate a number of different K_v channel subtypes. KCNE5 co-assembles with KCNQ1, a K_v alpha subunit best known for its role in ventricular repolarization and in multiple epithelia. This co-assembly induces a +140 mV shift in voltage dependence of activation (when co-expressed in CHO cells) which would inhibit KCNQ1 activity across the normal physiological voltage range in most tissues.^[7]

KCNE5 also inhibits activity of channels formed with KCNQ1 and KCNE1.^[8] While reportedly not affecting KCNQ2, KCNQ2/3 or KCNQ5 channel activity, KCNE5 inhibits KCNQ4 in CHO cells^[7] but not in oocytes.^[9]

Although it has no known effects on hERG (K_v11.1) or K_v1.x family channel activity, KCNE5 inhibits K_v2.1 activity 50% and accelerates activation, slows deactivation and accelerates the recovery from closed state inactivation of channels formed by K_v2.1 and the 'silent' alpha subunit, K_v6.4.^[10]

KCNE5 was previously reported to not regulate K_v4.2 or K_v4.3, but has been found to accelerate, and left-shift the voltage dependence of, inactivation of K_v4.3-KChIP2 channel complexes.^[11]

The KCNE family subunits are type I membrane proteins with an extracellular N-terminus and intracellular C-terminus.^[12] The transmembrane domain is alpha helical in KCNE1, 2 and 3 and predicted to also be helical in KCNE4 and KCNE5. The acknowledged role of members of the KCNE family is as K_v channel beta subunits, regulating the functional properties of K_v alpha subunits, with all three segments of the beta subunit contributing to binding, functional modulation and/or trafficking modulation to a greater or lesser degree. The high resolution structure of KCNE5 has not yet been determined, as of 2016. KCNE5 is an X-linked gene encoding a 143 residue protein in Homo sapiens.^[5]

Human KCNE5 transcripts are most highly expressed in cardiac and skeletal muscle, spinal cord and brain, and it is also detectable in placenta.^[5][13] In mice, Kcne5 transcript was detected in embryonic cranial nerve migrating crest cells, ganglia, somites and myoepicaridal layer.^[5]

This intronless gene is deleted in AMME contiguous gene syndrome and is potentially involved in the cardiac and neurologic abnormalities found in the AMME contiguous gene syndrome.^[5]

KCNE5 is expressed in the human placenta and its expression increases in preeclampsia, although causality has not been established for this phenomenon.^[13]

Inherited sequence variants in human KCNE5 are associated with atrial fibrillation and Brugada syndrome. Atrial fibrillation is the most common chronic cardiac arrhythmia, affecting 2-3 million in the United States alone, predominantly in the aging population. A minority of cases are linked to ion channel gene mutations, whereas the majority are associated with structural heart defects. Brugada syndrome is a relatively rare but lethal ventricular arrhythmia most commonly linked to voltage-gated sodium channel gene SCN5A mutations, but also associated with some K_v channel gene sequence variants.

KCNE5 mutation L65F is associated with atrial fibrillation and upregulates KCNQ1-KCNE1 currents when co-expressed with these subunits. In contrast, a polymorphism in KCNE5 encoding a P33S substitution was found to be less common in atrial fibrillation patients than in control subjects,^[14] although these findings were at odds with those of other studies.^[15]

KCNE5-Y81H was detected in a man with a type 1 Brugada pattern body-surface electrocardiogram, while KCNE5-D92E:E93X was detected in another case of Brugada and associated with premature sudden death in other male family members, but not females - significant because KCNE5 is an X-linked gene. These two gene variants did not affect KCNQ1-KCNE1 currents when co-expressed in CHO cells, but produced larger currents than wild-type KCNE5 when coexpressed with K_v4.3-KChIP2, giving a possible mechanism for Brugada syndrome, i.e., increased ventricular Ito density.^[16]

A KCNE5 non-coding region gene variant, the G variant of the rs697829 A/G polymorphism, has also been reported to associate with prolonged QT interval and higher hazard ratio for death, compared to the G variant.^[17]

The 2016 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: Geoffrey W Abbott (30 July 2016). "KCNE4 and KCNE5: K(+) channel regulation and cardiac arrhythmogenesis". Gene. Gene Wiki Review Series. 593 (2): 249–260. doi:10.1016/J.GENE.2016.07.069. ISSN 0378-1119. PMC 5166581. PMID 27484720. Wikidata Q38916407.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.