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. [5] [6]
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. [5] [6]
Voltage-gated potassium channels (Kv) 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. The KCNE4 gene encodes KCNE4 (originally named MinK-related peptide 3 or MiRP3), a member of the KCNE family of voltage-gated potassium (Kv) channel ancillary or β subunits. [7]
KCNE4 is best known for modulating the KCNQ1 Kv α subunit, but it also regulates KCNQ4, Kv1.x, Kv2.1, Kv4.x and BK α subunits in heterologous co-expression experiments and/or in vivo. KCNE4 often, but not always, acts as an inhibitory subunit to suppress potassium channel function, but this varies depending on the channel subtype.
KCNE4 strongly inhibits the KCNQ1 potassium channel, which is known to play important roles in human cardiac myocyte repolarization, and in multiple epithelial cell types. [8] KCNE4 inhibition of KCNQ1 requires calmodulin, which binds to both KCNQ1 and KCNE4. [9] KCNE4 can also inhibit complexes formed by KCNQ1 and KCNE1. [10] KCNE4 has no known effect on KCNQ2, KCNQ3 or KCNQ5 channels, but augments activity of KCNQ4 in HEK cells, mesenteric artery [11] and Xenopus laevis oocytes. [12]
KCNE4 strongly inhibits Kv1.1 and Kv1.3 channels when co-expressed in HEK cells and in Xenopus laevis oocytes, while leaving Kv1.2 and Kv1.4 currents unaffected. [13] KCNE4 augments Kv1.5 current and surface expression twofold in CHO cells (but had no effect in Xenopus oocytes). Kcne4 deletion from mice impaired currents attributable to Kv1.5, in ventricular myocytes. [14]
KCNE4 inhibited Kv2.1 currents by 90% but had little to no effect on currents generated by heteromers of Kv2.1 with the regulatory α subunit Kv6.4. [15]
KCNE4 slows activation and inactivation of Kv4.2 channels, and induces overshoot upon recovery from inactivation. Co-expression with KChIP2 produces intermediate gating kinetics in complexes with Kv4.2 and KCNE4. [16] Deletion of Kcne4 in mice impaired ventricular myocyte Ito, a current generated at least in part by Kv4.2. [14]
Although mouse KCNE4 reportedly had no effect on Kv4.3 when coexpressed in oocytes, [13] human KCNE4 was found to accelerate inactivation and recovery from inactivation of Kv4.3-KChIP2 complexes. [17]
KCNE4 has also been found to regulate the large-conductance Ca2+-activated potassium channel, BK. KCNE4 inhibits BK activity by positive-shifting the voltage dependence of BK activation and accelerating BK protein degradation. [18]
KCNE4 is a type 1 membrane protein, with the transmembrane segment predicted to be alpha-helical. No studies have as yet reported the number of KCNE4 subunits within a functional channel complex; it is likely to be either 2 or 4. The majority of studies of KCNE4 function, structure-function relationships and effects of pathological gene sequence variants within KCNE4 have utilized the widely reported 170 residue version of the protein encoded by exon 2 of the human KCNE4 gene. However, in 2016 a longer form of the KCNE4 protein, termed KCNE4L, was discovered. An additional N-terminal portion of 51 residues, encoded by exon 1 of the human KCNE4 gene, were found to also be expressed in multiple human tissues, extending the human protein to 221 residues, by far the longest of the KCNE subunits. Human KCNE4L exhibits some functional differences to the shorter 170 residue form now also termed KCNE4S. KCNE4L is predicted to also be expressed in other mammals, reptiles, amphibians and fish, although the house mouse (Mus musculus) appears to only express KCNE4S because the KCNE4L start site is lacking in the house mouse genome. [19]
Human KCNE4L transcripts are most highly expressed in uterus, and next most highly expressed in atria, adrenal gland, lymph nodes, pituitary gland, spleen and ureter. KCNE4L transcript is also detectable in cervix, colon, optic nerve, ovary, oviduct, pancreas, skin, retina, spinal cord, stomach, thymus, and vagina. [19]
In the rat heart, KCNE4 protein co-localizes with Kv4.2, a channel that KCNE4 also functionally regulates. [20] In mouse heart, KCNE4 is preferentially expressed in ventricles versus atria, and in young adult males much more than young adult females. This is because cardiac KCNE4 expression is positively regulated by dihydrotestosterone. [14] In rat mesenteric artery, KCNE4 augments KCNQ4 channel activity to regulate arterial tone. [21]
A single polymorphism in the KCNE4 intracellular N-terminal domain, E145D, has been reported to affect predisposition to the relatively common chronic cardiac arrhythmia, atrial fibrillation, in Chinese populations, [22] and to impair the ability of KCNE4 to inhibit KCNQ1. [23] If KCNE4 inhibits KCNQ1 in the atrium, it is conceivable that removing this inhibition could shorten the atrial effective refractory period, which could predispose to atrial fibrillation, but this mechanism has not yet been substantiated with in vivo data.
 | 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. |
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.
Kv7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the KCNQ1 gene. 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.
Potassium voltage-gated channel subfamily A member 1 also known as Kv1.1 is a shaker related voltage-gated potassium channel that in humans is encoded by the KCNA1 gene. Isaacs syndrome is a result of an autoimmune reaction against the Kv1.1 ion channel.
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.
Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the KCNE1 gene.
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.
The transmembrane cation channel superfamily was defined in InterPro and Pfam as the family of tetrameric ion channels. These include the sodium, potassium, calcium, ryanodine receptor, HCN, CNG, CatSper, and TRP channels. This large group of ion channels apparently includes families 1.A.1, 1.A.2, 1.A.3, and 1.A.4 of the TCDB transporter classification.
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Potassium voltage-gated channel subfamily D member 2 is a protein that in humans is encoded by the KCND2 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.
Potassium voltage-gated channel subfamily A member 2 also known as Kv1.2 is a protein that in humans is encoded by the KCNA2 gene.
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.
Kv channel-interacting protein 2 also known as KChIP2 is a protein that in humans is encoded by the KCNIP2 gene.
Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or Kv2.1, is a protein that, in humans, is encoded by the KCNB1 gene.
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.
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.
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.
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KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.
The cardiac transient outward potassium current (referred to as Ito1 or Ito ) is one of the ion currents across the cell membrane of heart muscle cells. It is the main contributing current during the repolarizing phase 1 of the cardiac action potential. It is a result of the movement of positively charged potassium (K+) ions from the intracellular to the extracellular space. Ito1 is complemented with Ito2 resulting from Cl− ions to form the transient outward current Ito.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.