8.A.10 The Slow Voltage-gated K+ Channel Accessory Protein (MinK or KCNE) Family

The MinK family, also called the KCNE family, is a small family of K+-selective channel accessory proteins found only in animals. MinK proteins are associated with and essential for the activities of K+ channel proteins such as the KvLQT1 protein (TC #1.A.1.15.1; VIC superfamily) encoded by the human LQT1 gene. A VIC superfamily (TC #1.A.1) member and the KvLQT1/MinK assembly generate the slowly activating K+ channel IKs. Some of these channels respond to a change in voltage very slowly; the current may reach its steady state only after 50 seconds.  The KCNQ1 channel is differentially regulated by KCNE1 and KCNE2 (Li et al. 2014).  KCNE2 exhibits an array of functions in the heart, stomach, thyroid and choroid plexus. A variety of interconnected disease manifestations caused by KCNE2 disruption involve both excitable cells such as cardiomyocytes, and non-excitable, polarized epithelia (Abbott 2015).

All sequenced MinK members are from mammals and are very similar. There are at least two isoforms, one found in intestinal or kidney epithelia, the other in cardiac tissue. MinK proteins are small (about 130 amino acids) with a single N-terminal transmembrane α-helical spanner, approximately at residues 45-65. The N-termini are extracellular while the large C-terminal tails are in the cytoplasm. The extracellular domains are glycosylated, and the activities of the proteins are regulated by phosphorylation of the cytoplasmic domains. They probably form heterooligomeric complexes and thereby modulate channel activity. There is evidence that residues in the MinK polypeptide chain are in close proximity to TMS6 in the channel complex, but are outside of the permeation pathway (Tapper and George, 2001). They not only affect channel gating and ion conduction, they also are required for efficient trafficking and cell surface expression (Chandrasekhar et al., 2006).  There are two MinK subunits (a dimer of β) per tetrameric channel complex (Morin and Kobertz, 2008).

KCNE genes (KCNE1-5) encode a family of Lundquist et al. 2006 mapped transcription start sites, delineated 5' genomic structure, and characterized functional promoter elements for each gene. hey also identified alternatively spliced transcripts for both KCNE1 and KCNE3, including a cardiac-specific KCNE1 transcript. Analysis of relative expression levels of KCNE1-5 in a panel of human tissues revealed distinct, but overlapping, expression patterns. The coexpression of multiple functionally distinct KCNE genes in some tissues inferred complex accessory subunit modification of potassium channels (Lundquist et al. 2006).

KCNE2 (also known as MiRP1) is expressed in the heart, is associated with human cardiac arrhythmia, and modulates cardiac Kv α subunits hERG and KCNQ1 in vitro. KCNE2 and KCNQ1 are also expressed in parietal cells, leading to speculation they form a native channel complex there. The murine kcne2 gene has been disrupted (Roepke et al., 2006). kcne2 (-/-) mice have a severe gastric phenotype with reduced parietal cell proton secretion, abnormal parietal cell morphology, achlorhydria, hypergastrinemia, and striking gastric glandular hyperplasia arising from an increase in the number of non-acid secretory cells. Thus, KCNE2 is essential for gastric acid secretion (Roepke et al., 2006).

N-Glycosylation of membrane proteins is critical for their proper folding, co-assembly and subsequent matriculation through the secretory pathway. Bas et al. (2011) examined the kinetics of N-glycan addition to type I transmembrane KCNE1 K+ channel β-subunits, where point mutations that prevent N-glycosylation at one consensus site give rise to disorders of the cardiac rhythm and congenital deafness. KCNE1 has two distinct N-glycosylation sites: a typical co-translational site and a consensus site ∼20 residues away that unexpectedly acquires N-glycans after protein synthesis (post-translational). Mutations that ablate the co-translational site concomitantly reduce glycosylation at the post-translational site, resulting in unglycosylated KCNE1 subunits that cannot reach the cell surface with their cognate K+ channel. This long range inhibition is highly specific for post-translational N-glycosylation because mutagenic conversion of the KCNE1 post-translational site into a co-translational site restores both monoglycosylation and anterograde trafficking (Bas et al., 2011).

Accessory β-subunits of the KCNE gene family modulate the function of various cation channel α-subunits by the formation of heteromultimers. Among the most dramatic changes of biophysical properties of a voltage-gated channel by KCNEs (TC# 8.A.10.1.1) are the effects of KCNE1 on KCNQ1 channels. KCNQ1 and KCNE1 form native I(Ks) channels. Strutz-Seebohm et al. (2011) characterized molecular determinants of the KCNE1 interaction with KCNQ1 channels. KCNE1 binds to the outer face of the KCNQ1 channel pore domain, modifies interactions between voltage sensor, S4-S5 linker and the pore domain, leading to structural modifications of the selectivity filter and voltage sensor domain. Molecular dynamics simulations suggest a stable interaction of the KCNE1 transmembrane α-helix with the pore domain S5/S6 and part of the voltage sensor domain S4 of KCNQ1 in a putative pre-open channel state. Formation of this state may induce slow activation gating, the pivotal characteristic of native cardiac I(Ks) channels.

Voltage-gated potassium (Kv) channels comprise pore-forming α-subunits and a multiplicity of regulatory proteins, including the cardiac-expressed and cardiac arrhythmia-linked transmembrane KCNE subunits. N-terminally extended (L) KCNE3 and KCNE4 isoforms regulate human cardiac Kv channel α-subunits (Abbott 2016). As for short isoforms, KCNE3S and KCNE4S, KCNE3L inhibits hERG; KCNE4L inhibits Kv1.1; neither form regulats the HCN1 pacemaker channel. Unlike KCNE4S, KCNE4L is a potent inhibitor of Kv4.2 and Kv4.3. Co-expression of cytosolic β-subunit KChIP2, which regulates Kv4 channels in cardiac myocytes, partially relieves Kv4.3 but not Kv4.2 inhibition. Inhibition of Kv4.2 and Kv4.3 by KCNE3L was weaker, and its inhibition of Kv4.2 was abolished by KChIP2. KCNE3L and KCNE4L also exhibited subunit-specific effects on Kv4 channel complex inactivation kinetics, voltage dependence and recovery. KCNE4L co- localized with Kv4.3 in human atrium (Abbott 2016).

In the heart, KCNE1 associates with the alpha-subunit KCNQ1 to generate the slowly activating, voltage-dependent potassium current (IKs) that controls the repolarization phase of cardiacaction potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K+ channels that are voltage-independent K+ channels in the physiological voltage range. They are important for controlling water and salt secretion and absorption (Barro-Soria et al. 2017). This difference between these two KCNE subunits is due to the fact that they affect different gating transitions (Barro-Soria et al. 2017).

The generalized transport reaction catalyzed by MinK in complexation with other channel proteins is:

K+ (in)  → K+ (out)



This family belongs to the .

 

References:

and Abbott GW. (2015). The KCNE2 K(+) channel regulatory subunit: Ubiquitous influence, complex pathobiology. Gene. 569(2):162-72.

and Abbott GW. (2016). KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation. Gene. 576(1 Pt 1):1-13.

Abbott, G.W. (2016). Regulation of human cardiac potassium channels by full-length KCNE3 and KCNE4. Sci Rep 6: 38412.

Abbott, G.W., B. Ramesh, and S.K. Srai. (2008). Secondary structure of the MiRP1 (KCNE2) potassium channel ancillary subunit. Protein Pept Lett 15: 63-75.

Angelo, K., T. Jespersen, M. Grunnet, M.S. Nielsen, D.A. Klaerke, and S.P. Olesen. (2002). KCNE5 induces time- and voltage-dependent modulation of the KCNQ1 current. Biophys. J. 83: 1997-2006.

Barro-Soria, R., R. Ramentol, S.I. Liin, M.E. Perez, R.S. Kass, and H.P. Larsson. (2017). KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions. Proc. Natl. Acad. Sci. USA 114: E7367-E7376.

Bas, T., G.Y. Gao, A. Lvov, K.D. Chandrasekhar, R. Gilmore, and W.R. Kobertz. (2011). Post-translational N-glycosylation of type I transmembrane KCNE1 peptides: implications for membrane protein biogenesis and disease. J. Biol. Chem. 286: 28150-28159.

Chandrasekhar, K.D., T. Bas, and W.R. Kobertz. (2006). KCNE1 subunits require co-assembly with K+ channels for efficient trafficking and cell surface expression. J. Biol. Chem. 281: 40015-40023.

Coetzee, W.A., Y. Amalillo, J. Chiu, A. Chow, D. Lau, T. McCormack, H. Moreno, M.S. Nadal, A. Ozaita, D. Pountney, M. Saganich, E. Vega-Saenz de Miera, and B. Rudy (1999). Molecular diversity of K+ channels. Ann. N.Y. Acad. Sci USA 868: 233-285.

Coey, A.T., I.D. Sahu, T.S. Gunasekera, K.R. Troxel, J.M. Hawn, M.S. Swartz, M.R. Wickenheiser, R.J. Reid, R.C. Welch, C.G. Vanoye, C. Kang, C.R. Sanders, and G.A. Lorigan. (2011). Reconstitution of KCNE1 into lipid bilayers: comparing the structural, dynamic, and activity differences in micelle and vesicle environments. Biochemistry 50: 10851-10859.

David, J.P., J.I. Stas, N. Schmitt, and E. Bocksteins. (2015). Auxiliary KCNE subunits modulate both homotetrameric Kv2.1 and heterotetrameric Kv2.1/Kv6.4 channels. Sci Rep 5: 12813.

Doi, K., T. Sato, T. Kuramasu, H. Hibino, T. Kitahara, A. Horii, N. Matsushiro, Y. Fuse, and T. Kubo. (2005). Ménière''s disease is associated with single nucleotide polymorphisms in the human potassium channel genes, KCNE1 and KCNE3. ORL J Otorhinolaryngol Relat Spec 67: 289-293.

Eldstrom, J. and D. Fedida. (2011). The voltage-gated channel accessory protein KCNE2: multiple ion channel partners, multiple ways to long QT syndrome. Expert Rev Mol Med 13: e38.

Heitzmann, D., V. Koren, M. Wagner, C. Sterner, M. Reichold, I. Tegtmeier, T. Volk, and R. Warth. (2007). KCNE beta subunits determine pH sensitivity of KCNQ1 potassium channels. Cell Physiol Biochem 19: 21-32.

Honoré, E., B. Attali, G. Romey, C. Heurteaux, P. Ricard, F. Lesage, M. Lazdunski, and J. Barhanin. (1991). Cloning, expression, pharmacology and regulation of a delayed rectifier K+ channel in mouse heart. EMBO. J. 10: 2805-2811.

Kroncke, B.M., W.D. Van Horn, J. Smith, C. Kang, R.C. Welch, Y. Song, D.P. Nannemann, K.C. Taylor, N.J. Sisco, A.L. George, Jr, J. Meiler, C.G. Vanoye, and C.R. Sanders. (2016). Structural basis for KCNE3 modulation of potassium recycling in epithelia. Sci Adv 2: e1501228.

Lee, S.M., J. Baik, D. Nguyen, V. Nguyen, S. Liu, Z. Hu, and G.W. Abbott. (2017). Kcne2 deletion impairs insulin secretion and causes type 2 diabetes mellitus. FASEB J. [Epub: Ahead of Print]

Li, P., H. Liu, C. Lai, P. Sun, W. Zeng, F. Wu, L. Zhang, S. Wang, C. Tian, and J. Ding. (2014). Differential Modulations of KCNQ1 by Auxiliary Proteins KCNE1 and KCNE2. Sci Rep 4: 4973.

Liu L., Hayashi K., Kaneda T., Ino H., Fujino N., Uchiyama K., Konno T., Tsuda T., Kawashiri MA., Ueda K., Higashikata T., Shuai W., Kupershmidt S., Higashida H. and Yamagishi M. (2013). A novel mutation in the transmembrane nonpore region of the KCNH2 gene causes severe clinical manifestations of long QT syndrome. Heart Rhythm. 10(1):61-7.

Lundquist, A.L., C.L. Turner, L.Y. Ballester, and A.L. George, Jr. (2006). Expression and transcriptional control of human KCNE genes. Genomics 87: 119-128.

Lvov, A., S.D. Gage, V.M. Berrios, and W.R. Kobertz. (2010). Identification of a protein-protein interaction between KCNE1 and the activation gate machinery of KCNQ1. J Gen Physiol 135: 607-618.

Mangubat, E.Z., T.-T. Tseng, and E. Jakobsson. (2003). Phylogenetic analyses of potassium channel auxiliary subunits. J. Mol. Microbiol. Biotechnol. (in press).

Mashanov, G.I., M. Nobles, S.C. Harmer, J.E. Molloy, and A. Tinker. (2010). Direct observation of individual KCNQ1 potassium channels reveals their distinctive diffusive behavior. J. Biol. Chem. 285: 3664-3675.

McCrossan, Z.A., T.K. Roepke, A. Lewis, G. Panaghie, and G.W. Abbott. (2009). Regulation of the Kv2.1 potassium channel by MinK and MiRP1. J. Membr. Biol. 228: 1-14.

Morin, T.J. and W.R. Kobertz. (2008). Counting membrane-embedded KCNE β-subunits in functioning K+ channel complexes. Proc. Natl. Acad. Sci. USA 105: 1478-1482.

O'Mahony, F., R. Alzamora, V. Betts, F. LaPaix, D. Carter, M. Irnaten, and B.J. Harvey. (2007). Female gender-specific inhibition of KCNQ1 channels and chloride secretion by 17β-estradiol in rat distal colonic crypts. J. Biol. Chem. 282: 24563-24573.

Preston, P., L. Wartosch, D. Günzel, M. Fromm, P. Kongsuphol, J. Ousingsawat, K. Kunzelmann, J. Barhanin, R. Warth, and T.J. Jentsch. (2010). Disruption of the K+ channel β-subunit KCNE3 reveals an important role in intestinal and tracheal Cl- transport. J. Biol. Chem. 285: 7165-7175.

Roepke, T.K., Anantharam, A., Kirchhoff, P., Busque, S.M., Young, J.B., Geibel, J.P., Lerner, D.J., and Abbott, G.W. (2006). The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J. Biol. Chem. 281: 23740-23747.

Romey, G., B. Attali, C. Chouabe, I. Abitbol, E. Guillemare, J. Barhanin, and M. Lazdunski. (1997). Molecular mechanism and functional significance of the MinK control of the KvLQT1 channel activity. J. Biol. Chem. 272: 16713-16716.

Sahu, I.D., A.F. Craig, M.M. Dunagan, K.R. Troxel, R. Zhang, A.G. Meiberg, C.N. Harmon, R.M. McCarrick, B.M. Kroncke, C.R. Sanders, and G.A. Lorigan. (2015). Probing Structural Dynamics and Topology of the KCNE1 Membrane Protein in Lipid Bilayers via Site-Directed Spin Labeling and Electron Paramagnetic Resonance Spectroscopy. Biochemistry 54: 6402-6412.

Sand, P.G., A. Luettich, T. Kleinjung, G. Hajak, and B. Langguth. (2010). An Examination of KCNE1 Mutations and Common Variants in Chronic Tinnitus. Genes (Basel) 1: 23-37.

Strutz-Seebohm, N., M. Pusch, S. Wolf, R. Stoll, D. Tapken, K. Gerwert, B. Attali, and G. Seebohm. (2011). Structural basis of slow activation gating in the cardiac I Ks channel complex. Cell Physiol Biochem 27: 443-452.

Tai, K.-K., K.-W. Wang, and S.A.N. Goldstein. (1997). MinK potassium channels are heteromultimeric complexes. J. Biol. Chem. 272: 1654-1658.

Tapper, A.R. and A.L. George, Jr. (2001). Location and orientation of minK within the IKs potassium channel complex. J. Biol. Chem. 276: 38249-38254.

Wang W., Kim HJ., Lee JH., Wong V., Sihn CR., Lv P., Perez Flores MC., Mousavi-Nik A., Doyle KJ., Xu Y. and Yamoah EN. (2014). Functional significance of K+ channel beta-subunit KCNE3 in auditory neurons. J Biol Chem. 289(24):16802-13.

Westhoff, M., C.I. Murray, J. Eldstrom, and D. Fedida. (2017). Photo-Cross-Linking of IKs Demonstrates State-Dependent Interactions between KCNE1 and KCNQ1. Biophys. J. 113: 415-425.

Zheng, R., K. Thompson, E. Obeng-Gyimah, D. Alessi, J. Chen, H. Cheng, and T.V. McDonald. (2010). Analysis of the interactions between the C-terminal cytoplasmic domains of KCNQ1 and KCNE1 channel subunits. Biochem. J. 428: 75-84.

Examples:

TC#NameOrganismal TypeExample
8.A.10.1.1

Slow voltage-dependent K+ channel auxiliary protein (β-subunit), MinK or K2NE1. KCNQ1-KCNE1 complexes may interact intermittently with the actin cytoskeleton via the C-terminal region (Mashanov et al., 2010; Coey et al., 2011).  The transmembrane region and the C-terminal cytoplasmic domains that abuts the KCNE1 TMS both interact with and regulate the KCNQ1 channel (Lvov et al. 2010; Zheng et al. 2010). Mutations in KCNE1 can cause Meniere's disease (Doi et al. 2005).

Mammals

MinK of Rattus norvegicus (130 aas; P15383)

 
8.A.10.1.2

Potassium voltage-gated channel Isk-related family member 1, of 129 aas and one TMS, KCNE1 (Sahu et al. 2015).  Mutations can give rise to hearing disorders including chronic tinitus (Sand et al. 2010).  KCNE proteins modulate both homomeric Kv.2.1 and heteromeric Kv2.1/Kv6.4 channels (David et al. 2015). Slow-activating channel complexes formed by KCNQ1 and KCNE1 are essential for human ventricular myocyte repolarization, while constitutively active KCNQ1-KCNE3 channels are important in the intestine. Inherited sequence variants in human KCNE1 and KCNE3 cause cardiac arrhythmias by different mechanisms (Abbott 2015). KCNE confers pH sensitivity to KCNQ1 (Heitzmann et al. 2007). State-dependent interactions between KCNE1 and KCNQ1 have been demonstrated (Westhoff et al. 2017).

Animals

KCNE1 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
8.A.10.2.1

K+ voltage-gated channel subfamily E member 2 (KCNE2) or minimum K+ channel-related peptide (MinK; MiRP1) (β-subunit) [associates with KCNH2/ERG1 and KCNQ1/KVLQT1 (McCrossan et al. 2009), as well as KCNQ2 and KCNQ3] (Eldstrom and Fedida, 2011Roepke et al., 2006). Regulated by PKCδ phosphorylation (O'Mahony et al., 2007).  A mutation (hERG T473P) in the transmembrane non-pore region  causes clinical manifestations of long QT syndrome (Liu et al. 2012).  Exhibits an array of functions in the heart, stomach, thyroid and choroid plexus. A variety of interconnected disease manifestations caused by KCNE2 disruption involve both excitable cells such as cardiomyocytes, and non-excitable, polarized epithelia (Abbott 2015).  It's secondary structure has been determined (Abbott et al. 2008). Deletion of the Kcne2 structural gene in mice and humans gives rise to impaired insulin secretion as well as type 2 diabetes mellitus (Lee et al. 2017).

Mammals

KCNE2 of Mus musculus (123 aas; Q9D808)

 
Examples:

TC#NameOrganismal TypeExample
8.A.10.3.1

KCNE3 (β-subunit) constitutively opens outwardly rectifying KCNQ1 (Kv7.1) K+ channels by abolishing their voltage-dependent gating. KCNQ1/KCNE3 heteromers are present in basolateral membranes of intestinal and tracheal epithelial cells where they may facilitate transepithelial Cl- secretion (Preston et al., 2010).  Mutations cause Meniere's disease and tinnitus.  KCNE3 regulates Kv4.2 in spiral gangion neurons (Wang et al. 2014) and other voltage-gated ion channels (Kroncke et al. 2016). KCNE3 induces the constitutive activation of KCNQ1 in a process involving interactions in both sides of the membrane (Kroncke et al. 2016).

Mammals

KCNE3 of Mus musculus (103 aas; AAH04629)

 
8.A.10.3.2

Potassium voltage-gated channel subfamily E regulatory subunit 5, KCNE5 of 142 aas and 1 TMS. It is a potassium channel ancillary subunit of that is essential for the generation of some native K+ currents by virtue of the formation of heteromeric ion channel complexes with voltage-gated potassium (Kv) channel pore-forming alpha subunits. It functions as an inhibitory beta-subunit of the repolarizing cardiac potassium ion channel KCNQ1 (Angelo et al. 2002).

KCNE5 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
8.A.10.4.1MinK-related peptide 3 (MiRK3) or KCNE4 (β-subunit)MammalsMiRP3 or KCNE4 of Mus musculus (170 aas; Q9WTW3)