Skip to main content

An evolutionarily conserved family of accessory subunits of K+ channels

Cell Biochemistry and Biophysics volume 46, pages 91–99 (2006)Cite this article

Abstract

Accessory subunits are an essential feature of voltage-gated potassium (Kv) channels. They determine trafficking to the plasma membrane, surface expression, gating, permeation, and pharmacology. At least three distinct classes of accessory subunits including the KCNE family can regulate Kv channel function. KCNE genes encode integral membrane proteins with a single transmembrane domain. KCNE genes span the eukaryotic kingdom and, in mutated form, can cause acquired and congenital disease. Here we review genetic, physiological, and biophysical aspects of KCNE proteins with particular emphasis on the Caenorhabditis elegans subfamily.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Takumi, T., Ohkubo, H., and Nakanishi, S. (1988) Cloning of a membrane protein that induces a slow voltage-gated potassium current. Science 242, 1042–1045.

    PubMed  Article  CAS  Google Scholar 

  2. Hausdorff, S. F., Goldstein, S. A., Rushin, E. E., and Miller, C. (1991) Functional characterization of a minimal K+ channel expressed from a synthetic gene. Biochemistry 30, 3341–3346.

    PubMed  Article  CAS  Google Scholar 

  3. Abbott, G., Sesti, F., Splawski, I., et al. (1999) MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97, 175–187.

    PubMed  Article  CAS  Google Scholar 

  4. Anantharam, A., Lewis, A., Panaghie, G., et al. (2003) RNA interference reveals that endogenous Xenopus MinK-related peptides govern mammalian K+channel function in oocyte expression studies. J. Biol. Chem. 278, 11,739–11,745.

    Article  CAS  Google Scholar 

  5. Bianchi, L., Kwok, S. M., Driscoll, M., and Sesti, F., (2003) A potassium channel-MiRP complex controls neurosensory function in Caenorhabditis elegans. J. Biol. Chem. 278, 12415–12424.

    PubMed  Article  CAS  Google Scholar 

  6. Park, K. H., Hernandez, L., Cai, S. Q., Wang, Y., and Sesti, F. (2005) A family of K+ channel ancillary subunits regulate taste sensitivity in Caenorhabditis elegans. J. Biol. Chem. 280, 21,893–21,899.

    CAS  Google Scholar 

  7. Piccini, M., Vitelli, F., Seri, M. et al. (1999) KCNE1-like gene is deleted in AMME contiguous gene syndrome: identification and characterization of the human and mouse homologs. Genomics 60, 251–257.

    PubMed  Article  CAS  Google Scholar 

  8. Tai, K. and Goldstein, S. (1998) The conduction pore of a cardiac potassium channel. Nature 391, 605–608.

    PubMed  Article  CAS  Google Scholar 

  9. Melman, Y. F., Um, S. Y., Krumerman, A., Kagan, A., and McDonald, T. V., (2004) KCNE1 binds to the KCNQ1 pore to regulate potassium channel activity. Neuron 42, 927–937.

    PubMed  Article  CAS  Google Scholar 

  10. Chen, H., Sesti, F., and Goldstein, S. A., (2003) Pore- and state-dependent cadmium block of I(Ks) channels formed with MinK-55C and wild-type KCNQ1 subunits. Biophys. J. 84, 3679–3689.

    PubMed  CAS  Google Scholar 

  11. Sesti, F. and Goldstein, S. A., (1998) Single-channel characteristics of wild-type IKs channels and channels formed with two minK mutants that cause long QT syndrome. J. Gen. Physiol. 112, 651–663.

    PubMed  Article  CAS  Google Scholar 

  12. Sesti, F., Tai, K. K., and Goldstein, S. A., (2000) MinK endows the I(Ks) potassium channel pore with sensitivity to internal tetraethylammonium. Biophys. J. 79, 1369–1378.

    PubMed  CAS  Google Scholar 

  13. Yang, Y., and Sigworth, F. J., (1998) Single-Channel Properties of IKs Potassium Channels. J. Gen. Physiol. 112, 665–678.

    PubMed  Article  CAS  Google Scholar 

  14. Pusch, M., (1998) Increase of the single-channel conductance of KvLQT1 potassium channels induced by the association with minK. Pflugers Arch. 437, 172–174.

    PubMed  Article  CAS  Google Scholar 

  15. Barhanin, J., Lesage, F., Guillemare, E., Fink, M., Lazdunski, M., and Romey, G., (1996) K(V)LQT1 and IsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 384, 78–80.

    PubMed  Article  CAS  Google Scholar 

  16. Sanguinetti, M., Curran, M., Zou, A., et al. (1996) Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 384, 80–83.

    PubMed  Article  CAS  Google Scholar 

  17. Marx, S. O., Kurokawa, J., Reiken, S., et al. (2002) Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 295, 496–499.

    PubMed  Article  CAS  Google Scholar 

  18. Kurokawa, J., Chen, L., and Kass, R. S. (2003) Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel. Proc. Natl. Acad. Sci. USA 100, 2122–2127.

    PubMed  Article  CAS  Google Scholar 

  19. McDonald, T., Yu, Z., Ming, Z., et al. (1997) A minK-HERG complex regulates the cardiac potassium current I(Kr). Nature 388, 289–292.

    PubMed  Article  CAS  Google Scholar 

  20. Lewis, A., McCrossan, Z. A., and Abbott, G. W., (2004) MinK, MiRP1, and MiRP2 diversify Kv3.1 and Kv3.2 potassium channel gating. J. Biol. Chem. 279, 7884–7892.

    PubMed  Article  CAS  Google Scholar 

  21. Tinel, N., Diochot, S., Lauritzen, I., Barhanin, J., Lazdunski, M., and Borsotto, M., (2000) M-type KCNQ2-KCNQ3 potassium channels are modulated by the KCNE2 subunit. FEBS Lett. 480, 137–141.

    PubMed  Article  CAS  Google Scholar 

  22. Tinel, N., Diochot, S., Borsotto, M., Lazdunski, M., and Barhanin, J., (2000) KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel. EMBO J. 19, 6326–6330.

    PubMed  Article  CAS  Google Scholar 

  23. Yu, H., Wu, J., Potapova, I. et al. (2001) MinK-related peptide 1: A beta subunit for the HCN ion channel subunit family enhances expression and speeds activation. Circ. Res. 88, E84-E87.

    PubMed  Article  CAS  Google Scholar 

  24. Zhang, M., Jiang, M., and Tseng, G., (2001) minK-related peptide 1 associates with Kv4.2 and modulates its gating function: potential role as beta subunit of cardiac transient outward channel?. Circ. Res. 88, 1012–1019.

    PubMed  Article  CAS  Google Scholar 

  25. Decher, N., Bundis, F., Vajna, R., and Steinmeyer, K., (2003) KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents. Pflugers Arch. 446, 633–640.

    PubMed  Article  CAS  Google Scholar 

  26. Proenza C. Angoli, D., Agranovich, E., Macri, V., and Accili, E. A., (2002) J. Biol. Chem. 277, 5101–5109.

    PubMed  Article  CAS  Google Scholar 

  27. Schroeder, B., Waldegger, S., Fehr, S., et al. (2000) A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature 403, 196–199.

    PubMed  Article  CAS  Google Scholar 

  28. Abbott, G., Butler, M., Bendahhou, S., Dalaks, M., Ptacek, L., and Goldstein, S., (2001) MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104, 217–231.

    PubMed  Article  CAS  Google Scholar 

  29. McCrossan, Z. A., Lewis, A., Panaghie, G., et al., (2003) MinK-related peptide 2 modulates Kv2.1 and Kv3.1 potassium channels in mammalian brain. J. Neurosci. 23, 8077–8091.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  31. Grunnet, M., Rasmussen, H. B., Hay-Schmidt, A., et al. (2003) KCNE4 is an inhibitory subunit to Kv1.1 and Kv1.3 potassium channels. Biophys. J. 85, 1525–1537.

    PubMed  CAS  Article  Google Scholar 

  32. Splawski, I., Tristani-Firouzi, M., Lehmann, M. H., Sanguinetti, M. C., and Keating, M. T., (1997) Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat. Genet. 17, 338–340.

    PubMed  Article  CAS  Google Scholar 

  33. Sesti, F., Abbott, G. W., Wei, J., et al. (2000) A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc. Natl. Acad. Sci. USA 97, 10613–10618.

    PubMed  Article  CAS  Google Scholar 

  34. Splawski, I., Shen, J., Timothy, K. W., et al. (2000) Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 102, 1178–1185.

    PubMed  CAS  Google Scholar 

  35. Abbott, G. W., and Goldstein, S. A., (2002) Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism. FASEB J. 16, 390–400.

    PubMed  Article  CAS  Google Scholar 

  36. Gordon, E., Roepke, T. K., and Abbott, G. W., (2006) Endogenous KCNE subunits govern Kv2.1 K+ channel activation kinetics in Xenopus oocyte studies. Biophys. J. 90, 1223–1231.

    PubMed  Article  CAS  Google Scholar 

  37. Takumi, T., Moriyoshi, K., Aramori, I., et al. (1991) Alteration of channel activities and gating by mutations of slow ISK potassium channel. J. Biol. Chem. 266, 22,192–22,198.

    CAS  Google Scholar 

  38. Goldstein, S. A., and Miller, C., (1991) Site-specific mutations in a minimal voltage-dependent K+ channel alter ion selectivity and open-channel block. Neuron 7, 403–408.

    PubMed  Article  CAS  Google Scholar 

  39. Melman, Y. F., Domenech, A., de la Luna, S., and McDonald, T. V. (2001) Structural determinants of KvLQT1 control by the KCNE family of proteins. J. Biol. Chem. 276, 6439–6444.

    PubMed  Article  CAS  Google Scholar 

  40. Melman, Y. F., Krumerman, A., and McDonald, T. V., (2002) A single transmembrane site in the KCNE-encoded proteins controls the specificity of KvLQT1 channel gating. J. Biol. Chem. 277, 25,187–25,194.

    Article  CAS  Google Scholar 

  41. Cui, J., Kagan, A., Qin, D., Mathew, J., Melman, Y. F., and McDonald, T. V., (2001) Analysis of the cyclic nucleotide binding domain of the HERG potassium channel and interactions with KCNE2. J. Biol. Chem. 276, 17,244–17,251.

    CAS  Google Scholar 

  42. Gage, S., and Kobertz, W., (2004) KCNE3 truncation mutants reveal a bipartite modulation of KCNQ1 K+ channels. J. Gen. Physiol. 124, 759–771.

    PubMed  Article  CAS  Google Scholar 

  43. Park, K. H., Kwok, S. M., Sharon, C., Berga, R., and Sesti, F. (2003) N-Glycosylation-dependent block is a novel mechanism for drug-induced cardiac arrhythmia. FASEB J. 17, 2308–2309.

    PubMed  CAS  Google Scholar 

  44. Lu, Y., Mahaut-Smith, M. P., Huang, C. L., and Vandenberg, J. I., (2003) Mutant MiRP1 subunits modulate HERG K+ channel gating: a mechanism for pro-arrhythmia in long QT syndrome type 6. J. Physiol. 551, 253–262.

    PubMed  Article  CAS  Google Scholar 

  45. Isbrandt, D., Friederich, P., Solth, A., et al. (2002) Identification and functional characterization of a novel KCNE2 (MiRP1) mutation that alters HERG channel kinetics. J. Mol. Med. 80, 524–532.

    PubMed  Article  CAS  Google Scholar 

  46. Yang, Y., Xia, M., Jin, Q., et al. (2004) Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am. J. Hum. Genet. 75, 899–905.

    PubMed  Article  CAS  Google Scholar 

  47. Panaghie, G., Tai, K. K., and Abbott, G. W., (2006) Interaction of KCNE subunits with the KCNQ1 K+ channel pore. J. Physiol. 570, 455–467.

    PubMed  Article  CAS  Google Scholar 

  48. Bianchi, L., Shen, Z., Dennis, A., et al. (1999) Human Mol. Genet. 8, 1499–1507.

    Article  CAS  Google Scholar 

  49. Tzounopoulos, T., Guy, H. R., Durell, S., Adelman, J. P., and Maylie, J., (1995) min K channels form by assembly of at least 14 subunits. Proc. Natl. Acad. Sci. USA 92, 9593–9597.

    PubMed  Article  CAS  Google Scholar 

  50. Wang, K. W., and Goldstein, S. A., (1995) Subunit composition of minK potassium channels. Neuron 14, 1303–1309.

    PubMed  Article  CAS  Google Scholar 

  51. Chen, H., Kim, L. A., Rajan, S., Xu, S., and Goldstein, S. A. (2003) Charybdotoxin binding in the I(Ks) pore demonstrates two MinK subunits in each channel complex. Neuron 40, 15–23.

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  53. Wang, K. W., Tai, K. K., and Goldstein, S. A., (1996) MinK residues line a potassium channel pore. Neuron 16, 571–577.

    PubMed  Article  CAS  Google Scholar 

  54. Tapper, A., and George, A., Jr., (2000) MinK subdomains that mediate modulation of and association with KvLQT1. J. Gen. Physiol. 116, 379–390.

    PubMed  Article  CAS  Google Scholar 

  55. Kurokawa, J., Motoike, H., and Kass, R., (2001) TEA(+)-sensitive KCNQ1 constructs reveal pore-independent access to KCNE1 in assembled I(Ks) channels. J. Gen. Physiol. 117, 43–52.

    PubMed  Article  CAS  Google Scholar 

  56. Cai, S. Q., Hernandez, L., Wang, Y., Park, K. H. and Sesti, F. (2005) MPS-1 is a K+ channel beta-subunit and a serine/threonine kinase. Nat. Neurosci. 8, 1503–1509.

    PubMed  Article  CAS  Google Scholar 

  57. Ryazanov, A. G., Pavur, K. S., and Dorovkov, M. V., (1999) Alpha-kinases: a new class of protein kinases with a novel catalytic domain. Curr. Biol. 9, R43-R45.

    PubMed  Article  CAS  Google Scholar 

  58. Runnels, L. W., Yue, L., and Clapham, D. E., (2001) TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 291, 1043–1047.

    PubMed  Article  CAS  Google Scholar 

  59. Drennan, D., and Ryazanov, A. G. (2004) Alpha-kinases: analysis of the family and comparison with conventional protein kinases. Prog. Biophys. Mol. Biol. 85, 1–32.

    PubMed  Article  CAS  Google Scholar 

  60. Stein, L. D., Bao, Z., Blasiar, D., et al. (2003) The genome sequence of Caenorhabditis briggsae: a platform for comparative genomics. PLoS Biol. 1, E45.

    PubMed  Article  CAS  Google Scholar 

  61. Bargmann, C., and Mori, I., (1997) Chemotaxis and thermotaxis. In C. elegans II (Riddle D. L., Meyer B. J., Priess J. R., eds.) Vol. 1, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp. 717–737.

    Google Scholar 

  62. Heitzmann, D., Grahammer, F., von Hahn, T., et al. (2004) Heteromeric KCNE2/KCNQ1 potassium channels in the luminal membrane of gastric parietal cells. J. Physiol. 561, 547–557.

    PubMed  Article  CAS  Google Scholar 

  63. Tobin, D., Madsen, D., Kahn-Kirby, A., et al. (2002) Combinatorial expression of TRPV channel proteins defines their sensory functions and subcellular localization in C. elegans neurons. Neuron 35, 307–318.

    PubMed  Article  CAS  Google Scholar 

  64. O'Hagan, R., Chalfie, M., and Goodman, M. B., (2005) The MEC-4 DEG/ENaC channel of Caenorhabditis elegans touch receptor neurons transduces mechanical signals. Nat. Neurosci. 8, 43–50.

    PubMed  Article  CAS  Google Scholar 

  65. Lundquist, A. L., Manderfield, L. J., Vanoye, C. G., et al. (2005) Expression of multiple KCNE genes in human heart may enable variable modulation of I(Ks). J. Mol. Cell. Cardiol. 38, 277–287.

    PubMed  Article  CAS  Google Scholar 

  66. Finley, M. R., Li, Y., Hua, F., et al. (2002) Expression and coassociation of ERG1, KCNQ1 and KCNE1 potassium channel proteins in horse heart. Am. J. Physiol. Heart Circ. Physiol. 283, H126–138.

    PubMed  CAS  Google Scholar 

  67. Chun, K., Koenen, M., Katus, H., and Zehelein, J. (2004) Expression of the IKr components KCNH2 (rERG) and KCNE2 (rMiRP1) during late rat heart development. Exp. Mol. Med. 36, 367–371.

    PubMed  CAS  Google Scholar 

  68. Jiang, M., Zhang, M., Tang, D. G., et al. (2004) KCNE2 protein is expressed in ventricles of different species, and changes in its expression contribute to electrical remodeling in diseased hearts. Circulation 109, 1783–1788.

    PubMed  Article  CAS  Google Scholar 

  69. Christensen, M., Estevez, A., Yin, X., et al. (2002) A primary culture system for functional analysis of C. elegans neurons and muscle cells. Neuron 33, 503–514.

    PubMed  Article  CAS  Google Scholar 

  70. Goodman, M., Hall, D., Avery, L., and Lockery, S., (1998) Active currents regulate sensitivity and dynamic range in C. elegans neurons. Neuron 20, 763–772.

    PubMed  Article  CAS  Google Scholar 

  71. Pierce-Shimomura, J., Faumont, S., Gaston, M., Pearson, B., and Lockery, S., (2001) The homeobox gene lim-6 is required for distinct chemosensory representations in C. elegans. Nature 410, 694–698.

    PubMed  Article  CAS  Google Scholar 

  72. Connor, J. A., and Stevens, C. F., (1971) Inward and delayed outward membrane currents in isolated neural somata under voltage clamp. J. Physiol. 213, 1–19.

    PubMed  CAS  Google Scholar 

  73. Connor, J. A., and Stevens, C. F., (1971) Voltage clamp studies of a transient outward membrane current in gastropod neural somata. J. Physiol 213, 21–30.

    PubMed  CAS  Google Scholar 

  74. Grahammer, F., Herling, A. W., Lang, H. J., et al. (2001) The cardiac K+ channel KCNQ1 is essential for gastric acid secretion. Gastroenterology 120, 1363–1371.

    PubMed  Article  CAS  Google Scholar 

  75. Dedek, K., and Waldegger, S., (2001) Colocalization of KCNQ1/KCNE channel subunits in the mouse gastrointestinal tract. Pflugers Arch. 442, 896–902.

    PubMed  Article  CAS  Google Scholar 

  76. Cui, J., Melman, Y., Palma, E., Fishman, G., and McDonald, T., (2000) Cyclic AMP regulates the HERG K(+) channel by dual pathways. Curr. Biol. 10, 671–674.

    PubMed  Article  CAS  Google Scholar 

  77. Qu, J., Kryukova, Y., Potapova, I. A., et al. (2004) MiRP1 modulates HCN2 channel expression and gating in cardiac myocytes. J. Biol. Chem. 279, 43,497–43,502.

    CAS  Google Scholar 

  78. Grunnet, M., Jespersen, T., Rasmussen, H. B., et al. (2002) KCNE4 is an inhibitory subunit to the KCNQ1 channel. J. Physiol. 542, 119–130.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

  1. Robert Wood Johnson Medical School Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, 683 Hoes Lane, 08854, Piscataway, NJ

    Shi-Qing Cai, Ki Ho Park & Federico Sesti

Authors
  1. Shi-Qing Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ki Ho Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Federico Sesti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Federico Sesti.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cai, SQ., Park, K.H. & Sesti, F. An evolutionarily conserved family of accessory subunits of K+ channels. Cell Biochem Biophys 46, 91–99 (2006). https://doi.org/10.1385/CBB:46:1:91

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/CBB:46:1:91

Index Entries

  • C. elegans
  • KCNE
  • chemotaxis
  • kinase