Molecular Biology of High-Conductance, Ca2+-Activated Potassium Channels

  • Pratap Meera
  • Martin Wallner
  • Ligia Toro


The pore-forming α-subunit of the large-conductance, voltage- and Ca2+-activated K+ channel (BK, BKCa, or Slo1) was first cloned by utilizing the Drosophila Slowpoke (Slo) mutant (Atkinson et al., 1991), which carries homozygous mutant Slowpoke alleles. Flight muscles from this mutant fly lacked a Ca2+-activated K+ current (Elkins et al, 1986), whereas functional exprcssion of the Stowpoke wild-type cDNA (dSlol) yielded voltage- and Ca2+-activated K+ currents in Xenopus oocytes (Adelman et al, 1992). A large variety of dSlol isoforms are generated by alternative splicing, and some of them show large functional differences, including changcs in kinctics, singlc-channel conduc-tance, and Ca2+ and voltage sensitivities (Lagrutta et al, 1994). A series of vertebrate BKCa Channel ±-subunit clones including human hSlol (Butler et al, 1993; Dworetzky et al, 1994; Pallanck and Ganetzky, 1994; Tseng-Crank et al, 1994; McCobb et al, 1995; Wallner et al, 1995; Vogalis et al, 1996; Jiang et al, 1997; Morita et al, 1997; Jones et al, 1998) were isolated by homology Screening, and an ortholog in Caenorhab-ditis. elegans, nSlol (Wei et al, 1996), has been identified (Fig. 1A). The deduced protein of these cDNA clones shows similarities to other Kv Channels in the voltage sensor and in the “pore” region, which determines ionic conductance and selectivity (Figs. 1B, 1C, and 2A).


Hair Cell Potassium Channel Splice Variant Voltage Sensor Activate Potassium Channel 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adelman, J. P., Shen, K. Z., Kavanaugh, M. P., Warren, R. A., Wu, Y. N., Lagrutta, A., Bond, C. T., and North, R. A., 1992, Calcium-activated potassium channels expressed from cloned complementary DNAs, Neuron 9:209–216.PubMedCrossRefGoogle Scholar
  2. Atkinson, N. S., Robertson, G. A., and Ganetzky, B., 1991, A component of calcium-activated potassium channels encoded by the Drosophila slo locus, Science 253:551–555.PubMedCrossRefGoogle Scholar
  3. Bezanilla, F. and Armstrong, C. M., 1977, Inactivation of the sodium channel. I. Sodium current experiments, J. Gen. Physiol. 70:549–566.PubMedCrossRefGoogle Scholar
  4. Brenner, R., Thomas, T. O., Becker, M. N., and Atkinson, N. S., 1996, Tissue-specific expression of a Ca2+-activated K+ channel is controlled by multiple upstream regulatory elements, J. Neurosci. 16:1827–1835.PubMedGoogle Scholar
  5. Butler, A., Tsunoda, S., McCobb, D. P., Wei, A., and Salkoff, L., 1993, mSlo, a complex mouse gene encoding “maxi ” calcium-activated potassium channels, Science 261:221–224.PubMedCrossRefGoogle Scholar
  6. Diaz, F., Meera, P., Amigo, J., Stefani, E., Alvarez, O., Toro, L., and Latorre, R., 1998, Role of the S4 segment in a voltage-dependent calcium-sensitive potassium (hSlo) channel, J. Biol. Chem. 273:32430–32436.PubMedCrossRefGoogle Scholar
  7. Dworetzky, S. I., Trojnacki, J. T., and Gribkoff, V. K., 1994, Cloning and expression of a human large-conductance calcium-activated potassium channel, Brain Res. Mol. Brain Res. 27:189–193.PubMedCrossRefGoogle Scholar
  8. Dworetzky, S. I., Boissard, C. G., Lum-Ragan, J. T., McKay, M. C, Post-Munson, D. J., Trojnacki, J. T., Chang, C. P., and Gribkoff, V. K., 1996, Phenotypic alteration of a human BK (hSlo) channel by hSloβ subunit coexpression: Changes in blocker sensitivity, activation/relaxation and inactivation kinetics, and protein kinase A modulation, J. Neurosci. 16:4543–4550.PubMedGoogle Scholar
  9. Elkins, T., Ganetzky, B., and Wu, C. F., 1986, A Drosophila mutation that eliminates a calcium-dependent potassium current, Proc. Natl. Acad. Sci. U.S.A. 83:8415–8419.PubMedCrossRefGoogle Scholar
  10. Ferrer, J., Wasson, J., Salkoff, L., and Permutt, M. A., 1996, Cloning of human pancreatic islet large conductance Ca2+-activated K+ channel (hSlo) cDNAs: Evidence for high levels of expression in pancreatic islets and identification of a flanking genetic marker, Diabetologia 39:891–898.PubMedCrossRefGoogle Scholar
  11. Fuchs, P. A. and Evans, M. G., 1990, Potassium currents in hair cells isolated from the cochlea of the chick, J. Physiol. (London) 429:529–551.Google Scholar
  12. Hoshi, T., Zagotta, W. N., and Aldrich, R. W., 1990, Biophysical and molecular mechanisms of Shaker potassium channel inactivation, Science 250:533–538.PubMedCrossRefGoogle Scholar
  13. Howard, J., and Hudspeth, A. J., 1988, Compliance of the hair bundle associated with gating of mechanoelectrical transduction channels in the bullfrog’s saccular hair cell, Neuron 1:189–199.PubMedCrossRefGoogle Scholar
  14. Jiang, G. J., Zidanic, M., Michaels, R. L., Michael, T. H., Griguer, C., and Fuchs, P. A., 1997, CSlo encodes calcium-activated potassium channels in the chick’s cochlea, Proc. R. Soc. London, Ser. B. 264:731–737.CrossRefGoogle Scholar
  15. Jiang, Z., Wallner, M., Meera, P., and Toro, L., 1999, Cloning and characterization of human and rodent MaxiK channel β subunit genes: Cloning and characterization, Genomics 55:57–67.PubMedCrossRefGoogle Scholar
  16. Joiner, W. J., Tang, M. D., Wang, L. -Y., Dworetzky, S. I., Boissard, C. G., Gan, L, Gribkoff, V. K., and Kaczmarek, L. K., 1998, Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits, Nat. Neurosci. 1:462–469.PubMedCrossRefGoogle Scholar
  17. Jones, E. M., Laus, C., and Fettiplace, R., 1998, Identification of Ca2+-activated K+ channel splice variants and their distribution in the turtle cochlea, Proc. R. Soc. London Ser. B 265:685–692.CrossRefGoogle Scholar
  18. Knaus, H. G., Eberhart, A., Kaczorowski, G. J., and Garcia, M. L., 1994a, Covalent attachment of charybdotoxin to the β-subunit of the high conductance Ca2+-activated K+ channel: Identification of the site of incorporation and implications for channel topology, J. Biol. Chem. 269:23336–23341.PubMedGoogle Scholar
  19. Knaus, H. G., Folander, K., Garcia-Calvo, M., Garcia, M. L., Kaczorowski, G. J., Smith, M., and Swanson, R., 1994b, Primary sequence and immunological characterization of β-subunit of high conductance Ca2+-activated K+ channel from smooth muscle, J. Biol. Chem. 269:17274–17278.PubMedGoogle Scholar
  20. Knaus, H. G., Garcia-Calvo, M., Kaczorowski, G. J., and Garcia, M. L., 1994c, Subunit composition of the high conductance calcium-activated potassium channel from smooth muscle, a representative of the mSlo and slowpoke family of potassium channels, J. Biol. Chem. 269:3921–3924.PubMedGoogle Scholar
  21. Knaus, H. G., Schwarzer, C., Koch, R. O., Eberhart, A., Kaczorowski, G. J., Glossmann, H., Wunder, F., Pongs, O., Garcia, M. L., and Sperk, G., 1996, Distribution of high-conductance Ca2+-activated K+ channels in rat brain: Targeting to axons and nerve terminals, J. Neurosci. 16:955–963.PubMedGoogle Scholar
  22. Lagrutta, A., Shen, K. Z., North, R. A., and Adelman, J. P., 1994, Functional differences among alternatively spliced variants of Slowpoke, a Drosophila calcium-activated potassium channel, J. Biol Chem. 269:20347–20351.PubMedGoogle Scholar
  23. Lopez, G. A., Jan, Y. N., and Jan, L. Y., 1994, Evidence that the S6 segment of the Shaker voltage-gated K+ channel comprises part of the pore, Nature 367:179–182.PubMedCrossRefGoogle Scholar
  24. McCobb, D. P., Fowler, N. L., Featherstone, T., Lingle, C. J., Saito, M., Krause, J. E., and Salkoff, L., 1995, A human calcium-activated potassium channel gene expressed in vascular smooth muscle, Am. J. Physiol. 269:H767–H777.PubMedGoogle Scholar
  25. McManus, O. B., Helms, L. M., Pallanck, L., Ganetzky, B., Swanson, R., and Leonard, R. J., 1995, Functional role of the beta subunit of high conductance calcium-activated potassium channels, Neuron 14:645–650.PubMedCrossRefGoogle Scholar
  26. Meera, P., Wallner, M., Jiang, Z., and Toro, L., 1996, A calcium switch for the functional coupling between α (hslo) and β subunits (Kv,Cabβ) of maxi K channels, FEBS Lett. 382:84–88.PubMedCrossRefGoogle Scholar
  27. Meera, P., Wallner, M., Song, M., and Toro, L., 1997, Large conductance voltage- and calcium-dependent K+ channel, a distinct member of voltage-dependent ion channels with seven N-terminal transmembrane segments (S0-S6), an extracellular N terminus, and an intracellular (S9-S10) C terminus, Proc. Natl. Acad. Sci. U.S.A. 94:14066–14071.PubMedCrossRefGoogle Scholar
  28. Morita, T., Hanaoka, K., Morales, M. M., Montrose-Raflzadeh, C., and Guggino, W. B., 1997, Cloning and characterization of maxi K+ channel alpha-subunit in rabbit kidney, Am. J. Physiol. 273:F615–F624.PubMedGoogle Scholar
  29. Nara, M., Dhulipala, P. D., Wang, Y. X., and Kotlikoff, M. I., 1998, Reconstitution of β-adrenergic modulation of large conductance, calcium-activated potassium (maxi-K) channels in Xenopus oocytes: Identification of the cAMP-dependent protein kinase phosphorylation site, J. Biol. Chem. 273:14920– 14924.PubMedCrossRefGoogle Scholar
  30. Navaratnam, D. S., Bell, T. J., Tu, T. D., Cohen, E. L., and Oberholtzer, J. C, 1997, Differential distribution of Ca2+-activated K+ channel splice variants among hair cells along the tonotopic axis of the chick cochlea, Neuron 19:1077–1085.PubMedCrossRefGoogle Scholar
  31. Nelson, M. T., Cheng, H., Rubart, M., Santana, L. F., Bonev, A. D., Knot, H. J., and Lederer, W. J., 1995, Relaxation of arterial smooth muscle by calcium sparks, Science 270:633–637.PubMedCrossRefGoogle Scholar
  32. Pallanck, L., and Ganetzky, B., 1994, Cloning and characterization of human and mouse homologs of the Drosophila calcium-activated potassium channel gene, slowpoke, Hum. Mol. Genet. 3:1239–1243.PubMedCrossRefGoogle Scholar
  33. Ponting, C. P., Phillips, C., Davies, K. E., and Blake, D. J., 1997, PDZ domains: Targeting signalling molecules to sub-membranous sites, Bioessays 19:469–479.PubMedCrossRefGoogle Scholar
  34. Ramanathan, K., Michael, T. H., Jiang, G. J., Hiel, H., and Fuchs, P. A., 1999, A molecular mechanism for electrical tuning of cochlear hair cells, Science 283:215–217.PubMedCrossRefGoogle Scholar
  35. Rosenblatt, K. P., Sun, Z. P., Heller, S., and Hudspeth, A. J., 1997, Distribution of Ca2+-activated K+ channel isoforms along the tonotopic gradient of the chicken’s cochlea, Neuron 19:1061–1075.PubMedCrossRefGoogle Scholar
  36. Saito, M., Nelson, C., Salkoff, L., and Lingle, C. J., 1997, A cysteine-rich domain defined by a novel exon in a slo variant in rat adrenal chromaffin cells and PC12 cells, J. Biol. Chem. 272:11710–11717.PubMedCrossRefGoogle Scholar
  37. Schopperle, W. M., Holmqvist, M. H., Zhou, Y., Wang, J., Wang, Z., Griffith, L. C., Keselman, I., Kusinitz, F., Dagan, D., and Levitan, I. B., 1998, Slob, a novel protein that interacts with the Slowpoke calcium-dependent potassium channel, Neuron 20:565–573.PubMedCrossRefGoogle Scholar
  38. Schreiber, M., and Salkoff, L., 1997, A novel calcium-sensing domain in the BK channel, Biophys. J. 73:1355–1363.PubMedCrossRefGoogle Scholar
  39. Schreiber, M., Wei, A., Yuan, A., Gaut, J., Saito, M., and Salkoff, L., 1998, Slo3, a novel pH-sensitive K+ channel from mammalian spermatocytes, J. Biol. Chem. 273:3509–3516.PubMedCrossRefGoogle Scholar
  40. Stefani, E., Ottolia, M., Noceti, F., Olcese, R., Wallner, M., Latorre, R., and Toro, L., 1997, Voltage-controlled gating in a large conductance Ca2+-sensitive K+ channel (hslo), Proc. Natl. Acad. Sci. U.S.A. 94:5427–5431.PubMedCrossRefGoogle Scholar
  41. Tanaka, Y., Meera, P., Song, M., Knaus, H.-G., and Toro, L., 1997, Molecular constituents of maxi KCa channels in human coronary smooth muscle: Predominant α+ β subunit complexes, J. Physiol. (London) 502:545–557.CrossRefGoogle Scholar
  42. Toro, L., Meera, P., Wallner, M., and Tanaka, Y., 1998, MaxiKCa, a unique member of the voltage-gated K channel superfamily, News Physiol. Sc. 13:112–117.Google Scholar
  43. Tseng-Crank, J., Foster, C. D., Krause, J. D., Mertz, R., Godinot, N., DiChiara, T. J., and Reinhart, P. H., 1994, Cloning, expression, and distribution of functionally distinct Ca2+-activated K+ channel isoforms from human brain, Neuron 13:1315–1330.PubMedCrossRefGoogle Scholar
  44. Vogalis, F., Vincent, T., Qureshi, I., Schmalz, F., Ward, M. W., Sanders, K. M., and Horowitz, B., 1996, Cloning and expression of the large-conductance Ca2+-activated K+ channel from colonic smooth muscle, Am. J. Physiol 271:G629–G639.PubMedGoogle Scholar
  45. Wallner, M., Meera, P., Ottolia, M., Kaczorowski, G., Latorre, R., Garcia, M. L., Stefani, E., and Toro, L., 1995, Characterization of and modulation by a β-subunit of a human maxi KCa channel cloned from myometrium, Recept. Channels 3:185–199.PubMedGoogle Scholar
  46. Wallner, M., Meera, P., and Toro, L., 1996, Determinant for β-subunit regulation in high-conductance voltage-activated and Ca2+-sensitive K+ channels: An additional transmembrane region at the N terminus, Proc. Natl. Acad. Sci. U.S.A. 93:14922–14927.PubMedCrossRefGoogle Scholar
  47. Wallner, M., Meera, P., and Toro, L., 1997, A new family of potassium channels: Relatives of voltage and calcium activated maxi K channels, Biophys. J. 72:A224Google Scholar
  48. Wallner, M., Pratap, M., and Toro, L. 1999, Molecular basis of fast inactivation in voltage and Ca2+- activated K+ channels: A transmembrane β subunit homolog, Proc. Natl. Acad. Sci. U.S.A. 96:4137– 4142.PubMedCrossRefGoogle Scholar
  49. Wei, A., Solaro, C., Lingle, C., and Salkoflf, L., 1994, Calcium sensitivity of BK-type KCa channels determined by a separable domain, Neuron 13:671–681.PubMedCrossRefGoogle Scholar
  50. Wei, A., Jegla, T., and Salkoff, L., 1996, Eight potassium channel families revealed by the C. elegans genome project, Neuropharmacology 35:805–829.PubMedCrossRefGoogle Scholar
  51. Xia, X., Hirschberg, B., Smolik, S., Forte, M., and Adelman, J. P., 1998, dSLo interacting protein 1, a novel protein that interacts with large-conductance calcium-activated potassium channels, J. Neurosci. 18:2360–2369.PubMedGoogle Scholar
  52. Xie, J. and McCobb, D. P., 1998, Control of alternative splicing of potassium channels by stress hormones, Science 280:443–446.PubMedCrossRefGoogle Scholar
  53. Yuan, A., Dourado, M., Butler, A., and SalkoflF, L., 1998, A novel K+ channel requiring both chloride and calcium for activation, Biophys. J. 74:A206.Google Scholar
  54. Yuan, A., Dourado, M., Butler, A., and Salkoff, L., 1999, A chloride sensing domain in a large conductance K+ channel, Biophys. J. 76:A329.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Pratap Meera
    • 1
  • Martin Wallner
    • 1
  • Ligia Toro
    • 1
  1. 1.Department of Anesthesiology, Department of Molecular and Medical Pharmacology, and Brain Research InstituteUniversity of California at Los AngelesLos AngelesUSA

Personalised recommendations