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High-conductance potassium channels of the SLO family

Key Points

  • Identification of the Slo gene family came hot on the heels of new advances in molecular cloning, and involved Drosophila melanogaster neurogenetics as well as numerous physiological and biophysical studies. These biophysical studies had identified Ca2+-dependent K+ currents in many systems, as well as unusually large (maxi-K) Ca2+- and Na+-dependent single-channel currents. The key to identifying the genes underlying these phenomena turned out to be the D rosophila slowpoke (slo) mutant.

  • The structures of the α-subunits of SLO family channels resemble those of voltage-gated K+ channels. However, they differ from those of voltage-gated ion channels in that they have an extensive carboxyl extension — the 'tail' — which is thought to confer distinctive properties, such as calcium-sensing, to SLO1 channels, whereas the 'core' domain containing the membrane-spanning segments confers voltage sensitivity.

  • Voltage-dependent channels are gated (opened and closed) in response to changes in transmembrane voltage. In ligand-gated channels, the binding of a ligand, such as a neurotransmitter, causes a conformational change of a 'ligand-binding domain' that is physically coupled to the pore of the channel. For SLO1 and SLO3 channels, this distinction breaks down because both voltage-gating and ligand-gating domains are present, indicating two independent sensing mechanisms that converge near the gates of the pore.

  • A complicated system of cooperativity, involving several Ca2+-sensing sites both on the same subunit and on different subunits, could underlie the responsiveness of SLO1 channels to a broad range of Ca2+ concentrations. This provides versatility and allows these channels to serve a wide variety of physiological roles in different cell types and cellular microdomains, where Ca2+ concentrations can vary extensively.

  • SLO1 channels have the largest single-channel conductance of all K+- selective channels. Several studies have indicated the presence of at least two salient underlying structural mechanisms: two rings of negative charges in the inner and outer pore of the channel's ionic conduction pathway and the size of the SLO1 inner pore region.

  • The functional diversity of SLO1 channels comes from many sources, such as alternative RNA splicing, post-translational modifications and β-subunits. β-subunits alone account for a great deal of diversity, such as enhanced sensitivity to Ca2+ and rapid channel inactivation.

  • The sensitivity of SLO1 to Ca2+ makes it an important negative feedback system for Ca2+ entry in many cell types. SLO1 channels are ubiquitously expressed in most tissues and have roles in neurons, smooth muscles, secretory endocrine cells and specialized sensory receptors.

Abstract

High-conductance, 'big' potassium (BK) channels encoded by the Slo gene family are among the largest and most complex of the extended family of potassium channels. The family of SLO channels apparently evolved from voltage-dependent potassium channels, but acquired a large conserved carboxyl extension, which allows channel gating to be altered in response to the direct sensing of several different intracellular ions, and by other second-messenger systems, such as those activated following neurotransmitter binding to G-protein-coupled receptors (GPCRs). This versatility has been exploited to serve many cellular roles, both within and outside the nervous system.

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Figure 1: Schematic representation of SLO α-subunits.
Figure 2: Properties of SLO1, SLO2 and SLO3 currents.
Figure 3: The S4 region aligned for SLO1, SLO3 and SLO2.
Figure 4: Inter-relatedness of SLO family proteins and similarity to two voltage-dependent channels.

References

  1. Butler, A., Tsunoda, S., McCobb, D. P., Wei, A. & Salkoff, L. mSlo, a complex mouse gene encoding “maxi” calcium-activated potassium channels. Science 261, 221–224 (1993). Cloning of the first mammalian Slo1 gene.

    CAS  PubMed  Article  Google Scholar 

  2. Pallanck, L. & Ganetzky, B. Cloning and characterization of human and mouse homologs of the Drosophila calcium-activated potassium channel gene, slowpoke. Hum. Mol. Genet. 3, 1239–1243 (1994).

    CAS  PubMed  Article  Google Scholar 

  3. Yuan, A. et al. SLO-2, a K+ channel with an unusual Cl dependence. Nature Neurosci. 3, 771–779 (2000). Cloning of the first SLO-2 channel, an unusual Cl-dependent channel, from C. elegans.

    CAS  PubMed  Article  Google Scholar 

  4. Joiner, W. J. et al. Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nature Neurosci. 1, 462–469 (1998).

    CAS  PubMed  Article  Google Scholar 

  5. Schreiber, M. et al. Slo3, a novel pH-sensitive K+ channel from mammalian spermatocytes. J. Biol. Chem. 273, 3509–3516 (1998). Cloning of the gene encoding the SLO3 channel, and functional characterization.

    CAS  PubMed  Article  Google Scholar 

  6. Bhattacharjee, A. et al. Slick (Slo2.1), a rapidly-gating sodium-activated potassium channel inhibited by ATP. J. Neurosci. 23, 11681–11691 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. Heyer, C. B. & Lux, H. D. Control of the delayed outward potassium currents in bursting pace-maker neurones of the snail, Helix pomatia. J. Physiol. 262, 349–382 (1976).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Gorman, A. L. & Thomas, M. V. Potassium conductance and internal calcium accumulation in a molluscan neurone. J. Physiol. 308, 287–313 (1980).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Pallotta, B. S., Magleby, K. L. & Barrett, J. N. Single channel recordings of Ca2+-activated K+ currents in rat muscle cell culture. Nature 293, 471–474 (1981).

    CAS  PubMed  Article  Google Scholar 

  10. Marty, A. Ca-dependent K channels with large unitary conductance in chromaffin cell membranes. Nature 291, 497–500 (1981).

    CAS  PubMed  Article  Google Scholar 

  11. Latorre, R., Vergara, C. & Hidalgo, C. Reconstitution in planar lipid bilayers of a Ca2+-dependent K+ channel from transverse tubule membranes isolated from rabbit skeletal muscle. Proc. Natl Acad. Sci. USA. 79, 805–809 (1982).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. Elkins, T., Ganetzky, B. & Wu, C. F. A Drosophila mutation that eliminates a calcium-dependent potassium current. Proc. Natl Acad. Sci. USA 83, 8415–8419 (1986).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. Atkinson, N. S., Robertson, G. A. & Ganetzky, B. A component of calcium-activated potassium channels encoded by the Drosophila slo locus. Science 253, 551–555 (1991). Cloning of the first slo1 gene from Drosophila using classic molecular-genetic techniques.

    CAS  PubMed  Article  Google Scholar 

  14. Adelman, J. P. et al. Calcium-activated potassium channels expressed from cloned complementary DNAs. Neuron 9, 209–216 (1992). Shows that alternative splicing of the Drosophila slo1 gene creates functional diversity.

    CAS  PubMed  Article  Google Scholar 

  15. Kameyama, M. et al. Intracellular Na+ activates a K+ channel in mammalian cardiac cells. Nature 309, 354–356 (1984). First detailed description of native K Na channels, recorded from guinea pig ventricular myocytes.

    CAS  PubMed  Article  Google Scholar 

  16. Luk, H. N. & Carmeliet, E. Na+-activated K+ current in cardiac cells: rectification, open probability, block and role in digitalis toxicity. Pflugers Arch. 416, 766–768 (1990).

    CAS  PubMed  Article  Google Scholar 

  17. Bader, C. R., Bernheim, L. & Bertrand, D. Sodium-activated potassium current in cultured avian neurones. Nature 317, 540–542 (1985).

    CAS  PubMed  Article  Google Scholar 

  18. Dryer, S. E., Fujii, J. T. & Martin, A. R. A Na+-activated K+ current in cultured brain stem neurones from chicks. J. Physiol. 410, 283–296 (1989).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Dryer, S. E. Na+-activated K+ channels and voltage-evoked ionic currents in brain stem and parasympathetic neurones of the chick. J. Physiol. 435, 513–532 (1991).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Schwindt, P. C., Spain, W. J. & Crill, W. E. Long-lasting reduction of excitability by a sodium-dependent potassium current in cat neocortical neurons. J. Neurophysiol. 61, 233–244 (1989).

    CAS  PubMed  Article  Google Scholar 

  21. Egan, T. M., Dagan, D., Kupper, J. & Levitan, I. B. Properties and rundown of sodium-activated potassium channels in rat olfactory bulb neurons. J. Neurosci. 12, 1964–1976 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. Dale, N. A large, sustained Na+- and voltage-dependent K+ current in spinal neurons of the frog embryo. J. Physiol. 462, 349–372 (1993).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Safronov, B. V. & Vogel, W. Properties and functions of Na+-activated K+ channels in the soma of rat motoneurones. J. Physiol. 497, 727–734 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Bischoff, U., Vogel, W. & Safronov, B. V. Na+-activated K+ channels in small dorsal root ganglion neurones of rat. J. Physiol. 510, 743–754 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Mitani, A. & Shattock, M. J. Role of Na+-activated K+ channel, Na+-K+-Cl cotransport, and Na+-K+ pump in [K]e changes during ischemia in rat heart. Am. J. Physiol. 263, H333–H340 (1992).

    CAS  PubMed  Google Scholar 

  26. Dryer, S. E. Na+-activated K+ channels: a new family of large-conductance ion channels. Trends Neurosci. 17, 155–160 (1994).

    CAS  PubMed  Article  Google Scholar 

  27. Saito, M. & Wu, C. F. Expression of ion channels and mutational effects in giant Drosophila neurons differentiated from cell division-arrested embryonic neuroblasts. J. Neurosci. 11, 2135–2150 (1991).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. Wei, A., Solaro, C., Lingle, C. & Salkoff, L. Calcium sensitivity of BK-type Kca channels determined by a separable domain. Neuron 13, 671–681 (1994). Functional demonstration of the modular structure of the SLO1 channel.

    CAS  PubMed  Article  Google Scholar 

  29. Yuan, A. et al. The sodium-activated potassium channel is encoded by a member of the Slo gene family. Neuron 37, 765–773 (2003). Identification of Slo2 as the gene encoding K Na channels.

    CAS  PubMed  Article  Google Scholar 

  30. Bargmann, C. I. Neurobiology of the Caenorhabditis elegans genome. Science 282, 2028–2033 (1998).

    CAS  Article  PubMed  Google Scholar 

  31. Magleby, K. L. Gating mechanism of BK (Slo1) channels: so near, yet so far. J. Gen. Physiol. 121, 81–96 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Meera, P., Wallner, M., Song, M. & Toro, L. 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. USA 94, 14066–14071 (1997). Defines the correct topology of the SLO1 channel.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. Schreiber, M., & Salkoff, L. A novel calcium-sensing domain in the BK channel. Biophys. J. 73, 1355–1363 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Santi, C. M. et al. Opposite regulation of Slick and Slack K+ channels by neuromodulators. J. Neurosci. 26, 5059–5068 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. Bhattacharjee, A., Gan, L. & Kaczmarek, L. K. Localization of the slack potassium channel in the rat central nervous system. J. Comp. Neurol. 454, 241–254 (2002).

    CAS  Article  PubMed  Google Scholar 

  36. Bhattacharjee, A., Christian, A. von Hehn, A., Mei, X. & Kaczmarek, L. K. Localization of the Na+-activated K+ channel Slick in the rat central nervous system. J. Comp. Neurol. 484, 80–92 (2005).

    CAS  PubMed  Article  Google Scholar 

  37. Cox, D. H., Cui, J. & Aldrich, R. W. Allosteric gating of a large conductance Ca-activated K+ channel. J. Gen. Physiol. 110, 257–281 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Cui, J. & Aldrich, R. W. Allosteric linkage between voltage and Ca2+-dependent activation of BK-type mslo1 K+channels. Biochemistry 39, 15612–15619 (2000). Erratum in: Biochemistry 40, 6190 (2001).

    CAS  PubMed  Article  Google Scholar 

  39. Rothberg, B. S. & Magleby, K. L. Voltage and Ca2+-activation of single large-conductance Ca2+-activated K+ channels described by a two-tiered allosteric gating mechanism. J. Gen. Physiol. 116, 75–99 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Schreiber, M., Yuan, A. & Salkoff, L. Transplantable sites confer calcium sensitivity to BK channels. Nature Neurosci. 2, 416–421 (1999). Functional demonstration of the C-terminal calcium bowl of SLO1 as a crucial calcium sensor for the channel.

    CAS  PubMed  Article  Google Scholar 

  41. Xia, X.-M., Zeng, X.-H. & Lingle, C. J. Multiple regulatory sites in large-conductance calcium-activated potassium channels. Nature 418, 880–884 (2002).

    CAS  PubMed  Article  Google Scholar 

  42. Xia, X.-M., Zhang, X. & Lingle, C. J. Ligand-dependent activation of Slo family channels is defined by interchangeable cytosolic domains. J. Neurosci. 24, 5585–5591 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. Diaz, L. et al. Role of the S4 segment in a voltage-dependent calcium-sensitive potassium (hSlo) channel. J. Biol. Chem. 273, 32430–32436 (1998).

    CAS  PubMed  Article  Google Scholar 

  44. Hu, L. et al. Participation of the S4 voltage sensor in the Mg2+-dependent activation of large conductance (BK) K+ channels. Proc. Natl Acad. Sci. USA 100, 10488–10493 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. Jiang, Y. et al. Crystal structure and mechanism of a calcium-gated potassium channel. Nature 417, 515–522 (2002). This landmark paper presents the first crystallographic structure of a complete Ca2+-activated K+ channel, and provides a molecular framework for understanding the mechanism of Ca2+-dependent gating.

    CAS  PubMed  Article  Google Scholar 

  46. Niu, X., Qian, X. & Magleby, K. L. Linker-gating ring complex as passive spring and Ca2+-dependent machine for a voltage- and Ca2+-activated potassium channel. Neuron 42, 745–756 (2004). Erratum in: Neuron 45, 637 (2005).

    CAS  PubMed  Article  Google Scholar 

  47. McManus, O. B. & Magleby, K. L. Accounting for the Ca2+-dependent kinetics of single large-conductance Ca2+-activated K+ channels in rat skeletal muscle. J. Physiol. 443, 739–777 (1991).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Horrigan, F. T., Cui, J. & Aldrich, R. W. Allosteric voltage gating of potassium channels I. Mslo ionic currents in the absence of Ca2+. J. Gen. Physiol. 114, 277–304 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Horrigan, F. T. & Aldrich, R. W. Allosteric voltage gating of potassium channels II. Mslo channel gating charge movement in the absence of Ca2+. J. Gen. Physiol. 114, 305–336 (1999). The first recordings of SLO1 gating currents and their incorporation into a formal kinetic model for a voltage- and Ca2+-dependent kinetic scheme.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Horrigan, F. T. & Aldrich, R. W. Coupling between voltage sensor activation, Ca2+ binding and channel opening in large conductance (BK) potassium channels. J. Gen. Physiol. 120, 267–305 (2002). Erratum in: J. Gen. Physiol. 120, 599 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Rothberg, B. S. & Magleby, K. L. Gating kinetics of single large-conductance Ca2+-activated K+ channels in high Ca2+ suggest a two-tiered allosteric gating mechanism. J. Gen. Physiol. 114, 93–124 (1999). Erratum in: J. Gen. Physiol. 114, 337 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Rothberg, B. S. & Magleby, K. L. Voltage and Ca2+ activation of single large-conductance Ca2+-activated channels described by a two tier allosteric gating mechanism. J. Gen. Physiol. 116, 75–99 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Zhang, X., Solaro, C. R. & Lingle, C. J. Allosteric regulation of BK channel gating by Ca2+ and Mg2+ through a nonselective, low affinity divalent cation site. J. Gen. Physiol. 118, 607–635 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Bao, L., Rapin, A. M., Holmstrand, E. C. & Cox, D. H. Elimination of the BKCa channel's high-affinity Ca2+ sensitivity. J. Gen. Physiol. 120, 173–189 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Xia, X.-M., Zeng, X. & Lingle, C. J. Multiple regulatory sites in large-conductance calcium-activated potassium channels. Nature 418, 880–884 (2002).

    CAS  PubMed  Article  Google Scholar 

  56. Shi, J. et al. Mechanism of magnesium activation of calcium-activated potassium channels. Nature 418, 876–880 (2002).

    CAS  PubMed  Article  Google Scholar 

  57. Zeng, X. H., Xia, X. M. & Lingle, C. J. Divalent cation sensitivity of BK channel activation supports the existence of three distinct binding sites. J. Gen. Physiol. 125, 273–286 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Niu, X. & Magleby, K. L. Stepwise contribution of each subunit to the cooperative activation of BK channels by Ca2+. Proc. Natl Acad. Sci. USA 99, 11441–11446 (2002). Erratum in: Proc. Natl Acad. Sci. USA 100, 763 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. Ferguson, W. B., McManus, O. B. & Magleby, K. L. Opening and closing transitions for BK channels often occur in two steps via sojourns through a brief lifetime subconductance state. Biophys. J. 65, 702–714 (1993).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Rothberg, B. S. & Magleby, K. L. Kinetic structure of large-conductance Ca2+-activated K+ channels suggests that the gating includes transitions through intermediate or secondary states. A mechanism for flickers. J. Gen. Physiol. 111, 751–780 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Bian, S., Favre, I. & Moczydlowski, E. Ca2+-binding of a COOH-terminal fragment of the Drosophila BK channel involved in Ca2+-dependent activation. Proc. Natl Acad. Sci. USA 98, 4776–4781 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. Bao, L., Kaldany, C., Holmstrand, E. C. & Cox, D. H. Mapping the BKCa channel's “Ca2+ bowl”: side chains essential for Ca2+ sensing. J. Gen. Physiol. 123, 475–489 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Zeng, X.-H., Xia, X. M. & Lingle, C. J. Divalent cation sensitivity of BK channel activation supports the existence of three distinct binding sites. J. Gen. Physiol. 125, 273–286 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Braun A. P. & Sy, L. Contribution of potential EF hand motifs to the calcium-dependent gating of a mouse brain large conductance, calcium-sensitive K+ channel. J. Physiol. 533, 681–695 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Shi, J. & Cui, J. Intracellular Mg2+ enhances the function of BK-type Ca2+-activated K+ channels. J. Gen. Physiol. 118, 589–606 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Qian, X., Niu, X. & Magleby, K. L. Intra- and intersubunit cooperativity in activation of BK channels by Ca2+. J. Gen. Physiol. 128, 389–404 (2006). Demonstrates complex cooperativity among Ca2+-sensing sites.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Piskorowski, R. & Aldrich, R. W. Calcium activation of BKCa potassium channels lacking the calcium bowl and RCK domains. Nature 420, 499–502 (2002).

    CAS  PubMed  Article  Google Scholar 

  68. Brelidze, T. I., Niu, X. & Magleby, K. L. A ring of eight conserved negatively charged amino acids doubles the conductance of BK channels and prevents inward rectification. Proc. Natl Acad. Sci. USA 100, 9017–9022 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. Nimigean, C. M, Chappie, J. S. & Miller, C. Electrostatic tuning of ion conductance in potassium channels. Biochemistry 42, 9263–9268 (2003). Along with reference 68, this paper shows that high single-channel conductance of SLO1 is determined electrostatically by a ring of negatively charged residues at the base of S6, which lines the intracellular opening to the K+ conduction pathway, and acts by focally increasing the local concentration of K+.

    CAS  PubMed  Article  Google Scholar 

  70. Haug, T. et al. Regulation of K+ flow by a ring of negative charges in the outer pore of BKCa channels. Part I: Aspartate 292 modulates K+ conduction by external surface charge effect. J. Gen. Physiol. 124, 173–184 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Li, W. & Aldrich, R. W. Unique inner pore properties of BK channels revealed by quaternary ammonium block. J. Gen. Physiol. 124, 43–57 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. McManus, O. B. et al. Functional role of the β subunit of high conductance calcium-activated potassium channels. Neuron 14, 645–650 (1995). First demonstration that the BK β1-subunit increases apparent voltage- and Ca2+-sensitivity when co-expressed with SLO1.

    CAS  PubMed  Article  Google Scholar 

  73. Brelidze, T. I. & Magleby, K. L. Probing the geometry of the inner vestibule of BK channels with sugars. J. Gen Physiol. 126, 105–121 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Nimigean, C. M., Magleby, K. L. The β subunit increases the Ca2+ sensitivity of large conductance Ca2+-activated potassium channels by retaining the gating in the bursting states. J. Gen. Physiol. 113, 425–440 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Nimigean, C. M. & Magleby, K. L. Functional coupling of the β1 subunit to the large conductance Ca2+-activated K+ channel in the absence of Ca2+. Increased Ca2+ sensitivity from a Ca2+-independent mechanism. J. Gen. Physiol. 115, 719–736 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Cox, D. H. & Aldrich, R. W. Role of the β1 subunit in large-conductance Ca2+-activated K+ channel gating energetics. Mechanisms of enhanced Ca2+ sensitivity. J. Gen. Physiol. 116, 411–432 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Cox, D. H. & Aldrich, R. W. Role of the β1 subunit in large-conductance Ca2+-activated K+ channel gating energetics: mechanisms of enhanced Ca2+ sensitivity. J. Gen. Physiol. 116, 411–432 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Xia, X. M., Ding, J. P. & Lingle, C. J. Molecular basis for the inactivation of Ca2+- and voltage-dependent BK channels in adrenal chromaffin cells and rat insulinoma tumor cells. J. Neurosci. 19, 5255–5264 (1999). Inactivating BK channels are created by BK β-subunits that confer N-type inactivation.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  79. Lagrutta, A., Shen, K. Z., North, R. A. & Adelman, J. P. Functional differences among alternatively spliced variants of Slowpoke, a Drosophila calcium-activated potassium channel. J. Biol. Chem. 269, 20347–20351 (1994).

    CAS  Article  PubMed  Google Scholar 

  80. Tseng-Crank, J. et al. Cloning, expression, and distribution of functionally distinct Ca2+-activated K+ channel isoforms from human brain. Neuron 13, 1315–1330 (1994).

    CAS  Article  PubMed  Google Scholar 

  81. Rosenblatt, K. P., Sun, Z. P., Heller, S. & Hudspeth, A. J. Distribution of Ca2+-activated K+ channel isoforms along the tonotopic gradient of the chicken's cochlea. Neuron 19, 1061–1075 (1997).

    CAS  Article  PubMed  Google Scholar 

  82. Navaratnam, D. S., Bell, T. J., Tu, T. D., Cohen, E. L. & Oberholtzer, J. C. Differential distribution of Ca2+-activated K+ channel splice variants among hair cells along the tonotopic axis of the chick cochlea. Neuron 19, 1077–1085 (1997).

    CAS  Article  PubMed  Google Scholar 

  83. Ramanathan, K., Michael, T. H., Jiang, G. J., Hiel, H. & Fuchs, P. A. A molecular mechanism for electrical tuning of cochlear hair cells. Science 283, 215–217 (1999).

    CAS  Article  PubMed  Google Scholar 

  84. Ramanathan, K. & Fuchs, P. A. Modeling hair cell tuning by expression gradients of potassium channel β subunits. Biophys. J. 82, 64–75 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Fettiplace, R. & Fuchs, P. A. Mechanisms of hair cell tuning. Annu. Rev. Physiol. 61, 809–834 (1999).

    CAS  PubMed  Article  Google Scholar 

  86. Xie, J. & McCobb, D. P. Control of alternative splicing of potassium channels by stress hormones. Science 280, 443–446 (1998).

    CAS  PubMed  Article  Google Scholar 

  87. Shipston, M. J. Alternative splicing of potassium channels: a dynamic switch of cellular excitability. Trends Cell Biol. 11, 353–358 (2001).

    CAS  PubMed  Article  Google Scholar 

  88. Schubert, R. & Nelson, M. T. Protein kinases: tuners of the BKCa channel in smooth muscle. Trends Pharmacol. Sci. 22, 505–512 (2001).

    CAS  PubMed  Article  Google Scholar 

  89. Weiger, T. M., Hermann, A. & Levitan, I. B. Modulation of calcium-activated potassium channels. J. Comp. Physiol. A Neuroethol. Sens. Neural. Behav. Physiol. 188, 79–87 (2002).

    CAS  PubMed  Article  Google Scholar 

  90. Tian, L. et al. Alternative splicing switches potassium channel sensitivity to protein phosphorylation. J. Biol. Chem. 276, 7717–7720 (2001).

    CAS  PubMed  Article  Google Scholar 

  91. Tian, L. et al. Distinct stoichiometry of BKCa channel tetramer phosphorylation specifies channel activation and inhibition by cAMP-dependent protein kinase. Proc. Natl Acad. Sci. USA 101, 11897–11902 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. White, R. E., Schonbrunn, A. & Armstrong, D. L. Somatostatin stimulates Ca2+-activated K+ channels through protein dephosphorylation. Nature 351, 570–573 (1991).

    CAS  PubMed  Article  Google Scholar 

  93. Zhou, X. B. et al. A molecular switch for specific stimulation of the BKCa channel by cGMP and cAMP kinase. J. Biol. Chem. 276, 43239–43245 (2001).

    CAS  PubMed  Article  Google Scholar 

  94. Liu, J., Asuncion-Chin, M., Liu, P. & Dopico, A. M. CaM kinase II phosphorylation of slo Thr107 regulates activity and ethanol responses of BK channels. Nature Neurosci. 9, 41–49 (2005).

    PubMed  Article  CAS  Google Scholar 

  95. Knaus, H. G., Garcia-Calvo, M., Kaczorowski, G. J. & Garcia, M. L. 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 (1994).

    CAS  PubMed  Article  Google Scholar 

  96. Knaus, H. G. et al. Primary sequence and immunological characterization of β-subunit of high conductance Ca2+-activated K+ channel from smooth muscle. J. Biol. Chem. 269, 17274–17278 (1994). Cloning of the first BK β-subunit, by biochemical purification and molecular cloning.

    CAS  PubMed  Article  Google Scholar 

  97. Orio, P., Rojas, P., Ferreira, G. & Latorre, R. New disguises for an old channel: MaxiK channel β-subunits. News Physiol. Sci. 17, 156–161 (2002).

    CAS  PubMed  Google Scholar 

  98. Bao, L. & Cox, D. H. Gating and ionic currents reveal how the BKCa channel's Ca2+ sensitivity is enhanced by its β1 subunit. J. Gen. Physiol. 126, 393–412 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Valverde, M. A. et al. Acute activation of Maxi-K channels (hSlo) by estradiol binding to the β-subunit. Science 285, 1929–1931 (1999).

    CAS  Article  PubMed  Google Scholar 

  100. Wallner, M., Meera, P. & Toro, L. Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels: a transmembrane β-subunit homolog. Proc. Natl Acad. Sci. USA 96, 4137–4142 (1999). Shows that inactivating BK channels are created by BK β-subunits that confer N-type inactivation.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. Uebele, V. N. et al. Cloning and functional expression of two families of β-subunits of the large conductance calcium-activated K+ channel. J. Biol. Chem. 275, 23211–23218 (2000).

    CAS  PubMed  Article  Google Scholar 

  102. Behrens, R. et al. hKCNMB3 and hKCNMB4, cloning and characterization of two members of the large-conductance calcium-activated potassium channel β-subunit family. FEBS Lett. 474, 99–106 (2000).

    CAS  PubMed  Article  Google Scholar 

  103. Brenner, R. Vasoregulation by the β1 subunit of the calcium-activated potassium channel. Nature 407, 870–876 (2000).

    CAS  PubMed  Article  Google Scholar 

  104. Xia, X.-M., Ding, J., Zeng, X. H., Duan, K.-L. & Lingle, C. Rectification and rapid activation at low Ca2+ of Ca2+-activated, voltage-dependent BK currents: consequences of rapid inactivation by a novel β-subunit. J. Neurosci. 20, 4890–4903 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. Zeng, X. H., Ding, J. P., Xia, X. M. & Lingle, C. J. Gating properties conferred on BK channels by the β3b auxiliary subunit in the absence of its NH2- and COOH termini. J. Gen. Physiol. 117, 607–628 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Meera, P., Wallner, M. & Toro, L. A neuronal β-subunit (KCNMB4) makes the large conductance, voltage- and Ca21-activated K+ channel resistant to charybdotoxin and iberiotoxin. PNAS 97, 5562–5567 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. Schopperle, W. M. et al. Slob, a novel protein that interacts with the Slowpoke calcium-dependent potassium channel. Neuron 20, 565–573 (1998).

    CAS  PubMed  Article  Google Scholar 

  108. Marrion, N. V. & Tavalin, S. J. Selective activation of Ca2+-activated K+ channels by co-localized Ca2+ channels in hippocampal neurons. Nature 395, 900–905 (1998). Functional evidence that native BK channels are tightly colocalized, and are co-activated with voltage-gated Ca2+ channels in hippocampal neurons.

    CAS  Article  PubMed  Google Scholar 

  109. Knaus, H. G. et al. Distribution of high-conductance Ca2+-activated K+ channels in rat brain: targeting to axons and nerve terminals. J. Neurosci. 16, 955–963 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. Wanner, S. G. et al. High-conductance calcium-activated potassium channels in rat brain: pharmacology, distribution, and subunit composition. Biochemistry 38, 5392–5400 (1999).

    CAS  PubMed  Article  Google Scholar 

  111. Swensen, A. M. & Bean, B. P. Ionic mechanisms of burst firing in dissociated Purkinje neurons. J. Neurosci. 23, 9650–9663 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  112. Womack, M. D. & Khodakhah, K. Dendritic control of spontaneous bursting in cerebellar Purkinje cells. J. Neurosci. 24, 3511–3521 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  113. Lancaster, B. & Nicoll, R. A. Properties of two calcium-activated hyperpolarizations in rat hippocampal neurones. J. Physiol. 389, 187–203 (1987).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Storm, J. F. Intracellular injection of a Ca2+ chelator inhibits spike repolarization in hippocampal neurons. Brain Res. 435, 387–392 (1987). Erratum in: Brain Res. 443, 410 (1988).

    CAS  PubMed  Article  Google Scholar 

  115. Faber, E. S. & Sah, P. Calcium-activated potassium channels: multiple contributions to neuronal function. Neuroscientist 9, 181–194 (2003).

    CAS  PubMed  Article  Google Scholar 

  116. Robitaille, R., Garcia, M. L., Kaczorowski, G. J. & Charlton, M. P. Functional co-localization of calcium and calcium-gated potassium channels in control of transmitter release. Neuron 11, 645–655 (1993).

    CAS  PubMed  Article  Google Scholar 

  117. Wang, Z. W., Saifee, O., Nonet, M. L. & Salkoff, L. SLO-1 potassium channels control quantal content of neurotransmitter release at the C. elegans neuromuscular junction. Neuron 32, 867–881 (2001).

    CAS  PubMed  Article  Google Scholar 

  118. Hu, H. et al. Presynaptic Ca2+-activated K+ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release. J. Neurosci. 21, 9585–9597 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. Raffaelli, G., Saviane, C., Mohajerani, M. H., Pedarzani, P. & Cherubini, E. BK potassium channels control transmitter release at CA3–CA3 synapses in the rat hippocampus. J. Physiol. 15, 147–157 (2004).

    Article  CAS  Google Scholar 

  120. Sun, X. P., Yazejian, B. & Grinnell, A. D. Electrophysiological properties of BK channels in Xenopus motor nerve terminals. J. Physiol. 557, 207–228 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Williams, S. E. et al. Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science 306, 2093–2097 (2004).

    CAS  PubMed  Article  Google Scholar 

  122. Tang, X. D. et al. Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels. Nature 425, 531–535 (2003).

    CAS  PubMed  Article  Google Scholar 

  123. Horrigan, F. T., Heinemann, S. H. & Hoshi, T. Heme regulates allosteric activation of the Slo1 BK channel. J. Gen. Physiol. 126, 7–21 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. Davies, A. G. et al. A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans. Cell 115, 655–666 (2003).

    CAS  Article  PubMed  Google Scholar 

  125. Sausbier, M. et al. Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency. Proc. Natl Acad. Sci. USA 101, 9474–9478 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  126. Meredith, A. L., Thorneloe, K. S., Werner, M. E., Nelson, M. T. & Aldrich, R. W. Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel. J. Biol. Chem. 279, 36746–36752 (2004). Along with reference 125, this paper shows that mice in which the Slo1 gene has been deleted exhibit pleiotropic physiological effects, related to smooth muscle and neuronal dysfunctions.

    CAS  PubMed  Article  Google Scholar 

  127. Ruttiger, L. et al. Deletion of the Ca2+-activated potassium (BK) α-subunit but not the BK β1-subunit leads to progressive hearing loss. Proc. Natl Acad. Sci. USA 101, 12922–12927 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  128. Sausbier, M. et al. Elevated blood pressure linked to primary hyperaldosteronism and impaired vasodilation in BK channel-deficient mice. Circulation 112, 60–68 (2005).

    CAS  PubMed  Article  Google Scholar 

  129. Werner, M. E., Zvara, P., Meredith, A. L., Aldrich, R. W. & Nelson, M. T. Erectile dysfunction in mice lacking the large-conductance calcium-activated potassium (BK) channel. J. Physiol. 567, 545–556 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Du, W. et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nature Genet. 37, 733–738 (2005).

    CAS  PubMed  Article  Google Scholar 

  131. Jan, Y. N., Jan, L. Y. & Dennis, M. J. Two mutations of synaptic transmission in Drosophila. Proc. R. Soc. Lond. B Biol. Sci. 198, 87–108 (1977).

    CAS  PubMed  Article  Google Scholar 

  132. Salkoff, L. & Wyman, R. Genetic modification of potassium channels in Drosophila Shaker mutants. Nature 293, 228–230 (1981).

    CAS  PubMed  Article  Google Scholar 

  133. Papazian, D. M., Schwarz, T. L., Tempel, B. L., Jan, Y. N. & Jan, L. Y. Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. Science 237, 749–753 (1987).

    CAS  PubMed  Article  Google Scholar 

  134. Titus, S. A., Warmke, J. W. & Ganetzky, B. The Drosophila erg K+ channel polypeptide is encoded by the seizure locus. J. Neurosci. 17, 875–881 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  135. Warmke, J. W. & Ganetzky, B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc. Natl Acad. Sci. USA 91, 3438–3442 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. Loughney, K., Kreber, R. & Ganetzky, B. Molecular analysis of the para locus, a sodium channel gene in Drosophila. Cell 58, 1143–1154 (1989).

    CAS  Article  PubMed  Google Scholar 

  137. Benzer S. From the gene to behavior. JAMA 218, 1015–1022 (1971).

    CAS  PubMed  Article  Google Scholar 

  138. Wei, A. et al. K+ current diversity is produced by an extended gene family conserved in Drosophila and mouse. Science 248, 599–603 (1990).

    CAS  PubMed  Article  Google Scholar 

  139. Reinhart, P., Chung, S. & Levitan, I. A family of calcium-dependent potassium channels from rat brain. Neuron 2, 1031–1041 (1989).

    CAS  PubMed  Article  Google Scholar 

  140. Egan, T. M., Dagan, D. & Levitan, I. B. Properties and modulation of a calcium activated potassium channel in rat olfactory bulb neurons. J. Neurophysiol. 69, 1433–1442 (1993).

    CAS  PubMed  Article  Google Scholar 

  141. Crest, M. et al. Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca2+-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom. J. Biol. Chem. 267, 1640–1647 (1992).

    CAS  PubMed  Article  Google Scholar 

  142. Knaus, H. et al. Themorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels. Biochemistry 33, 5819–5828 (1994).

    CAS  PubMed  Article  Google Scholar 

  143. Latorre, R., Vergara, C. & Hidalgo, C. Reconstitution in planar lipid bilayers of a Ca2+-dependent K+ channel from transverse tubule membranes isolated from rabbit skeletal muscle. Proc. Natl Acad. Sci. USA 79, 805–809 (1982).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  144. McKay, M. Opening of large-conductance calcium-activated potassium channels by the substituted benzimidazolone NS004. J. Neurophysiol. 71, 1873–1882 (1994).

    CAS  PubMed  Article  Google Scholar 

  145. Holland, M., Langton, P. D., Standen, N. B. & Boyle, J. P. Effects of the BKCa channel activator, NS1619, on rat cerebral artery smooth muscle. Br. J. Pharmacol. 117, 119–129 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. Tanaka, Y., Meera, P., Song, M., Knaus, H. G. & Toro, L. Molecular constituents of maxi KCa channels in human coronary smooth muscle: predominant α+ β subunit complexes. J. Physiol. 502, 545–557 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

Supported by grants from the National Institutes of Health to L.S.

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Glossary

Delayed rectifier voltage gated K+ channels

Slowly activating and either non-inactivating or very slowly inactivating voltage-sensitive K+-selective channels.

Low-stringency DNA hybridization

A technique in which a radioactively labelled strand of DNA is used to isolate a similar but non-identical strand of DNA.

Inward rectification

A functional property that is characteristic of some ion channels, preferentially permitting an ion current to flow into, rather than out of, a cell.

Afterhyperpolarization

The negative voltage that persists for a short period of time immediately following some action potentials.

M current

A K+ current that is modulated by the activation of muscarinic receptors. It participates in determining the subthreshold excitability of neurons and their responsiveness to synaptic input. The underlying channel is thought to consist of KCNQ K+ channel subunits.

Site-directed mutagenesis

The generation of a mutation at a predetermined position in a DNA sequence by various genetic engineering methods.

Cellular microdomains

Subcellular areas or compartments that have distinctive structural features, such as a clustering of protein complexes.

Symmetrical KCl

Equimolar concentration of KCl on both sides of the membrane.

Selectivity filter

Molecular features in the pore of an ion channel that aid in discriminating between different ion types.

Splice variants

Alternative forms of a protein derived from alternative processing of its mRNA.

Quantal content

The number of quanta — unitary packets of transmitter — released per action potential.

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Salkoff, L., Butler, A., Ferreira, G. et al. High-conductance potassium channels of the SLO family. Nat Rev Neurosci 7, 921–931 (2006). https://doi.org/10.1038/nrn1992

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