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.
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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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.
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).
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.
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).
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.
Bhattacharjee, A. et al. Slick (Slo2.1), a rapidly-gating sodium-activated potassium channel inhibited by ATP. J. Neurosci. 23, 11681–11691 (2003).
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).
Gorman, A. L. & Thomas, M. V. Potassium conductance and internal calcium accumulation in a molluscan neurone. J. Physiol. 308, 287–313 (1980).
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).
Marty, A. Ca-dependent K channels with large unitary conductance in chromaffin cell membranes. Nature 291, 497–500 (1981).
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).
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).
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.
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.
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.
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).
Bader, C. R., Bernheim, L. & Bertrand, D. Sodium-activated potassium current in cultured avian neurones. Nature 317, 540–542 (1985).
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).
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).
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).
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).
Dale, N. A large, sustained Na+- and voltage-dependent K+ current in spinal neurons of the frog embryo. J. Physiol. 462, 349–372 (1993).
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).
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).
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).
Dryer, S. E. Na+-activated K+ channels: a new family of large-conductance ion channels. Trends Neurosci. 17, 155–160 (1994).
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).
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.
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.
Bargmann, C. I. Neurobiology of the Caenorhabditis elegans genome. Science 282, 2028–2033 (1998).
Magleby, K. L. Gating mechanism of BK (Slo1) channels: so near, yet so far. J. Gen. Physiol. 121, 81–96 (2003).
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.
Schreiber, M., & Salkoff, L. A novel calcium-sensing domain in the BK channel. Biophys. J. 73, 1355–1363 (1997).
Santi, C. M. et al. Opposite regulation of Slick and Slack K+ channels by neuromodulators. J. Neurosci. 26, 5059–5068 (2006).
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).
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).
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).
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).
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).
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.
Xia, X.-M., Zeng, X.-H. & Lingle, C. J. Multiple regulatory sites in large-conductance calcium-activated potassium channels. Nature 418, 880–884 (2002).
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).
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).
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).
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.
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).
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).
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).
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.
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).
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).
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).
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).
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).
Xia, X.-M., Zeng, X. & Lingle, C. J. Multiple regulatory sites in large-conductance calcium-activated potassium channels. Nature 418, 880–884 (2002).
Shi, J. et al. Mechanism of magnesium activation of calcium-activated potassium channels. Nature 418, 876–880 (2002).
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).
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).
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).
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).
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).
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).
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).
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).
Shi, J. & Cui, J. Intracellular Mg2+ enhances the function of BK-type Ca2+-activated K+ channels. J. Gen. Physiol. 118, 589–606 (2001).
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.
Piskorowski, R. & Aldrich, R. W. Calcium activation of BKCa potassium channels lacking the calcium bowl and RCK domains. Nature 420, 499–502 (2002).
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).
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+.
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).
Li, W. & Aldrich, R. W. Unique inner pore properties of BK channels revealed by quaternary ammonium block. J. Gen. Physiol. 124, 43–57 (2004).
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.
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
Ramanathan, K. & Fuchs, P. A. Modeling hair cell tuning by expression gradients of potassium channel β subunits. Biophys. J. 82, 64–75 (2002).
Fettiplace, R. & Fuchs, P. A. Mechanisms of hair cell tuning. Annu. Rev. Physiol. 61, 809–834 (1999).
Xie, J. & McCobb, D. P. Control of alternative splicing of potassium channels by stress hormones. Science 280, 443–446 (1998).
Shipston, M. J. Alternative splicing of potassium channels: a dynamic switch of cellular excitability. Trends Cell Biol. 11, 353–358 (2001).
Schubert, R. & Nelson, M. T. Protein kinases: tuners of the BKCa channel in smooth muscle. Trends Pharmacol. Sci. 22, 505–512 (2001).
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).
Tian, L. et al. Alternative splicing switches potassium channel sensitivity to protein phosphorylation. J. Biol. Chem. 276, 7717–7720 (2001).
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).
White, R. E., Schonbrunn, A. & Armstrong, D. L. Somatostatin stimulates Ca2+-activated K+ channels through protein dephosphorylation. Nature 351, 570–573 (1991).
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).
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).
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).
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.
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).
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).
Valverde, M. A. et al. Acute activation of Maxi-K channels (hSlo) by estradiol binding to the β-subunit. Science 285, 1929–1931 (1999).
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.
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).
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).
Brenner, R. Vasoregulation by the β1 subunit of the calcium-activated potassium channel. Nature 407, 870–876 (2000).
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).
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).
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).
Schopperle, W. M. et al. Slob, a novel protein that interacts with the Slowpoke calcium-dependent potassium channel. Neuron 20, 565–573 (1998).
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.
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).
Wanner, S. G. et al. High-conductance calcium-activated potassium channels in rat brain: pharmacology, distribution, and subunit composition. Biochemistry 38, 5392–5400 (1999).
Swensen, A. M. & Bean, B. P. Ionic mechanisms of burst firing in dissociated Purkinje neurons. J. Neurosci. 23, 9650–9663 (2003).
Womack, M. D. & Khodakhah, K. Dendritic control of spontaneous bursting in cerebellar Purkinje cells. J. Neurosci. 24, 3511–3521 (2004).
Lancaster, B. & Nicoll, R. A. Properties of two calcium-activated hyperpolarizations in rat hippocampal neurones. J. Physiol. 389, 187–203 (1987).
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).
Faber, E. S. & Sah, P. Calcium-activated potassium channels: multiple contributions to neuronal function. Neuroscientist 9, 181–194 (2003).
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).
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).
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).
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).
Sun, X. P., Yazejian, B. & Grinnell, A. D. Electrophysiological properties of BK channels in Xenopus motor nerve terminals. J. Physiol. 557, 207–228 (2004).
Williams, S. E. et al. Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science 306, 2093–2097 (2004).
Tang, X. D. et al. Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels. Nature 425, 531–535 (2003).
Horrigan, F. T., Heinemann, S. H. & Hoshi, T. Heme regulates allosteric activation of the Slo1 BK channel. J. Gen. Physiol. 126, 7–21 (2005).
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).
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).
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.
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).
Sausbier, M. et al. Elevated blood pressure linked to primary hyperaldosteronism and impaired vasodilation in BK channel-deficient mice. Circulation 112, 60–68 (2005).
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).
Du, W. et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nature Genet. 37, 733–738 (2005).
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).
Salkoff, L. & Wyman, R. Genetic modification of potassium channels in Drosophila Shaker mutants. Nature 293, 228–230 (1981).
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).
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).
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).
Loughney, K., Kreber, R. & Ganetzky, B. Molecular analysis of the para locus, a sodium channel gene in Drosophila. Cell 58, 1143–1154 (1989).
Benzer S. From the gene to behavior. JAMA 218, 1015–1022 (1971).
Wei, A. et al. K+ current diversity is produced by an extended gene family conserved in Drosophila and mouse. Science 248, 599–603 (1990).
Reinhart, P., Chung, S. & Levitan, I. A family of calcium-dependent potassium channels from rat brain. Neuron 2, 1031–1041 (1989).
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).
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).
Knaus, H. et al. Themorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels. Biochemistry 33, 5819–5828 (1994).
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).
McKay, M. Opening of large-conductance calcium-activated potassium channels by the substituted benzimidazolone NS004. J. Neurophysiol. 71, 1873–1882 (1994).
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).
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).
Supported by grants from the National Institutes of Health to L.S.
The authors declare no competing financial interests.
- 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.
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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