TABLE 2

KCa1.1 channels

Channel name KCa1.1
Description Large conductance, calcium- and voltage-activated potassium channel
Other names Slo1,2,3,4,5,6,7,8, Slo1, BK channel, maxi K+ channel
Molecular information Human: 1182aa, NM_001014797 (transcript variant 1), chr. 10q22.3,6 KCNMA1
Mouse: 1171aa, NM_010610, chr. 14;
Rat: 1243aa, NM_031828, chr. 15p16
Associated subunits KCNMB1–4,29 BK-β,9,10 heteromeric association with Slack (rat),11 β2-adrenergic receptor23
Functional assays Voltage clamp, membrane potential, radioligand binding
Current Maxi K+ calcium-activated current in cochlea, smooth muscle, neurones in brain
Conductance 260pS2,3,4,5,6,7,8
Ion selectivity PK/PNa > 50
Activation Calcium and voltage
Inactivation Inactivating KCa1.1 channels have been studied extensively in chromaffin cells and have been reported in other cell types30,31; inactivation is conferred by the β2- and β3-subunits
Activators Intracellular calcium, NS1608 and NS1619,12 BMS204352,13 DHS-1,14 estradiol,16 Mg2+ (1–10 nM)27
Gating inhibitors None
Blockers TEA (0.14 mM), charybdotoxin (2.9 nM), and iberiotoxin (1.7 nM)17; paxilline (1.9 nM)15; slotoxin (1.5 nM)18; BmP09 Chinese scorpion toxin (27 nM)28
Radioligands [125I]charybdotoxin (Kd = 34 pM),19 [125I]iberiotoxin-D17Y/Y36F mutant (Kd = 5 pM),20 [19F]racemic BMS20435213
Channel distribution Ubiquitous, brain (cerebellum, habenula, striatum, olfactory bulb, neocortex, granule and pyramidal cells of the hippocampus), skeletal muscle, smooth muscle (vascular, uterine, gastric, bladder), adrenal cortex, cochlear hair cells, odontoblasts, pancreatic islet cells, colonic and kidney epithelium
Physiological functions Pleiotropic, selectivity coupled with N-type, voltage-activated calcium channels to mediate fast afterhyperpolarization in neurones, electrical tuning of nonspiking properties of cochlear hair cells, presynaptic regulation of neurotransmitter release, effector of calcium sparks in smooth muscles
Mutations and pathophysiology Mouse knockouts of α- and β-subunits viable, ataxia,26 defects in audition,25 incontinence,24,32 erectile dysfunction33
Pharmacological significance Channel openers may have applications in stroke, epilepsy, bladder over-reactivity, asthma, hypertension, gastric hypermotility and psychoses13,17,21
Comments Multiple alternative splice forms exist; stress hormones control alternative splicing22

  • aa, amino acids; chr., chromosome; TEA, tetraethylammonium; NS1608, N-(3-(trifluoromethyl)phenyl)-N′-(2-hydroxy-5-chlorophenyl) urea; NS1619, 1-(2-hydroxy-5-trifluoromethyl-phenyl)-5-trifluoromethyl-1,3-dihydro-benzimidazol-2-one; BMS204352, (+/-)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6(trifluoromethyl)-2H-indol-2-one.

  • ↵1. Atkinson NS, Robertson GA, and Ganetzky B (1991) A component of calcium-activated potassium channels encoded by the Drosophila slo locus. Science 253:551-555

  • ↵2. Butler A, Tsunoda S, McCobb DP, Wei A, and Salkoff L (1993) mSlo, a complex mouse gene encoding `maxi' calcium-activated potassium channels. Science 261:221-224

  • ↵3. Knaus HG, Garcia-Calvo M, Kaczorowski GJ, and Garcia, ML (1994) 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

  • ↵4. 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

  • ↵5. Lagrutta A, Shen KZ, North RA, and Adelman JP (1994) Functional differences among alternatively spliced variants of Slowpoke, a Drosophila calcium-activated potassium channel. J Biol Chem 269:20347-20351

  • ↵6. Tseng-Crank J, Foster CD, Krause JD, Mertz R, Godinot N, DiChiara TJ, and Reinhart PH (1994) Cloning, expression, and distribution of functionally distinct Ca (2+)-activated K+ channel isoforms from human brain. Neuron 13:1315-1330

  • ↵7. Wei A, Solaro C, Lingle C, and Salkoff L (1994) Calcium sensitivity of BK-type KCa channels determined by a separable domain. Neuron 13:671-681

  • ↵8. 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 USA 94:14066-14071

  • ↵9. Jiang Z, Wallner M, Meera P, and Toro L (1999) Human and rodent MaxiK channel beta-subunit genes: cloning and characterization. Genomics 55:57-67

  • ↵10. Weiger TM, Holmqvist MH, Levitan IB, Clark FT, Sprague S, Huang WJ, Ge P, Wang C, Lawson D, Jurman ME, et al. (2000) A novel nervous system beta subunit that downregulates human large conductance calcium-dependent potassium channels. J Neurosci 20:3563-3570

  • ↵11. Joiner WJ, Tang MD, Wang LY, Dworetzky SI, Boissard CG, Gan L, Gribkoff VK, and Kaczmarek LK (1998) Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits Nat Neurosci 1:462-469

  • ↵12. Strobaek D, Christophersen P, Holm NR, Moldt P, Ahring PK, Johansen TE, and Olesen SP (1996) Modulation of the Ca2+-dependent K+ channel, hslo, by the substituted diphenylurea NS 1608, paxilline and internal Ca2+. Neuropharmacology 35:903-914

  • ↵13. Gribkoff VK, Starrett JE, Dworetzky SI, Hewawasam P, Boissard CG, Cook DA, Frantz SW, Heman K, Hibbard JR, Huston K, et al. (2001) Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-Kpotassium channels. Nat Med 7:471-477

  • ↵14. McManus OB, Harris GH, Giangiacomo KM, Feigenbaum P, Reuben JP, Addy ME, Burka JF, Kaczorowski GJ, and Garcia, ML (1993) An activator of calcium-dependent potassium channels isolated from a medicinal herb. Biochemistry 32:6128-6133

  • ↵15. Sanchez M and McManus OB (1996) Paxilline inhibition of the alpha-subunit of the high conductance calcium-activated potassium channel. Neuropharmacology 35:963-968

  • ↵16. Valverde MA, Rojas P, Amigo J, Cosmelli D, Orio P, Bahamonde MI, Mann GE, Vergara C and Latorre R (1999) Acute activation of Maxi-K channels (hSlo) by estradiol binding to the beta subunit. Science 285:1929-1931

  • ↵17. Kaczorowski GJ, Knaus HG, Leonard RJ, McManus OB, and Garcia ML (1996) High-conductance calcium-activated potassium channels; structure, pharmacology, and function. J Bioenerg Biomembr 28:255-267

  • ↵18. Garcia-Valdes J, Zamudio FZ, Toro L, and Possani LD (2001) Slotoxin, alphaKTx1.11, a new scorpion peptide blocker of MaxiK channels that differentiates between alpha and alpha + beta (beta1 or beta4) complexes. FEBS Lett 505:369-373

  • ↵19. Garcia-Calvo M, Knaus HG, McManus OB, Giangiacomo KM, Kaczorowski GJ, and Garcia ML (1994) Purification and reconstitution of the high-conductance, calcium-activated potassium channel from tracheal smooth muscle. J Biol Chem 269:676-682

  • ↵20. Koschak A, Koch RO, Liu J, Kaczorowski GJ, Reinhart PH, Garcia ML, and Knaus HG (1997) [125I]Iberiotoxin-D19Y/Y36F, the first selective, high specific activity radioligand for high-conductance calcium-activated potassium channels. Biochemistry 36:1943-1952

  • ↵21. Coghlan MJ, Carrol WA, and Gopalakrishnan M (2001) Recent developments in the biology and medicinal chemistry of potassium channel modulators: update from a decade of progress. J Med Chem 44:1-27

  • ↵22. Xie J and McCobb DP (1998) Control of alternative splicing of potassium channels by stress hormones. Science 280:443-446

  • ↵23. Liu G, Shi J, Yang L, Cao L, Park SM, Cui J, and Marx SO (2004) Assembly of a Ca2+-dependent BK channel signaling complex by binding to beta2 adrenergic receptor. EMBO J 23:2196-2205

  • ↵24. Meredith AL, Thorneloe KS, Werner ME, Nelson MT, and Aldrich RW (2004) Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K + channel. J Biol Chem 279:36746-36752

  • ↵25. Ruttiger L, Sausbier M, Zimmermann U, Winter H, Braig C, Engel J, Knirsch M, Arntz C, Langer P, et al. (2004) Deletion of the Ca2+-activated potassium (BK) alpha-subunit but not the BK beta1-subunit leads to progressive hearing loss. Proc Natl Acad Sci USA 101:12922-12927

  • ↵26. Sausbier M, Hu H, Arntz C, Feil S, Kamm S, Adelsberger H, Sausbier U, Sailer CA, Feil R, Hofmann F, et al. (2004) Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency. Proc Natl Acad Sci USA 101:9474-9478

  • ↵27. Shi J, Krishnamoorthy G, Yang Y, Hu L, Chaturvedi N, Harilal D, Qin J, and Cui J (2002) Mechanism of magnesium activation of calcium-activated potassium channels. Nature (Lond) 418:876-880

  • ↵28. Yao J, Chen X, Li H, Zhou Y, Yao L, Wu G, Zhang N, Zhou Z, Xu T, Wu H, et al. (2005) BmP09, a long-chain scorpion peptide blocker of BK channels. J Biol Chem 280:14819-14828

  • ↵29. Brenner R, Jegla TJ, Wickenden A, Liu Y, and Aldrich RW (2000) Cloning and functional characterization of novel BK potassium channel beta subunits, hKCNMB3 and hKCNMB4. J Biol Chem 275:6453-6461

  • ↵30. Xia XM, Ding JP, and Lingle CJ (1999) 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

  • ↵31. Lingle CJ, Solaro CR, Prakriya M, and Ding JP (1996) Calcium-activated potassium channels in adrenal chromaffin cells. Ion Channels 4:261-301

  • ↵32. Petkov GV, Bonev AD, Heppner TJ, Brenner R, Aldrich RW, and Nelson MT (2001) Related beta1-subunit of the Ca2+-activated K+ channel regulates contractile activity of mouse urinary bladder smooth muscle. J Physiol 537:443-452

  • ↵33. Werner ME, Zvara P, Meredith AL, Aldrich RW, and Nelson MT (2005) Erectile dysfunction in mice lacking the large conductance calcium-activated potassium (BK) channel. J Physiol 567 (Pt 2):545-556