Download PDF
Planta Med 2003; 69(10): 885-892
DOI: 10.1055/s-2003-45095
Review
© Georg Thieme Verlag Stuttgart · New York

Natural Modulators of Large-Conductance Calcium-Activated Potassium Channels

Antonio Nardi1 , Vincenzo Calderone2 , Silvio Chericoni3 , Ivano Morelli3
  • 1Dipartimento di Scienze Farmaceutiche, Università di Pisa, Pisa, Italy
  • 2Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Pisa, Italy
  • 3Dipartimento di Chimica Bioorganica e Biofarmacia, Università di Pisa, Pisa, Italy
Further Information

Publication History

Received: March 10, 2003

Accepted: June 19, 2003

Publication Date:
02 December 2003 (online)

   Permissions and Reprints

Abstract

Large-conductance calcium-activated potassium channels, also known as BK or Maxi-K channels, occur in many types of cell, including neurons and myocytes, where they play an essential role in the regulation of cell excitability and function. These properties open a possible role for BK-activators (also called BK-openers) and/or BK-blockers as effective therapeutic agents for different neurological, urological, respiratory and cardiovascular diseases. The synthetic benzimidazolone derivatives NS004 and NS1619 are the pioneer BK-activators and have represented the reference models which led to the design of several novel and heterogeneous synthetic BK-openers, while very few synthetic BK-blockers have been reported. Even today, the research towards identifying new BK-modulating agents is proceeding with great impetus and is giving an ever-increasing number of new molecules. Among these, also a handsome number of natural BK-modulator compounds, belonging to different structural classes, has appeared in the literature. The goal of this paper is to provide a possible simple classification of the broad structural heterogeneity of the natural BK-activating agents (terpenes, phenols, flavonoids) and blockers (alkaloids and peptides), and a concise overview of their chemical and pharmacological properties as well as potential therapeutic applications.

Key words

Natural products - potassium channels - large-conductance calcium-activated BK channels - BK-activators - BK-blockers

References

  • 1 Calderone V. Large-conductance calcium-activated potassium channels: function, pharmacology and drugs.  Curr Med Chem. 2002;  9 1385-95
    PubMedGoogle Scholar
  • 2 Garcia-Calvo M, Knaus H -G, McManus O B, Giangiacomo K M, Kaczorowski G J, Garcia M L. Purification and reconstitution of the high-conductance, calcium-activated potassium channel from tracheal smooth muscle.  J Biol Chem. 1994;  269 676-82
    PubMedGoogle Scholar
  • 3 Dworetzky S I, Boissard C G, Lum-Ragan J T, McKay M C, Post-Munson D J, Trojnacki J T, Chang C P, Gribkoff V K. Phenotypic alteration of a human BK (hSlo) channel by hSlobeta subunit coexpression: changes in blocker sensitivity, activation/relaxation and inactivation kinetics, and protein kinase A modulation.  J Neurosci. 1996;  16 4543-50
    PubMedGoogle Scholar
  • 4 Nilius B, Droogmans G. Ion channels and their functional role in vascular endothelium.  Physiol Rev. 2001;  81 1415-59
    PubMedGoogle Scholar
  • 5 Wu S -N. Large-conductance Ca2+-activated K+ channels: physiological role and pharmacology.  Curr Med Chem. 2003;  10 649-61
    CrossrefPubMedGoogle Scholar
  • 6 Papassotiriou J, Kohler R, Prenen J, Krause H, Akbar M, Eggermont J, Paul M, Distler A, Nilius B, Hoyer J. Endothelial K+ channel lacks the Ca2+ sensitivity-regulating β subunit.  FASEB J. 2000;  14 885-94
    PubMedGoogle Scholar
  • 7 Sun D, Huang A, Koller A, Kaley G. Endothelial KCa channels mediate flow-dependent dilation of arterioles of skeletal muscle and mesentery.  Microvasc Res. 2001;  61 179-86
    PubMedGoogle Scholar
  • 8 Gribkoff V K, Starrett JE J r, Dworetzky S I. The pharmacology and molecular biology of large-conductance calcium-activated (BK) potassium channels.  Adv Pharmacol. 1997;  37 319-48
    PubMedGoogle Scholar
  • 9 Robitaille R, Garcia M L, Kaczorowski G J, Charlton M P. Functional colocalization of calcium and calcium-gated potassium channels in control of transmitter release.  Neuron. 1993;  11 645-55
    CrossrefPubMedGoogle Scholar
  • 10 Gola M, Crest M. Colocalization of active KCa channels and Ca2+ channels within Ca2+ domains in Helix neurons.  Neuron. 1993;  10 689-99
    CrossrefPubMedGoogle Scholar
  • 11 Volk K A, Matsuda J J, Shibata E F. A voltage-dependent potassium current in rabbit coronary artery smooth muscle cells.  J Physiol (Lond). 1991;  439 751-68
    PubMedGoogle Scholar
  • 12 Perez G, Toro L. Differential modulation of large-conductance KCa channels by PKA in pregnant and nonpregnant myometrium.  Am J Physiol. 1994;  266 C1459-63
    PubMedGoogle Scholar
  • 13 Kume H, Mikawa K, Takagi K, Kotlikoff M I. Role of G proteins and KCa channels in the muscarinic and beta-adrenergic regulation of airway smooth muscle.  Am J Physiol. 1995;  268 L221-9
    PubMedGoogle Scholar
  • 14 Vogalis F. Potassium channels in gastrointestinal smooth muscle.  J Auton Pharmacol. 2000;  20 207-19
    CrossrefPubMedGoogle Scholar
  • 15 Tanaka Y, Horinouchi T, Tanaka H, Shigenobu K, Koike K. BK channels play an important role as a negative feedback mechanism in the regulation of spontaneous rhythmic contraction of urinary bladder smooth muscles.  Nippon Yakurigaku Zasshi. 2002;  120 106P-8
    PubMedGoogle Scholar
  • 16 Pelaia G, Gallelli L, Vatrella A, Grembiale R D, Maselli R, De Sarro G B, Marsico S A. Potential role of potassium channel openers in the treatment of asthma and chronic obstructive pulmonary disease.  Life Sci. 2002;  70 977-90
    CrossrefPubMedGoogle Scholar
  • 17 Hewawasam P, Erway M, Thalody G, Weiner H, Boissard C G, Gribkoff V K, Meanwell N A, Lodge N, Starrett JE J r. The synthesis and structure-activity relationships of 1,3-diaryl 1,2,4-(4H)-triazol-5-ones: a new class of calcium-dependent, large conductance, potassium (maxi-K) channel opener targeted for urge urinary incontinence.  Bioorg Med Chem Lett. 2002;  12 1117-20
    CrossrefPubMedGoogle Scholar
  • 18 Starrett JE J r, Dworetsky S I, Gribkoff V K. Modulators of large-conductance calcium-activated potassium (BK) channels as potential therapeutic targets.  Curr Pharm Des. 1996;  2 413-28
    PubMedGoogle Scholar
  • 19 Berger M G, Rusch N J. Voltage and calcium-gated potassium channels: functional expression and therapeutic potential in the vasculature.  Perspec Drug Disc Des. 1999;  15/16 313-32
    PubMedGoogle Scholar
  • 20 Wickenden A. K(+) channels as therapeutic drug targets.  Pharmacol Ther. 2002;  94 157-82
    CrossrefPubMedGoogle Scholar
  • 21 Rundfeldt C. Potassium channels and neurodegenerative diseases.  Drug News Perspect. 1999;  12 99-104
    CrossrefPubMedGoogle Scholar
  • 22 Gribkoff V K, Starrett JE J r, Dworetsky S I. Maxi-K potassium channels: form, function and modulation of a class of endogenous regulators of intracellular calcium.  Neuroscientist. 2001;  7 166-77
    PubMedGoogle Scholar
  • 23 Hewawasam P, Fan W, Knipe J, Moon S L, Boissard C G, Gribkoff V K, Starrett JE J r. The synthesis and structure-activity relationships of 4-aryl-3-aminoquinolin-2-ones: a new class of calcium-dependent, large conductance, potassium (maxi-K) channel openers targeted for post-stroke neuroprotection.  Bioorg Med Chem Lett. 2002;  12 1779-83
    CrossrefPubMedGoogle Scholar
  • 24 Archer S L. Potassium channels and erectile dysfunction.  Vasc Pharmacol. 2002;  38 61-71
    PubMedGoogle Scholar
  • 25 Olesen S -P, Watjen F. Benzimidazole derivatives, their preparation and use. European Patent Application, EP 0 477 819 1992
    Google Scholar
  • 26 Olesen S -P, Munch E, Moldt P, Drejer J. Selective activation of Ca2+-dependent K+ channels by novel benzimidazolone.  Eur J Pharmacol. 1994;  251 53-9
    CrossrefPubMedGoogle Scholar
  • 27 McManus O B, Harris G H, Giangiacomo K M, Feigenbaum P, Reuben J P, Addy M E, Burka J F, Kaczorowski G J, Garcia M L. An activator of calcium-dependent potassium channels isolated from a medicinal herb.  Biochemistry. 1993;  32 6128-33
    CrossrefPubMedGoogle Scholar
  • 28 Giangiacomo K M, Kamassah A, Harris G, McManus O B. Mechanism of Maxi-K channel activation by dehidrosoyasaponin-I.  J Gen Physiol. 1998;  112 485-501
    CrossrefPubMedGoogle Scholar
  • 29 Singh S B, Goetz M A, Zink D L, Dombrowski A W, Polishook J D, Garcia M L, Schmalhofer W, McManus O B, Kaczorowski G J. Maxikdiol: a novel dihydroxyisoprimane as an agonist of maxi-K channels.  J Chem Soc Perkin Trans. 1994;  1 3349-52
    PubMedGoogle Scholar
  • 30 Imaizumi Y, Sakamoto K, Yamada A, Hotta A, Susumu O, Muraki K, Uchiyama M, Ohwada T. Molecular basis of pimarane compounds as novel activators of large-conductance Ca2+-activated K+ channel α-subunit.  Mol Pharmacol. 2002;  62 836-46
    CrossrefPubMedGoogle Scholar
  • 31 Ondeyka J G, Ball R G, Garcia M L, Dombrowski A W, Sabnis G, Kaczorowski G J, Zink D L, Bills G F, Goetz M A, Schmalhofer W A, Singh S B. A carotane sesquiterpene as a potent modulator of the Maxi-K channel from Arthrinium phaesospermum .  Bioorg Med Chem Lett. 1995;  5 733-4
    CrossrefPubMedGoogle Scholar
  • 32 Lee S H, Hensens O D, Helms G L, Liesch J M, Zink D L, Giacobbe R A, Bills G F, Stevens-Miles S, Garcia M L, Schmalhofer W A, McManus O B, Kaczorowski G J. L-735,334, a novel sesquiterpenoid potassium channel-agonist from Trichoderma virens .  J Nat Prod. 1995;  58 1822-8
    CrossrefPubMedGoogle Scholar
  • 33 Burns J, Yokota T, Ashihara H, Lean M EJ, Crozier A. Plant foods and herbal sources of resveratrol.  J Agric Food Chem. 2002;  50 3337-40
    CrossrefPubMedGoogle Scholar
  • 34 Li H -F, Chen S -A, Wu S -N. Evidence for the stimulatory effect of resveratrol on Ca2+-activated K+ current in vascular endothelial cells.  Cardiovasc Res. 2000;  45 1035-45
    CrossrefPubMedGoogle Scholar
  • 35 Wu S -N, Chen C -C, Li H -F, Lo Y -K, Chen S -A, Chiang H -T. Stimulation of the BK(Ca) channel in cultured smooth muscle cells of human trachea by magnolol.  Thorax. 2002;  57 67-74
    CrossrefPubMedGoogle Scholar
  • 36 Lambert J D, Zhao D, Meyers R O, Kuester R K, Timmermann B N, Dorr R T. Nordihydroguaiaretic acid: hepatotoxicity and detoxification in the mouse.  Toxicon. 2002;  40 1701-8
    CrossrefPubMedGoogle Scholar
  • 37 Nagano N, Imaizumi Y, Hirano M, Watanabe M. Opening of Ca2+-dependent K+ channels by nordihydroguaiaretic acid in porcine coronary arterial smooth muscle cells.  Jpn J Pharmacol. 1996;  70 281-4
    PubMedGoogle Scholar
  • 38 Yamamura H, Nagano N, Hirano M, Muraki K, Watanabe M, Imaizumi Y. Activation of Ca2+-dependent K+ current by nordihydroguaiaretic acid in porcine coronary arterial smooth muscle cells.  J Pharmacol Exp Ther. 1999;  291 140-6
    PubMedGoogle Scholar
  • 39 Yamamura H, Sakamoto K, Ohya S, Muraki K, Imaizumi Y. Mechanisms underlying the activation of large conductance Ca2+-activated K+ channels by nordihydroguaiaretic acid.  Jpn J Pharmacol. 2002;  89 53-63
    CrossrefPubMedGoogle Scholar
  • 40 Li Y, Starrett J E, Meanwell N A, Johnson G, Harte W E, Dworetzky S I, Boissard C G, Gribkoff V K. The discovery of novel openers of Ca2+-dependent large-conductance potassium channels: pharmacophore search and physiological evaluation of flavonoids.  Bioorg Med Chem Lett. 1997;  7 759-62
    CrossrefPubMedGoogle Scholar
  • 41 Calderone V, Chericoni S, Testai L, Morelli I, Martinotti E. Role of potassium channels in the vasodilator response of flavonoids naringine and naringenine. IX Congress of the Italian Society of Pharmacognosy Taormina (Messina, Italy); 26th October, 2001: P25
    Google Scholar
  • 42 Calderone V, Testai L, Martinelli C, Chericoni S, Morelli I, Martinotti E. Role of BK potassium channel in the vasorelaxing effect of flavonoids. X Congress of the Italian Society of Pharmacognosy S. Margherita di Pula (Cagliari, Italy); 2nd-6th October, 2002: P38
    Google Scholar
  • 43 Koh D -S, Reid G, Vogel W. Activating effect of the flavonoid phloretin on Ca(2+)-activated K+ channels in myelinated nerve fibers of Xenopus laevis .  Neurosci Lett. 1994;  165 167-70
    CrossrefPubMedGoogle Scholar
  • 44 Kidd P M. A review of nutrients and botanicals in the integrative management of cognitive dysfunction.  Altern Med Rev. 1999;  4 144-61
    PubMedGoogle Scholar
  • 45 Bonoczk P, Gulyas B, Adam-Vizi V, Nemes A, Karpati E, Kiss B, Kapas M, Szantay C, Koncz I, Zelles T, Vas A. Role of sodium channel inhibition in neuroprotection: effect of vinpocetine.  Brain Res Bull. 2000;  53 245-54
    CrossrefPubMedGoogle Scholar
  • 46 Wu S -N, Li H -F, Chiang H -T. Vinpocetine-induced stimulation of calcium-activated potassium currents in rat pituitary GH3 cells.  Biochem Pharmacol. 2001;  61 877-92
    CrossrefPubMedGoogle Scholar
  • 47 Coghlan M J, Carroll W A, Gopalakrishnan M. Recent developments in the biology and medicinal chemistry of potassium channel modulators: update from a decade of progress.  J Med Chem. 2001;  44 1627-53
    CrossrefPubMedGoogle Scholar
  • 48 Li Y, Johnson G, Romine J L, Meanwell N A, Martin S W, Dworetzky S I, Boissard C G, Gribkoff V K, Starrett JE J r. Novel openers of Ca2+-dependent large-conductance potassium channel: symmetrical pharmacophore and electrophysiological evaluation of bisphenols.  Bioorg Med Chem Lett. 2003;  13 1437-9
    CrossrefPubMedGoogle Scholar
  • 49 Olesen S -P, Moldt P, Pedersen O. International Patent Application. 1994: WO 9 422 807
    Google Scholar
  • 50 Hu S, Fink C A, Kim H S, Lappe R W. Novel and potent BK channel openers: CGS 7181 and its analogs.  Drug Dev Res. 1997;  41 10-21
    CrossrefPubMedGoogle Scholar
  • 51 Legros C, Bougis P E, Martin-Eauclaire M -F. Molecular biology of scorpion toxins active on potassium channels.  Perspect Drug Disc Des. 1999;  15/16 1-14
    PubMedGoogle Scholar
  • 52 Miller C, Moczydlowski E, Latorre R, Phillips M. Charybdotoxin, a protein inhibitor of single Ca2+-activated K+ channels from mammalian skeletal muscle.  Nature. 1985;  313 316-8
    CrossrefPubMedGoogle Scholar
  • 53 Attali B, Romey G, Honoré E, Schmid-Alliana A, Mattéi M G, Lesage F, Ricard P, Barhanin J, Lazdunski M. Cloning, functional expression, and regulation of two K+ channels in human T lymphocytes.  J Biol Chem. 1992;  267 8650-7
    PubMedGoogle Scholar
  • 54 Giangiacomo K M, Garcia M L, McManus O B. Mechanism of iberiotoxin block of the large-conductance calcium-activated potassium channel from bovine aortic smooth muscle.  Biochemistry. 1992;  31 6719-27
    CrossrefPubMedGoogle Scholar
  • 55 Candia S, Garcia M L, Latorre R. Mode of action of iberiotoxin, a potent blocker of the large conductance Ca2+-activated K+ channel.  Biophys J. 1992;  63 583-90
    PubMedGoogle Scholar
  • 56 Galvez A, Gimenez Gallego G, Reuben J P, Roy Contancin L, Feigenbaum P, Kaczowroski G J, Garcia M L. Purification and characterization of a unique, potent, peptidyl probe for the high conductance calcium-activated potassium channel from venom of the scorpion Buthus tamulus.  J Biol Chem. 1990;  265 11 083-90
    PubMedGoogle Scholar
  • 57 Garcia M L, Kaczorowski G J. Pharmacology of high-conductance calcium-activated potassium channels.  Curr Res Ion Channel Modul. 1998;  3 213-20
    PubMedGoogle Scholar
  • 58 Garcia-Valdes J, Zamudio F Z, Toro L, Possani L D. Slotoxin, αKTx1.11, a new scorpion peptide blocker of MaxiK channels that differentiates between α and α+β (β1 or β4) complexes.  FEBS Letters. 2001;  505 369-73
    CrossrefPubMedGoogle Scholar
  • 59 Wu Y, Wang Z -F, Shi Y -L. Beta-agkistrodotoxin inhibits large-conductance calcium-activated potassium channels in rat hippocampal CA1 pyramidal neurons.  Brain Res. 2002;  940 21-6
    CrossrefPubMedGoogle Scholar
  • 60 Armando-Hardy M, Ellory J C, Ferreira H G, Fleminger S, Lew V L. Inhibition of the calcium-induced increase in the potassium permeability of human red blood cells by quinine.  J Physiol. 1975;  250 32P-3
    PubMedGoogle Scholar
  • 61 Burgess G M, Claret M, Jenkinson D H. Effects of quinine and apamin on the calcium-dependent potassium permeability of mammalian hepatocytes and red cells.  J Physiol. 1981;  317 67-90
    PubMedGoogle Scholar
  • 62 Cook N S. Potassium channels: structure, classification, function and therapeutic potential. Ellis Horwood Limited Southampton; 1990
    Google Scholar
  • 63 Knaus H -G, McManus O B, Lee S H, Schmalhofer W A, Garcia-Calvo M, Helms L M, Sanchez M, Giangiacomo K, Reuben J P, Smith AB I II, Kaczorowski GJ and Garcia M L. Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels.  Biochemistry. 1994;  33 5819-28
    CrossrefPubMedGoogle Scholar
  • 64 Sanchez M, McManus O B. Paxilline inhibition of the alpha-subunit of the high-conductance calcium-activated potassium channel.  Neuropharmacol. 1996;  35 963-8
    CrossrefPubMedGoogle Scholar
  • 65 DeFarias F P, Carvalho M F, Lee S H, Kaczorowski G J, Suarez-Kurtz G. Effects of the K+ channel blockers paspalitrem-C and paxilline on mammalian smooth muscle.  Eur J Pharmacol. 1996;  314 123-8
    CrossrefPubMedGoogle Scholar
  • 66 Wang Z G, Liu G Z. Advances in natural products in China.  TIPS. 1985;  6 423-5
    PubMedGoogle Scholar
  • 67 Wang G, Lemos J R. Tetrandrine blocks a slow, large-conductance, Ca2+-activated K+ channel besides inhibiting a noninactivating Ca2+ current in isolated nerve terminals of the rat neurohypophysis.  Pflugers Arch. 1992;  421 558-65
    PubMedGoogle Scholar
  • 68 Wu S -N, Li H F, Lo Y C. Characterization of tetrandrine-induced inhibition of large-conductance calcium-activated potassium channels in a human endothelial cell line (HUV-EC-C).  J Pharmacol Exp Ther. 2000;  292 188-95
    PubMedGoogle Scholar
  • 69 Wang G, Lemos J R. Tetrandrine: a new ligand to block voltage-dependent Ca2+ and Ca(2+)-activated K+ channels.  Life Sci. 1995;  56 295-306
    PubMedGoogle Scholar

Prof. Ivano Morelli

Dipartimento di Chimica Bioorganica e Biofarmacia

Università degli Studi di Pisa

via Bonanno 33

56126 Pisa

Italy

Phone: +39-050-44074

Fax: +39-050-43321

Email: bioorg@farm.unipi.it

      >