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Research ArticleArticle

The Small Molecule NS11021 Is a Potent and Specific Activator of Ca2+-Activated Big-Conductance K+ Channels

Bo Hjorth Bentzen, Antonio Nardi, Kirstine Calloe, Lars Siim Madsen, Søren-Peter Olesen and Morten Grunnet
Molecular Pharmacology October 2007, 72 (4) 1033-1044; DOI: https://doi.org/10.1124/mol.107.038331
Bo Hjorth Bentzen
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Antonio Nardi
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Kirstine Calloe
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Lars Siim Madsen
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Søren-Peter Olesen
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Morten Grunnet
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Abstract

Large-conductance Ca2+- and voltage-activated K+ channels (Kca1.1/BK/MaxiK) are widely expressed ion channels. They provide a Ca2+-dependent feedback mechanism for the regulation of various body functions such as blood flow, neurotransmitter release, uresis, and immunity. In addition, a mitochondrial K+ channel with KCa1.1-resembling properties has been found in the heart, where it may be involved in regulation of energy consumption. In the present study, the effect of a novel NeuroSearch compound, 1-(3,5-bis-trifluoromethyl-phenyl)-3-[4-bromo-2-(1H-tetrazol-5-yl)-phenyl]-thiourea (NS11021), was investigated on cloned KCa1.1 expressed in Xenopus laevis oocytes and mammalian cells using electrophysiological methods. NS11021 at concentrations above 0.3 μM activated KCa1.1 in a concentration-dependent manner by parallel-shifting the channel activation curves to more negative potentials. Single-channel analysis revealed that NS11021 increased the open probability of the channel by altering gating kinetics without affecting the single-channel conductance. NS11021 (10 μM) influenced neither a number of cloned Kv channels nor endogenous Na+ and Ca2+ channels (L- and T-type) in guinea pig cardiac myocytes. In conclusion, NS11021 is a novel KCa1.1 channel activator with better specificity and a 10 times higher potency compared with the most broadly applied KCa1.1 opener, NS1619. Thus, NS11021 might be a valuable tool compound when addressing the physiological and pathophysiological roles of KCa1.1 channels.

Footnotes

  • The work was supported by The Danish National Research Foundation and by a grant from Danish Cardiovascular Research Academy (B.H.B.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.038331.

  • ABBREVIATIONS: NS1619, 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one; NS1608, N-(3-(trifluoromethyl)phenyl)-N′-(2-hydroxy-5-chlorophenyl)urea; BMS-204352, (3S)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one; NS11021, 1-(3,5-bis-trifluoromethyl-phenyl)-3-[4-bromo-2-(1H-tetrazol-5-yl)-phenyl]-thiourea; HEK, human embryonic kidney; DMSO, dimethyl sulfoxide; KB130015, 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran; diCl-DHAA, 12,14-dichlorodehydroabietic acid; NS-8, 2-amino-5-(fluoro-phenyl)-4-methyl-1H-pyrrole-3-carbonitrile.

    • Received May 21, 2007.
    • Accepted July 16, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (4)
Molecular Pharmacology
Vol. 72, Issue 4
1 Oct 2007
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Research ArticleArticle

The Small Molecule NS11021 Is a Potent and Specific Activator of Ca2+-Activated Big-Conductance K+ Channels

Bo Hjorth Bentzen, Antonio Nardi, Kirstine Calloe, Lars Siim Madsen, Søren-Peter Olesen and Morten Grunnet
Molecular Pharmacology October 1, 2007, 72 (4) 1033-1044; DOI: https://doi.org/10.1124/mol.107.038331

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Research ArticleArticle

The Small Molecule NS11021 Is a Potent and Specific Activator of Ca2+-Activated Big-Conductance K+ Channels

Bo Hjorth Bentzen, Antonio Nardi, Kirstine Calloe, Lars Siim Madsen, Søren-Peter Olesen and Morten Grunnet
Molecular Pharmacology October 1, 2007, 72 (4) 1033-1044; DOI: https://doi.org/10.1124/mol.107.038331
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