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Mutagenesis and Functional Analysis of Ion Channels Heterologously Expressed in Mammalian Cells
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Mutagenesis and Functional Analysis of Ion Channels Heterologously Expressed in Mammalian Cells

Published on: October 1, 2010

Effects of channel modulators on cloned large-conductance calcium-activated potassium channels

V K Gribkoff1, J T Lum-Ragan, C G Boissard

  • 1Central Nervous System Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA. gribkoff_v@bms.com

Molecular Pharmacology
|July 1, 1996
PubMed

Insights

This study comprehensively examined blockers and openers of large-conductance (BK) Ca(2+)-activated K+ channels, revealing complex interactions and providing insights into BK channel molecular pharmacology.

Area of Science:

  • Molecular pharmacology
  • Ion channel biophysics
  • Cellular physiology

Background:

  • Large-conductance (BK) Ca(2+)-activated K+ channels play crucial roles in cellular excitability.
  • Understanding BK channel modulation is essential for various physiological processes.
  • Previous studies identified several compounds affecting BK channels, but a comprehensive pharmacological characterization was lacking.

Purpose of the Study:

  • To characterize the effects of known BK channel blockers and openers.
  • To investigate the molecular determinants of BK channel modulation.
  • To establish a foundation for future research on BK channel pharmacology.

Main Methods:

  • Expression of cloned mouse (mSlo) and human (hSlo) BK channels in Xenopus laevis oocytes and HEK 293 cells.
  • Electrophysiological recordings to measure BK channel current.
  • Application of various pharmacological agents, including toxins, alkaloids, and synthetic compounds.
  • Analysis of concentration-response relationships and interactions between blockers and openers.

Main Results:

  • Iberiotoxin and charybdotoxin were potent blockers, with iberiotoxin being more potent.
  • Paxilline showed complex blocking effects.
  • Several compounds, including NS004, NS1619, phloretin, niflumic acid, flufenamic acid, and NPPB, acted as BK channel openers.
  • Interactions between blockers and openers included competitive and noncompetitive antagonism.
  • NS1619, niflumic acid, and phloretin increased hSlo BK channel activity and shifted the voltage dependence.

Conclusions:

  • This study provides the first comprehensive molecular pharmacology of BK channels.
  • Identified distinct pharmacological profiles for various BK channel modulators.
  • Revealed complex interactions between BK channel blockers and openers.
  • Laid the groundwork for understanding the molecular basis of BK channel regulation.

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