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Glibenclamide opens ATP-sensitive potassium channels in Xenopus oocyte follicular cells during metabolic stress

E Guillemare1, M Lazdunski, E Honoré

  • 1Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.

Molecular Pharmacology
|March 1, 1995
PubMed

Insights

Metabolic inhibition transforms glibenclamide from a blocker to an activator of ATP-sensitive potassium (KATP) channels in Xenopus oocyte follicular cells. This switch, driven by internal acidosis, reveals new insights into KATP channel regulation.

Area of Science:

  • Cell Biology
  • Ion Channel Physiology
  • Xenopus Oocyte Research

Background:

  • ATP-sensitive potassium (KATP) channels are crucial in cellular energy homeostasis.
  • Glibenclamide is a well-established KATP channel blocker in various cell types, including Xenopus oocyte follicular cells.
  • Metabolic inhibition, induced by dinitrophenol (DNP), significantly alters cellular conditions.

Purpose of the Study:

  • To investigate the effect of metabolic inhibition on glibenclamide's action on KATP channels in Xenopus oocyte follicular cells.
  • To elucidate the mechanism behind glibenclamide's altered function under metabolic stress.
  • To explore the interplay between metabolic state, ion channel activity, and drug response.

Main Methods:

  • Utilized Xenopus oocyte follicular cells as a model system.
  • Applied metabolic inhibition using dinitrophenol (DNP).
  • Assessed KATP channel activity using pharmacological agents like glibenclamide, P1060, U-37883A, tedisamil, and LH 35, and measured channel conductance.

Main Results:

  • Metabolic inhibition with DNP reversed glibenclamide's effect, converting it from a blocker to an activator of KATP channels.
  • DNP-treated cells remained sensitive to KATP channel openers like P1060, but this effect became glibenclamide-insensitive.
  • Glibenclamide activation in DNP-treated cells (EC50 of 3 microM) was antagonized by non-sulfonylurea KATP channel blockers.
  • Internal acidosis resulting from DNP treatment was identified as the key factor in glibenclamide's functional switch.

Conclusions:

  • Internal acidosis is the critical determinant in converting glibenclamide from a KATP channel blocker to an activator.
  • Xenopus oocyte follicular cells provide a valuable model for studying the complex regulation of KATP channels under metabolic stress.
  • Findings highlight the context-dependent nature of drug action on ion channels.

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