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Related Experiment Videos

Kir6.2-dependent high-affinity repaglinide binding to beta-cell K(ATP) channels.

Ann Maria K Hansen1, John Bondo Hansen, Richard D Carr

  • 1Novo Nordisk A/S, Discovery, Diabetes Biology, DK-2760 Måløv, Denmark.

British Journal of Pharmacology
|January 29, 2005
PubMed
Summary

The Kir6.2 subunit is essential for high-affinity binding of repaglinide to the SUR1 receptor, influencing its hypoglycemic action. Glibenclamide and similar drugs bind SUR1 independently of Kir6.2.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • The ATP-sensitive potassium (KATP) channel comprises Kir6.2 pore-forming subunits and SUR1 regulatory subunits.
  • The Kir6.2 N-terminus mediates sulfonylurea binding and channel closure.
  • Functional uncoupling of Kir6.2 and SUR1 occurs upon N-terminal deletion of Kir6.2 (Kir6.2ΔN14).

Purpose of the Study:

  • To investigate the interaction of hypoglycemic agents repaglinide and glibenclamide with SUR1.
  • To determine the effect of Kir6.2 on these drug-SUR1 interactions.
  • To explore how functional uncoupling impacts drug binding affinities.

Main Methods:

  • Binding experiments conducted on membrane preparations in ATP-free buffer at 37°C.
  • Co-expression of SUR1 with wild-type Kir6.2 and N-terminally deleted Kir6.2 (Kir6.2ΔN14).

Related Experiment Videos

  • Whole-cell patch-clamp electrophysiology to assess channel function.

    • Main Results:

    • Repaglinide exhibited low affinity for SUR1 alone but high affinity when co-expressed with Kir6.2 (approx. 150-fold increase).
    • Glibenclamide, tolbutamide, and nateglinide showed only marginally lower affinity for SUR1 compared to Kir6.2/SUR1.
    • Repaglinide binding affinity was low with Kir6.2ΔN14/SUR1, while glibenclamide, tolbutamide, and nateglinide affinities were minimally affected.
    • Inhibition of Kir6.2ΔN14/SUR1 currents by repaglinide and nateglinide was abolished.

    Conclusions:

    • Kir6.2 induces a conformational change in SUR1, crucial for high-affinity repaglinide binding, or is part of the binding site itself.
    • Glibenclamide, tolbutamide, and nateglinide binding to SUR1 appears independent of Kir6.2.
    • The distinct binding mechanisms of repaglinide and sulfonylureas highlight differential drug interactions with the KATP channel complex.