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Related Experiment Videos

A functional CFTR-NBF1 is required for ROMK2-CFTR interaction

C M McNicholas1, M W Nason, W B Guggino

  • 1Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520-8026, USA.

The American Journal of Physiology
|December 31, 1997
PubMed
Summary

The cystic fibrosis transmembrane conductance regulator (CFTR) enhances ROMK2 channel sensitivity to glibenclamide. The first nucleotide-binding fold (NBF1) of CFTR is crucial for this interaction, as mutations in NBF1 reduce glibenclamide sensitivity.

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Area of Science:

  • * Molecular physiology
  • * Ion channel function

Background:

  • * Previous studies showed cystic fibrosis transmembrane conductance regulator (CFTR) enhances glibenclamide sensitivity of the ROMK2 channel.
  • * The precise mechanism of this interaction requires further characterization.

Purpose of the Study:

  • * To investigate the role of CFTR's first nucleotide-binding fold (NBF1) in mediating the enhanced glibenclamide sensitivity of ROMK2.
  • * To determine if mutations within NBF1 affect the interaction between CFTR and ROMK2.

Main Methods:

  • * Two-microelectrode voltage-clamp technique in Xenopus oocytes.
  • * Coexpression of ROMK2 with wild-type and mutant CFTR constructs.
  • * Measurement of whole-cell potassium (K+) currents and glibenclamide inhibition.

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Main Results:

  • * Glibenclamide inhibited K+ currents by 56% in oocytes expressing both ROMK2 and CFTR, versus 11% in oocytes with ROMK2 alone.
  • * Truncated CFTR (CFTR-K593X) with intact NBF1 retained partial enhancement (46% inhibition).
  • * CFTR mutants with altered or absent NBF1 (CFTR-K370X, CFTR-G551D, CFTR-A455E) significantly reduced glibenclamide inhibition of ROMK2 currents (12-25%).

Conclusions:

  • * The NBF1 domain of CFTR is essential for the interaction with ROMK2 that confers glibenclamide sensitivity.
  • * Mutations affecting NBF1 disrupt this interaction, leading to reduced sulfonylurea sensitivity.