Targeting kidney CLC-K channels: pharmacological profile in a human cell line versus Xenopus oocytes

Biochim Biophys Acta. 2014 Oct;1838(10):2484-91. doi: 10.1016/j.bbamem.2014.05.017. Epub 2014 May 24.

Abstract

CLC-K chloride channels play a crucial role in kidney physiology and genetic mutations, affecting their function are responsible for severe renal salt loss in humans. Thus, compounds that selectively bind to CLC-Ka and/or CLC-Kb channels and modulate their activity may have a significant therapeutic potential. Here, we compare the biophysical and pharmacological behaviors of human CLC-K channels expressed either in HEK293 cells or in Xenopus oocytes and we show that CLC-K channel properties are greatly influenced by the biochemical environment surrounding the channels. Indeed, in HEK293 cells the potentiating effect of niflumic acid (NFA) on CLC-Ka/barttin and CLC-Kb/barttin channels seems to be absent while the blocking efficacy of niflumic acid and benzofuran derivatives observed in oocytes is preserved. The NFA block does not seem to involve the accessory subunit barttin on CLC-K1 channels. In addition, the sensitivity of CLC-Ks to external Ca(2+) is reduced in HEK293 cells. Based on our findings, we propose that mammalian cell lines are a suitable expression system for the pharmacological profiling of CLC-Ks.

Keywords: Bartter syndrome; CLC-K chloride channel; HEK293 cell; Hypertension; Kidney; Pharmacology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal* / pharmacokinetics
  • Anti-Inflammatory Agents, Non-Steroidal* / pharmacology
  • Benzofurans* / pharmacokinetics
  • Benzofurans* / pharmacology
  • Chloride Channels* / antagonists & inhibitors
  • Chloride Channels* / genetics
  • Chloride Channels* / metabolism
  • Drug Delivery Systems*
  • HEK293 Cells
  • Humans
  • Kidney / metabolism*
  • Niflumic Acid* / pharmacokinetics
  • Niflumic Acid* / pharmacology
  • Oocytes / cytology
  • Oocytes / metabolism*
  • Species Specificity
  • Xenopus laevis

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzofurans
  • CLCNKA protein, human
  • CLCNKB protein, human
  • Chloride Channels
  • Niflumic Acid
  • benzofuran