Cells (Mar 2023)

Zoledronic Acid Blocks Overactive Kir6.1/SUR2-Dependent K<sub>ATP</sub> Channels in Skeletal Muscle and Osteoblasts in a Murine Model of Cantú Syndrome

  • Rosa Scala,
  • Fatima Maqoud,
  • Conor McClenaghan,
  • Theresa M. Harter,
  • Maria Grazia Perrone,
  • Antonio Scilimati,
  • Colin G. Nichols,
  • Domenico Tricarico

DOI
https://doi.org/10.3390/cells12060928
Journal volume & issue
Vol. 12, no. 6
p. 928

Abstract

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Cantú syndrome (CS) is caused by the gain of function mutations in the ABCC9 and KCNJ8 genes encoding, respectively, for the sulfonylureas receptor type 2 (SUR2) and the inwardly rectifier potassium channel 6.1 (Kir6.1) of the ATP-sensitive potassium (KATP) channels. CS is a multi-organ condition with a cardiovascular phenotype, neuromuscular symptoms, and skeletal malformations. Glibenclamide has been proposed for use in CS, but even in animals, the drug is incompletely effective against severe mutations, including the Kir6.1wt/V65M. Patch-clamp experiments showed that zoledronic acid (ZOL) fully reduced the whole-cell KATP currents in bone calvaria cells from wild type (WT/WT) and heterozygous Kir6.1wt/V65MCS mice, with IC50 for ZOL block 50 of 100 nM in each case. Interestingly, KATP currents in the bone of heterozygous SUR2wt/A478V mice were less sensitive to ZOL inhibition, showing an IC50 of ~500 nM and a slope of ~0.3. In homozygous SUR2A478V/A478V cells, ZOL failed to fully inhibit the KATP currents, causing only ~35% inhibition at 100 μM, but was responsive to glibenclamide. ZOL reduced the KATP currents in Kir6.1wt/VMCS mice in both skeletal muscle and bone cells but was not effective in the SUR2[A478V] mice fibers. These data indicate a subunit specificity of ZOL action that is important for appropriate CS therapies.

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