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

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 Kir6.1 wt/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 Kir6.1 wt/V65M CS mice, with IC 50 for ZOL block < 1 nM in each case. ZOL fully reduced KATP current in excised patches in skeletal muscle fibers in WT/WT and CS mice, with IC 50 of 100 nM in each case. Interestingly, KATP currents in the bone of heterozygous SUR2 wt/A478V mice were less sensitive to ZOL inhibition, showing an IC 50 of ~500 nM and a slope of ~0.3. In homozygous SUR2 A478V/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 Kir6.1 wt/VM CS 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.