Find in Library

Cantú syndrome (CS) is caused by the gain of function mutations in the <i>ABCC9</i> and <i>KCNJ8</i> 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/V65MCS mice, with IC₅₀ 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 IC₅₀ 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 IC₅₀ 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/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.