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

Cantu 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 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 similar to 500 nM and a slope of similar to 0.3. In homozygous SUR2(A478V/A478V) cells, ZOL failed to fully inhibit the KATP currents, causing only similar to 35% inhibition at 100 mu M, 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.

Automated summary

Cantu syndrome is caused by gain of function mutations in the ABCC9 and KCNJ8 genes, resulting in defects in the KATP channels. Glibenclamide has been proposed as a treatment, but it is not effective against certain mutations. Zoledronic acid was found to effectively reduce KATP currents in skeletal muscle and bone cells of Cantu syndrome mice, but not in SUR2 mutant mice. This indicates the importance of subunit specificity for appropriate therapy.