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
Affiliations
Rosa Scala
Sections of Pharmacology, Medicinal Chemistry, Department of Pharmacy—Pharmaceutical Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy
Fatima Maqoud
Sections of Pharmacology, Medicinal Chemistry, Department of Pharmacy—Pharmaceutical Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy
Conor McClenaghan
Center for the Investigation of Membrane Excitability Diseases, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110-1010, USA
Theresa M. Harter
Center for the Investigation of Membrane Excitability Diseases, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110-1010, USA
Maria Grazia Perrone
Sections of Pharmacology, Medicinal Chemistry, Department of Pharmacy—Pharmaceutical Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy
Antonio Scilimati
Sections of Pharmacology, Medicinal Chemistry, Department of Pharmacy—Pharmaceutical Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy
Colin G. Nichols
Center for the Investigation of Membrane Excitability Diseases, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110-1010, USA
Domenico Tricarico
Sections of Pharmacology, Medicinal Chemistry, Department of Pharmacy—Pharmaceutical Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy
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.