{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T07:53:09Z","timestamp":1792309989939,"version":"4.4.0"},"reference-count":48,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:00:00Z","timestamp":1679011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Societ\u00e0 Italiana di Farmacologia (SIF)"},{"name":"\u201cErasmus + for Traineeship\u201d fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cant\u00fa 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 &lt; 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 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 \u03bcM, 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.<\/jats:p>","DOI":"10.3390\/cells12060928","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T06:48:35Z","timestamp":1679294915000},"page":"928","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Zoledronic Acid Blocks Overactive Kir6.1\/SUR2-Dependent KATP Channels in Skeletal Muscle and Osteoblasts in a Murine Model of Cant\u00fa Syndrome"],"prefix":"10.3390","volume":"12","author":[{"given":"Rosa","family":"Scala","sequence":"first","affiliation":[{"name":"Sections of Pharmacology, Medicinal Chemistry, Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Maqoud","sequence":"additional","affiliation":[{"name":"Sections of Pharmacology, Medicinal Chemistry, Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conor","family":"McClenaghan","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa M.","family":"Harter","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4195-5228","authenticated-orcid":false,"given":"Maria Grazia","family":"Perrone","sequence":"additional","affiliation":[{"name":"Sections of Pharmacology, Medicinal Chemistry, Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2740-6425","authenticated-orcid":false,"given":"Antonio","family":"Scilimati","sequence":"additional","affiliation":[{"name":"Sections of Pharmacology, Medicinal Chemistry, Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin G.","family":"Nichols","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Tricarico","sequence":"additional","affiliation":[{"name":"Sections of Pharmacology, Medicinal Chemistry, Department of Pharmacy\u2014Pharmaceutical Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"C920","DOI":"10.1152\/ajpcell.00154.2022","article-title":"Kir6.1 and SUR2B and Cant\u00fa syndrome","volume":"323","author":"McClenaghan","year":"2022","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1002\/ajmg.a.31348","article-title":"Cantu syndrome in a woman and her two daughters: Further confirmation of autosomal dominant inheritance and review of the cardiac manifestations","volume":"140","author":"Grange","year":"2006","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1161\/CIRCRESAHA.112.300514","article-title":"KATP Channels and Cardiovascular Disease","volume":"112","author":"Nichols","year":"2013","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/ng.2324","article-title":"Dominant missense mutations in ABCC9 cause Cant\u00fa syndrome","volume":"44","author":"Harakalova","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/humu.22555","article-title":"Cant\u00fa Syndrome Resulting from Activating Mutation in the KCNJ8 Gene","volume":"35","author":"Cooper","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/ajmg.c.31753","article-title":"Cant\u00fa syndrome: Findings from 74 patients in the International Cant\u00fa Syndrome Registry","volume":"181","author":"Grange","year":"2019","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"103996","DOI":"10.1016\/j.ejmg.2020.103996","article-title":"Cant\u00fa syndrome versus Zimmermann-Laband syndrome: Report of nine individuals with ABCC9 variants","volume":"63","author":"Niceta","year":"2020","journal-title":"Eur. J. Med. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e121153","DOI":"10.1172\/jci.insight.121153","article-title":"Cardiovascular consequences of KATP overactivity in Cantu syndrome","volume":"3","author":"Huang","year":"2018","journal-title":"JCI Insight"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"604885","DOI":"10.3389\/fphar.2020.604885","article-title":"Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cant\u00f9 Syndrome","volume":"11","author":"Scala","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"zqaa004","DOI":"10.1093\/function\/zqaa004","article-title":"The Mechanism of High-Output Cardiac Hypertrophy Arising from Potassium Channel Gain-of-Function in Cant\u00fa Syndrome","volume":"1","author":"McClenaghan","year":"2020","journal-title":"Function"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Scala, R., Maqoud, F., Zizzo, N., Passantino, G., Mele, A., Camerino, G., McClenaghan, C., Harter, T., Nichols, C., and Tricarico, D. (2021). Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome. Cells, 10.","DOI":"10.3390\/cells10071791"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17387","DOI":"10.1074\/jbc.M117.804971","article-title":"Conserved functional consequences of disease-associated mutations in the slide helix of Kir6.1 and Kir6.2 subunits of the ATP-sensitive potassium channel","volume":"292","author":"Cooper","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1172\/JCI4552","article-title":"Impairment of skeletal muscle adenosine triphosphate\u2013sensitive K+ channels in patients with hypokalemic periodic paralysis","volume":"103","author":"Tricarico","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1124\/mol.54.1.197","article-title":"The Biophysical and Pharmacological Characteristics of Skeletal Muscle ATP-Sensitive K+ Channels Are Modified in K+-Depleted Rat, an Animal Model of Hypokalemic Periodic Paralysis","volume":"54","author":"Tricarico","year":"1998","journal-title":"Mol. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s00424-009-0771-y","article-title":"Human KATP channelopathies: Diseases of metabolic homeostasis","volume":"460","author":"Olson","year":"2009","journal-title":"Pflugers Arch."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/bjp.2008.42","article-title":"Acetazolamide prevents vacuolar myopathy in skeletal muscle of K+ -depleted rats","volume":"154","author":"Tricarico","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1006\/bbrc.1997.6320","article-title":"Modulation of ATP-Sensitive K+Channel by Insulin in Rat Skeletal Muscle Fibers","volume":"232","author":"Tricarico","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/S0960-8966(03)00095-6","article-title":"Involvement of 3Na+\/2K+ ATP-ase and Pi-3 kinase in the response of skeletal muscle ATP-sensitive K+ channels to insulin","volume":"13","author":"Tricarico","year":"2003","journal-title":"Neuromuscul. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/sj.bjp.0705233","article-title":"Dualistic actions of cromakalim and new potent 2H-1,4-benzoxazine derivatives on the native skeletal muscle KATP channel","volume":"139","author":"Tricarico","year":"2003","journal-title":"Br. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.yjmcc.2005.04.006","article-title":"KATP channel therapeutics at the bedside","volume":"39","author":"Jahangir","year":"2005","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"110","DOI":"10.2174\/1574884713666180412150153","article-title":"Targeting Brain Tumors with Nanomedicines: Overcoming Blood Brain Barrier Challenges","volume":"13","author":"Khaitan","year":"2018","journal-title":"Curr. Clin. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Luu, W., Bjork, J., Salo, E., Entenmann, N., Jurgenson, T., Fisher, C., and Klein, A.H. (2019). Modulation of SUR1 KATP Channel Subunit Activity in the Peripheral Nervous System Reduces Mechanical Hyperalgesia after Nerve Injury in Mice. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092251"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Maqoud, F., Scala, R., Tragni, V., Leonardo Pierri, C., Grazia Perrone, M., Scilimati, A., and Tricarico, D. (2021). Zoledronic Acid as a Novel Dual Blocker of KIR6. 1\/2-SUR2 Subunits of ATP-Sensitive K + Channels: Role in the Adverse Drug Reactions. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13091350"},{"key":"ref_24","first-page":"113","article-title":"Antiproliferative effects of neuroprotective drugs targeting big Ca2+-activated K+ (BK) channel in the undifferentiated neuroblastoma cells","volume":"20","author":"Curci","year":"2016","journal-title":"Curr. Top. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Maqoud, F., Curci, A., Scala, R., Pannunzio, A., Campanella, F., Coluccia, M., Passantino, G., Zizzo, N., and Tricarico, D. (2018). Cell Cycle Regulation by Ca2+-Activated K+ (BK) Channels Modulators in SH-SY5Y Neuroblastoma Cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082442"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"106453","DOI":"10.1016\/j.bpc.2020.106453","article-title":"Evidence of Cadmium and Mercury Involvement in the A\u03b242 Aggregation Process","volume":"266","author":"Meleleo","year":"2020","journal-title":"Biophys. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e00585","DOI":"10.1002\/prp2.585","article-title":"The hydroxypropyl-\u03b2-cyclodextrin-minoxidil inclusion complex improves the cardiovascular and proliferative adverse effects of minoxidil in male rats: Implications in the treatment of alopecia","volume":"8","author":"Maqoud","year":"2020","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.bcp.2014.06.023","article-title":"Dual response of the KATP channels to staurosporine: A novel role of SUR2B, SUR1 and Kir6.2 subunits in the regulation of the atrophy in different skeletal muscle phenotypes","volume":"91","author":"Mele","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e00028","DOI":"10.1002\/prp2.28","article-title":"Database search of spontaneous reports and pharmacological investigations on the sulfonylureas and glinides-induced atrophy in skeletal muscle","volume":"2","author":"Mele","year":"2014","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"130","DOI":"10.2174\/1871527320666210119095626","article-title":"ATP-sensitive Potassium Channel Subunits in Neuroinflammation: Novel Drug Targets in Neurodegenerative Disorders","volume":"21","author":"Maqoud","year":"2022","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"837534","DOI":"10.3389\/fphar.2022.837534","article-title":"Bisphosphonates Targeting Ion Channels and Musculoskeletal Effects","volume":"13","author":"Scala","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1530\/JOE-20-0346","article-title":"Oxtr\/TRPV1 expression and acclimation of skeletal muscle to cold-stress in male mice","volume":"249","author":"Conte","year":"2021","journal-title":"J. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1085\/jgp.201511495","article-title":"Differential mechanisms of Cant\u00fa syndrome\u2013associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel","volume":"146","author":"Cooper","year":"2015","journal-title":"J. Gen. Physiol."},{"key":"ref_34","first-page":"9","article-title":"From Morocco to Italy: How Women\u2019s Bodies Reflect their Change of Residence","volume":"40","author":"Maqoud","year":"2016","journal-title":"Coll. Antropol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1172\/JCI130571","article-title":"Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity","volume":"130","author":"McClenaghan","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Scala, R., Maqoud, F., Angelelli, M., Latorre, R., Perrone, M.G., Scilimati, A., and Tricarico, D. (2019). Zoledronic Acid Modulation of TRPV1 Channel Currents in Osteoblast Cell Line and Native Rat and Mouse Bone Marrow-Derived Osteoblasts: Cell Proliferation and Mineralization Effect. Cancers, 11.","DOI":"10.3390\/cancers11020206"},{"key":"ref_37","first-page":"e145934","article-title":"Complex consequences of Cantu syndrome SUR2 variant R1154Q in genetically modified mice","volume":"6","author":"Zhang","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.4065\/83.9.1032","article-title":"Bisphosphonates: Mechanism of Action and Role in Clinical Practice","volume":"83","author":"Drake","year":"2008","journal-title":"Mayo Clin. Proc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1152\/physiolgenomics.00121.2016","article-title":"Molecular structure and function of big calcium-activated potassium channels in skeletal muscle: Pharmacological perspectives","volume":"49","author":"Maqoud","year":"2017","journal-title":"Physiol. Genom."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.bone.2010.08.008","article-title":"Novel actions of bisphosphonates in bone: Preservation of osteoblast and osteocyte viability","volume":"49","author":"Bellido","year":"2011","journal-title":"Bone"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1073\/pnas.0505974103","article-title":"Hybrid assemblies of ATP-sensitive K+ channels determine their muscle-type-dependent biophysical and pharmacological properties","volume":"103","author":"Tricarico","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"368","DOI":"10.3389\/fvets.2019.00368","article-title":"Thymidine Phosphorylase Expression and Microvascular Density Correlation Analysis in Canine Mammary Tumor: Possible Prognostic Factor in Breast Cancer","volume":"6","author":"Zizzo","year":"2019","journal-title":"Front. Veter. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.bone.2010.07.016","article-title":"Bisphosphonates\u2019 antitumor activity: An unravelled side of a multifaceted drug class","volume":"48","year":"2011","journal-title":"Bone"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1002\/cmdc.201600465","article-title":"Targeting Cancer Cells with a Bisphosphonate Prodrug","volume":"11","author":"Matsumoto","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1210\/clinem\/dgab302","article-title":"Randomized Controlled Trial Evaluating the Use of Zoledronic Acid in Duchenne Muscular Dystrophy","volume":"106","author":"Zacharin","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_46","first-page":"e5222","article-title":"Zoledronic Acid vs Placebo in Pediatric Glucocorticoid-Induced Osteoporosis: A Randomized, Double-Blind, Phase 3 Trial","volume":"106","author":"Ward","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.nmd.2019.05.002","article-title":"Rhabdomyolysis and myoglobinuria following bisphosphonate infusion in patients with Duchenne muscular dystrophy","volume":"29","author":"Lemon","year":"2019","journal-title":"Neuromuscul. Disord."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.nmd.2018.08.004","article-title":"Myoglobinuria in two patients with Duchenne muscular dystrophy after treatment with zoledronate: A case-report and call for caution","volume":"28","author":"Ivanyuk","year":"2018","journal-title":"Neuromuscul. Disord."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/6\/928\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:57:56Z","timestamp":1760122676000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/6\/928"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,17]]},"references-count":48,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["cells12060928"],"URL":"https:\/\/doi.org\/10.3390\/cells12060928","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,17]]}}}