title: The shifting landscape of KATP channelopathies and the need for 'sharper' therapeutics.
abstract: ATP-sensitive potassium (KATP) channels play fundamental roles in the regulation of endocrine, neural and cardiovascular function. Small-molecule inhibitors (e.g., sulfonylurea drugs) or activators (e.g., diazoxide) acting on SUR1 or SUR2 have been used clinically for decades to manage the inappropriate secretion of insulin in patients with Type 2 diabetes, hyperinsulinism and intractable hypertension. More recently, the discovery of rare disease-causing mutations in KATP channel-encoding genes has highlighted the need for new therapeutics for the treatment of certain forms of neonatal diabetes mellitus, congenital hyperinsulinism and Cantu syndrome. Here, we provide a high-level overview of the pathophysiology of these diseases and discuss the development of a flexible high-throughput screening platform to enable the development of new classes of KATP channel modulators.
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Sujay V
authors.initials: SV
authors.lastname: Kharade
authors.affiliation: Department of Cell Biology & Physiology & the Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Nichols
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Jerod S
authors.initials: JS
authors.lastname: Denton
mesh_terms: D000227:Adenine Nucleotides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism; D053447:Channelopathies / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000151:congenital / Q000188:drug therapy; D006983:Hypertrichosis / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015640:Ion Channel Gating; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010009:Osteochondrodysplasias / Q000188:drug therapy / Q000378:metabolism; D021381:Protein Transport
chemical_list: D000227:Adenine Nucleotides; D007004:Hypoglycemic Agents; D054086:KATP Channels
keywords: Cantu syndrome; KATP channels; chemical chaperone; diabetes; high-throughput screening; insulin; pancreas; thallium flux; trafficking