title: K(ATP) channel gain-of-function leads to increased myocardial L-type Ca(2+) current and contractility in Cantu syndrome.
abstract: Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) KATP channel subunits. We show that patients with CS, as well as mice with constitutive (cGOF) or tamoxifen-induced (icGOF) cardiac-specific Kir6.1 GOF subunit expression, have enlarged hearts, with increased ejection fraction and increased contractility. Whole-cell voltage-clamp recordings from cGOF or icGOF ventricular myocytes (VM) show increased basal L-type Ca(2+) current (LTCC), comparable to that seen in WT VM treated with isoproterenol. Mice with vascular-specific expression (vGOF) show left ventricular dilation as well as less-markedly increased LTCC. Increased LTCC in KATP GOF models is paralleled by changes in phosphorylation of the pore-forming α1 subunit of the cardiac voltage-gated calcium channel Cav1.2 at Ser1928, suggesting enhanced protein kinase activity as a potential link between increased KATP current and CS cardiac pathophysiology.
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Mark D
authors.initials: MD
authors.lastname: Levin
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Gautam K
authors.initials: GK
authors.lastname: Singh
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Hai Xia
authors.initials: HX
authors.lastname: Zhang
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Keita
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Beth A
authors.initials: BA
authors.lastname: Kozel
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Phyllis K
authors.initials: PK
authors.lastname: Stein
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Atilla
authors.initials: A
authors.lastname: Kovacs
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Westenbroek
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280 wcatt@uw.edu cnichols@wustl.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Dorothy Katherine
authors.initials: DK
authors.lastname: Grange
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; wcatt@uw.edu cnichols@wustl.edu.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006983:Hypertrichosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010009:Osteochondrodysplasias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D064233:Sulfonylurea Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: C577510:ABCC9 protein, human; C577511:Abcc9 protein, mouse; C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D054086:KATP Channels; D064233:Sulfonylurea Receptors; C092520:uK-ATP-1 potassium channel; D007545:Isoproterenol
keywords: KATP; KCNJ8; Kir6.1; cardiovascular system; transgenic