KATP channel gain-of-function leads to increased myocardial L-type Ca2+ current and contractility in Cantu syndrome

Mark D. Levin, Gautam K. Singh, Hai Xia Zhang, Keita Uchida, Beth A. Kozel, Phyllis K. Stein, Atilla Kovacs, Ruth E. Westenbroek, William A. Catterall, Dorothy Katherine Grange, Colin G. Nichols

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 Ca2+ current (LTCC), comparable to that seen in WT VM treated with isoproterenol. Mice with vascularspecific 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.

Original languageEnglish
Pages (from-to)6773-6778
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number24
DOIs
StatePublished - Jun 14 2016

Keywords

  • Cardiovascular system
  • K
  • KCNJ8
  • Kir6.1
  • Transgenic

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