K(ATP) channel gain-of-function leads to increased myocardial L-type Ca(2+) current and contractility in Cantu syndrome

Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):6773-8. doi: 10.1073/pnas.1606465113. Epub 2016 May 31.

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.

Keywords: KATP; KCNJ8; Kir6.1; cardiovascular system; transgenic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Calcium Signaling / drug effects
  • Calcium Signaling / genetics
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Female
  • Heart Ventricles / metabolism*
  • Heart Ventricles / pathology
  • Heart Ventricles / physiopathology
  • Humans
  • Hypertrichosis / genetics
  • Hypertrichosis / metabolism*
  • Hypertrichosis / pathology
  • Hypertrichosis / physiopathology
  • Isoproterenol / pharmacology
  • KATP Channels / genetics
  • KATP Channels / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Myocardial Contraction*
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Osteochondrodysplasias / genetics
  • Osteochondrodysplasias / metabolism*
  • Osteochondrodysplasias / pathology
  • Osteochondrodysplasias / physiopathology
  • Sulfonylurea Receptors / genetics
  • Sulfonylurea Receptors / metabolism*

Substances

  • ABCC9 protein, human
  • Abcc9 protein, mouse
  • CACNA1C protein, mouse
  • Calcium Channels, L-Type
  • KATP Channels
  • Sulfonylurea Receptors
  • uK-ATP-1 potassium channel
  • Isoproterenol

Supplementary concepts

  • Cantu syndrome