Glibenclamide and HMR1098 normalize Cantú syndrome-associated gain-of-function currents

J Cell Mol Med. 2019 Aug;23(8):4962-4969. doi: 10.1111/jcmm.14329. Epub 2019 May 22.


Cantú syndrome (CS) is caused by dominant gain-of-function mutation in ATP-dependent potassium channels. Cellular ATP concentrations regulate potassium current thereby coupling energy status with membrane excitability. No specific pharmacotherapeutic options are available to treat CS but IKATP channels are pharmaceutical targets in type II diabetes or cardiac arrhythmia treatment. We have been suggested that IKATP inhibitors, glibenclamide and HMR1098, normalize CS channels. IKATP in response to Mg-ATP, glibenclamide and HMR1098 were measured by inside-out patch-clamp electrophysiology. Results were interpreted in view of cryo-EM IKATP channel structures. Mg-ATP IC50 values of outward current were increased for D207E (0.71 ± 0.14 mmol/L), S1020P (1.83 ± 0.10), S1054Y (0.95 ± 0.06) and R1154Q (0.75 ± 0.13) channels compared to H60Y (0.14 ± 0.01) and wild-type (0.15 ± 0.01). HMR1098 dose-dependently inhibited S1020P and S1054Y channels in the presence of 0.15 mmol/L Mg-ATP, reaching, at 30 μmol/L, current levels displayed by wild-type and H60Y channels in the presence of 0.15 mmol/L Mg-ATP. Glibenclamide (10 μmol/L) induced similar normalization. S1054Y sensitivity to glibenclamide increases strongly at 0.5 mmol/L Mg-ATP compared to 0.15 mmol/L, in contrast to D207E and S1020P channels. Experimental findings agree with structural considerations. We conclude that CS channel activity can be normalized by existing drugs; however, complete normalization can be achieved at supraclinical concentrations only.

Keywords: ABCC9; Cantú syndrome; HMR1098; electrophysiology; glibenclamide; pharmacology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / pharmacology
  • Cardiomegaly / genetics*
  • Cryoelectron Microscopy
  • Gain of Function Mutation
  • Gene Expression
  • Glucuronides / pharmacology*
  • Glyburide / pharmacology*
  • HEK293 Cells
  • Humans
  • Hypertrichosis / genetics*
  • KATP Channels / genetics
  • Osteochondrodysplasias / genetics*
  • Potassium / metabolism
  • Potassium Channel Blockers / pharmacology*
  • Potassium Channels / chemistry
  • Potassium Channels / genetics*
  • Potassium Channels / ultrastructure
  • Sulfonamides / pharmacology*


  • Glucuronides
  • HMR 1098 glucuronide
  • KATP Channels
  • Potassium Channel Blockers
  • Potassium Channels
  • Sulfonamides
  • Adenosine Triphosphate
  • Potassium
  • Glyburide

Supplementary concepts

  • Cantu syndrome