4.5 Article

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

Journal

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 23, Issue 8, Pages 4962-4969

Publisher

WILEY
DOI: 10.1111/jcmm.14329

Keywords

ABCC9; Cantu syndrome; electrophysiology; glibenclamide; HMR1098; pharmacology

Funding

  1. Austrian Science Fund
  2. China Scholarship Council
  3. E-Rare 2 Joint Transnational CantuTreat
  4. Austrian Science Fund (FWF) [I2101] Funding Source: Austrian Science Fund (FWF)

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Cantu 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 I-KATP channels are pharmaceutical targets in type II diabetes or cardiac arrhythmia treatment. We have been suggested that I-KATP inhibitors, glibenclamide and HMR1098, normalize CS channels. I-KATP in response to Mg-ATP, glibenclamide and HMR1098 were measured by inside-out patch-clamp electrophysiology. Results were interpreted in view of cryo-EM I-KATP 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 mu mol/L, current levels displayed by wild-type and H60Y channels in the presence of 0.15 mmol/L Mg-ATP. Glibenclamide (10 mu mol/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.

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