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

Autor: Houtman MJC; Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands., Chen X; Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria., Qile M; Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands., Duran K; Center for Molecular Medicine, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., van Haaften G; Center for Molecular Medicine, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Stary-Weinzinger A; Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria., van der Heyden MAG; Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Jazyk: angličtina
Zdroj: Journal of cellular and molecular medicine [J Cell Mol Med] 2019 Aug; Vol. 23 (8), pp. 4962-4969. Date of Electronic Publication: 2019 May 22.
DOI: 10.1111/jcmm.14329
Abstrakt: 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 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 IC 50 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.
(© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
Databáze: MEDLINE
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