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Block of hERG Channels by Berberine: Mechanisms of Voltage- and State-Dependence Probed With Site-Directed Mutant Channels

Rodriguez-Menchaca, Aldo MSc*; Ferrer-Villada, Tania PhD*; Lara, Jesus MD, PhD*; Fernandez, David PhD†; Navarro-Polanco, Ricardo A PhD*; Sanchez-Chapula, Jose A MD, PhD*

Journal of Cardiovascular Pharmacology: January 2006 - Volume 47 - Issue 1 - pp 21-29
doi: 10.1097/01.fjc.0000191564.52242.00
Original Article

Berberine prolongs the duration of cardiac action potentials without affecting resting membrane potential or action potential amplitude. Controversy exists regarding whether berberine exerts this action by preferential block of different components of the delayed rectifying potassium current, IKr and IKs. Here we have studied the effects of berberine on hERG (IKr) and KCNQ1/KCNE1 (IKs) channels expressed in HEK-293 cells and Xenopus oocytes. In HEK-293 cells, the IC50 for berberine was 3.1 ± 0.5 μM on hERG compared with 11 ± 4% decreases on KCNQ1/KCNE1 channels by 100 μM berberine. Likewise in oocytes, hERG channels were more sensitive to block by berberine (IC50 = 80 ± 5 μM) compared with KCNQ1/KCNE1 channels (∼20% block at 300 μM). hERG block was markedly increased by membrane depolarization. Mutation to Ala of Y652 or F656 located on the S6 domain, or V625 located at the base of the pore helix of hERG decreased sensitivity to block by berberine. An inactivation-deficient mutant hERG channel (G628C/S631C) was also blocked by berberine. Together these findings indicate that berberine preferentially blocks the open state of hERG channels by interacting with specific residues that were previously reported to be important for binding of more potent antagonists.

From the *Unidad “Carlos Mendez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Mexico; and †Department of Physiology, Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT.

Received for publication August 8, 2005; accepted October 4, 2005.

This work was supported by SEP-SESIC (Mexico) Grant No. 2003-06-001-007 and Fondo Ramon Alvarez-Buylla (Universidad de Colima, Mexico).

Reprints: Jose A. Sanchez-Chapula, CUIB, Universidad de Colima, Apdo. Postal 199, CP 28000, Colima, Col. México (e-mail: sancheza@cgic.ucol.mx).

© 2006 Lippincott Williams & Wilkins, Inc.