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(Circulation. 2002;105:2830.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Pharmacological Rescue of Human K⁺ Channel Long-QT2 Mutations

Human Ether-a-Go-Go-Related Gene Rescue Without Block

Sridharan Rajamani, PhD; Corey L. Anderson, BS; Blake D. Anson, PhD; Craig T. January, MD, PhD

From the Departments of Medicine (Cardiology) (S.R., C.L.A., B.D.A., C.T.J.) and Physiology (C.T.J.), University of Wisconsin, Madison.

Correspondence to Craig T. January, MD, PhD, Section of Cardiology, Room H6/354, University of Wisconsin Hospital, 600 Highland Ave, Madison, WI 53792. E-mail ctj{at}medicine.wisc.edu

Background— Defective protein trafficking is a consequence of gene mutations. Human long-QT (LQT) syndrome results from mutations in several genes, including the human ether-a-go-go-related gene (HERG), which encodes a delayed rectifier K⁺ current. Trafficking-defective mutant HERG protein is a mechanism for reduced delayed rectifier K⁺ current in LQT2, and high-affinity HERG channel-blocking drugs can result in pharmacological rescue.

Methods and Results— We postulated that drug molecules modified to remove high-affinity HERG block may still stabilize mutant proteins in a conformation required for rescue. We tested terfenadine carboxylate (fexofenadine) and terfenadine, structurally similar drugs with markedly different affinities for HERG block, for rescue of trafficking-defective LQT2 mutations. Terfenadine rescued the N470D mutation but blocked the channels. In contrast, fexofenadine rescued N470D with a half-maximal rescue concentration of 177 nmol/L, which is 350-fold lower than the half-maximal channel block concentration. The G601S mutation was also rescued without channel block.

Conclusions— Pharmacological rescue can occur without channel block. This could represent a new antiarrhythmic paradigm in the treatment of some trafficking-defective LQT2 mutations.

Key Words: genes • long-QT syndrome • proteins • pharmacology • fexofenadine

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