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J Biol Chem, Vol. 275, Issue 8, 5997-6006, February 25, 2000

Expression of Distinct ERG Proteins in Rat, Mouse, and Human Heart
RELATION TO FUNCTIONAL I_Kr CHANNELS^*

Amber L. Pond, Bridget K. Scheve, Andrew T. Benedict, Kevin Petrecca^§, David R. Van Wagoner^¶, Alvin Shrier^§, and Jeanne M. Nerbonne

From the  Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, the ^§ Department of Physiology, McGill University, Montreal, Quebec PQH3 G1Y6, Canada, and the ^¶ Cleveland Clinic Foundation, Cleveland, Ohio 44195

One form of inherited long QT syndrome, LQT2, results from mutations in HERG1, the human ether-a-go-go-related gene, which encodes a voltage-gated K⁺ channel  subunit. Heterologous expression of HERG1 gives rise to K⁺ currents that are similar (but not identical) to the rapid component of delayed rectification, I_Kr, in cardiac myocytes. In addition, N-terminal splice variants of HERG1 and MERG1 (mouse ERG1) referred to as HERG1b and MERG1b have been cloned and suggested to play roles in the generation of functional I_Kr channels. In the experiments here, antibodies generated against HERG1 were used to examine ERG1 protein expression in heart and in brain. In Western blots of extracts of QT-6 cells expressing HERG1, MERG1, or RERG1 (rat ERG1) probed with antibodies targeted against the C terminus of HERG1, a single 155-kDa protein is identified, whereas a 95-kDa band is evident in blots of extracts from cells expressing MERG1b or HERG1b. In immunoblots of fractionated rat (and mouse) brain and heart membrane proteins, however, two prominent high molecular mass proteins of 165 and 205 kDa were detected. Following treatment with glycopeptidase F, the 165- and 205-kDa proteins were replaced by two new bands at 175 and 130 kDa, suggesting that ERG1 is differentially glycosylated in rat/mouse brain and heart. In human heart, a single HERG1 protein with an apparent molecular mass of 145 kDa is evident. In rats, ERG1 protein (and I_Kr) expression is higher in atria than ventricles, whereas in humans, HERG1 expression is higher in ventricular, than atrial, tissue. Taken together, these results suggest that the N-terminal alternatively spliced variants of ERG1 (i.e. ERG1b) are not expressed at the protein level in rat, mouse, or human heart and that these variants do not, therefore, play roles in the generation of functional cardiac I_Kr channels.

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^* This work was supported by grants from the Washington University/Monsanto/Searle Biomedical Research Program (to J. M. N.), the NHLBI, National Institutes of Health (to J. M. N.), and the Medical Research Council of Canada (to A. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Washington University School of Medicine, Dept. of Molecular Biology and Pharmacology, Box 8103, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-2564; Fax: 314-362-7058; E-mail: jnerbonn@pharmsun.wustl.edu.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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