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J. Biol. Chem., Vol. 279, Issue 23, 23900-23907, June 4, 2004

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Functional Polymorphism in the Carboxyl Terminus of the -Subunit of the Human Epithelial Sodium Channel^*

Frederick F. Samaha¶, Ronald C. Rubenstein¶||**, Wusheng Yan¶**, Mohan Ramkumar, Daniel I. Levy, Yoon J. Ahn, Shaohu Sheng, and Thomas R. Kleyman¶¶

From the Medicine and ^||Pediatrics, University of Pennsylvania, the Philadelphia Veterans Affairs Medical Center, and the ^**Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 and the Departments of Medicine and of ^¶¶Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

A common human epithelial sodium channel (ENaC) polymorphism, T663A, is present in the cytoplasmic C terminus of the -subunit, although it is unclear whether this polymorphism segregates with blood pressure. We examined whether this polymorphism was associated with differences in functional Na⁺ channel expression. Whole cell amiloride-sensitive currents in Xenopus oocytes expressing wild type channels (T663) were significantly 1.3–2.0-fold higher than currents measured in oocytes expressing channels with an Ala, Gly or Leu, or Lys at position 663. In contrast, differences in functional human ENaC expression were not observed with oocytes expressing channels having Thr (wild type), Ser, or Asp at this position. The surface expression of channels, measured using an epitope-tagged -subunit, was significantly reduced in oocytes expressing T663A when compared with oocytes expressing T663. The corresponding polymorphism was generated in the mouse -subunit (mA692T) and was not associated with differences in functional -mouse ENaC expression. The polymorphism is present in a region that is not well conserved between human and mouse. We generated a mouse/human chimera by replacement of the distal C terminus of the mouse -subunit with the distal C terminus of the human -subunit. Co-expression of this m(1–678)/h(650–669)T663A chimera with mouse led to a significant reduction in whole cell Na⁺ currents and surface expression when compared with m(1–678)/h(650–669)T663-m. Our results suggest that hT663A is a functional polymorphism that affects human ENaC surface expression.

Received for publication, February 23, 2004 , and in revised form, March 26, 2004.

^* This work was supported by a grant from the Veterans Affairs Healthcare Network 4 (to F. F. S.), by Grants DK54354 and DK51391 (to T. R. K.) and DK58046 (to R. C. R.) from the National Institutes of Health, and by a grant from the Cystic Fibrosis Foundation (to Y. J. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ These authors contributed equally to this work.

An Established Investigator of the American Heart Association. To whom correspondence should be addressed: Division of Pulmonary Medicine, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Abramson 410C, Philadelphia, PA 19104. Tel.: 215-590-1281; Fax: 215-590-1283; E-mail: rrubenst{at}mail.med.upenn.edu.

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