Abstract
A common human epithelial sodium channel (ENaC) polymorphism, alphaT663A, is present in the cytoplasmic C terminus of the alpha-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 (alphaT663betagamma) were significantly approximately 1.3-2.0-fold higher than currents measured in oocytes expressing channels with an Ala, Gly or Leu, or Lys at position alpha663. 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 beta-subunit, was significantly reduced in oocytes expressing alphaT663Abetagamma when compared with oocytes expressing alphaT663betagamma. The corresponding polymorphism was generated in the mouse alpha-subunit (malphaA692T) and was not associated with differences in functional alphabetagamma-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 alpha-subunit with the distal C terminus of the human alpha-subunit. Co-expression of this m(1-678)/h(650-669)T663A chimera with mouse betagamma led to a significant reduction in whole cell Na(+) currents and surface expression when compared with m(1-678)/h(650-669)T663-mbetagamma. Our results suggest that halphaT663A is a functional polymorphism that affects human ENaC surface expression.
Highlights
A common human epithelial sodium channel (ENaC) polymorphism, ␣T663A, is present in the cytoplasmic C terminus of the ␣-subunit, it is unclear whether this polymorphism segregates with blood pressure
Whole cell amiloride-sensitive currents in Xenopus oocytes expressing wild type channels (␣T663␥) were significantly ϳ1.3–2.0-fold higher than currents measured in oocytes expressing channels with an Ala, Gly or Leu, or Lys at position ␣663
A common T663A polymorphism is present within the C terminus of the ␣-subunit of human ENaC [15, 16]
Summary
Vol 279, No 23, Issue of June 4, pp. 23900 –23907, 2004 Printed in U.S.A. Functional Polymorphism in the Carboxyl Terminus of the ␣-Subunit of the Human Epithelial Sodium Channel*. A common human epithelial sodium channel (ENaC) polymorphism, ␣T663A, is present in the cytoplasmic C terminus of the ␣-subunit, it is unclear whether this polymorphism segregates with blood pressure. We examined whether this polymorphism was associated with differences in functional Na؉ channel expression. The higher currents observed with ␣T663␥ channels were associated with higher levels of cell surface expression of channels, suggesting that this polymorphism altered channel trafficking This polymorphism is present in the distal C terminus of the ␣-subunit, a region that is not well conserved between the human and mouse ␣-subunit.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
