Functional polymorphism in the carboxyl terminus of the α-subunit of the human epithelial sodium channel

A common human epithelial sodium channel (ENaC) polymorphism, αT663A, is present in the cytoplasmic C terminus of the α-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 (αT663β γ) 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 α663. 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 β-subunit, was significantly reduced in oocytes expressing αT663Aβγ when compared with oocytes expressing αT663βγ. The corresponding polymorphism was generated in the mouse α-subunit (mαA692T) and was not associated with differences in functional αβγ-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 α-subunit with the distal C terminus of the human α-subunit. Co-expression of this m(1-678)/h(650-669)T663A chimera with mouse βγ led to a significant reduction in whole cell Na⁺ currents and surface expression when compared with m(1-678)/h(650-669)T663-mβγ. Our results suggest that hαT663A is a functional polymorphism that affects human ENaC surface expression.