Peptide block of constitutively activated Na+ channels in Liddle's disease.

Academic Article

Abstract

  • Hypertension is a multifactorial disorder that results in an increased risk of cardiovascular and end-stage renal disease. Liddle's disease represents a specific hypertensive disease and expresses itself in the human population as an autosomal dominant trait. Recent experimental evidence indicates that patients with Liddle's disease have constitutively active amiloride-sensitive Na+ channels and that these channels are phenotypically expressed in lymphocytes obtained from normal and affected members of the original Liddle's kindred. Linkage analysis indicates that this disease results from a deletion of the carboxy-terminal region of the beta-subunit of a recently cloned epithelial Na+ channel (ENaC). We report the successful immunopurification and reconstitution of both normal and constitutively active lymphocyte Na+ channels into planar lipid bilayers. These channels display all of the characteristics typical of renal Na+ channels, including sensitivity to protein kinase A phosphorylation. We demonstrate that gating of normal Na+ channels is removed by cytoplasmic trypsin digestion and that the constitutively active Liddle's Na+ channels are blocked by a beta- or gamma-ENaC carboxy-terminal peptide in a GTP-dependent fashion.

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    Keywords

  • Amiloride, Amino Acid Sequence, B-Lymphocytes, Cell Transformation, Viral, GTP-Binding Proteins, Genes, Dominant, Guanosine 5'-O-(3-Thiotriphosphate), Herpesvirus 4, Human, Humans, Hypertension, Immunologic Techniques, Ion Channel Gating, Lipid Bilayers, Molecular Sequence Data, Peptides, Reference Values, Sodium Channel Blockers, Sodium Channels, Trypsin, Virulence Factors, Bordetella

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    Author List

  • Ismailov II; Berdiev BK; Fuller CM; Bradford AL; Lifton RP; Warnock DG; Bubien JK; Benos DJ

    • Start Page

  • C214

    • End Page

  • C223

    • Volume

  • 270

    • Issue

  • 1 Pt 1