title: Peptide block of constitutively activated Na+ channels in Liddle's disease.
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.
authors.affiliation: Department of Physiology and Biophysics, University of Alabama at Birmingham, USA.
authors.forename: I I
authors.initials: II
authors.lastname: Ismailov
authors.forename: B K
authors.initials: BK
authors.lastname: Berdiev
authors.forename: C M
authors.initials: CM
authors.lastname: Fuller
authors.forename: A L
authors.initials: AL
authors.lastname: Bradford
authors.forename: R P
authors.initials: RP
authors.lastname: Lifton
authors.forename: D G
authors.initials: DG
authors.lastname: Warnock
authors.forename: J K
authors.initials: JK
authors.lastname: Bubien
authors.forename: D J
authors.initials: DJ
authors.lastname: Benos
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000378:metabolism; D002472:Cell Transformation, Viral; D019204:GTP-Binding Proteins / Q000502:physiology; D005799:Genes, Dominant; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D007158:Immunologic Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008051:Lipid Bilayers / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D012016:Reference Values; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000302:isolation & purification; D014357:Trypsin / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D008051:Lipid Bilayers; D010455:Peptides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D010566:Virulence Factors, Bordetella; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000584:Amiloride; D014357:Trypsin; D019204:GTP-Binding Proteins