Peptide block of constituitively activated na+ channels in liddle's
disease.
Ismailov, Iskander I., Bakhram K. Berdiev, Catherine M. Fuller, Anne
Lynn Bradford, Richard P. Lifton, David G. Warnock, James K. Bubien,
and Dale J. Benos.
Departments of Physiology and Biophysics and Medicine, The
University of Alabama at Birmingham and Department of Veteran
Affairs, Birmingham VA Medical Center, Birmingham, Alabama 35294 and
Howard Hughes Medical Institute, Departments of Medicine and
Genetics, Boyer Center for Molecular Medicine, Yale University, New
Haven, CT 06510
APStracts 2:0241C, 1995.
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 constituitively 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 C-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
constituitively 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
constituitively active Liddle's Na+ channels are blocked by a [beta]-
or [delta]-ENaC carboxy-terminal peptide in a GTP-dependent fashion.
Received 17 March 1995; accepted in final form 20 June 1995.
APS Manuscript Number C153-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 11 July 1995.