Liddle's disease: abnormal regulation of amiloride-sensitive Na+ channels by beta-subunit mutation.
Liddle's disease is an autosomal dominant genetic disorder characterized by severe low renin hypertension ("pseudoaldosteronism") that has been genetically linked to a locus on chromosome 16 encoding the beta-subunit of an amiloride-sensitive Na+ channel (ASSC) (15). Peripheral blood lymphocytes (PBL) express ASSC that are functionally indistinguishable from those expressed by Na(+)-reabsorbing renal epithelial cells (3, 5). The amiloride-sensitive Na+ conductance in PBL from affected and unaffected individuals from the original Liddle's pedigree was examined using whole cell patch clamp. Typically, the basal Na+ currents in cells from affected individuals were maximally activated. Basal Na+ currents in cells from unaffected individuals were minimal and could be maximally activated by superfusion with 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate (CPT-cAMP). Affected cells could not be further stimulated with CPT-cAMP. Superfusion with a supermaximal concentration of amiloride (2 microM) inhibited both the cAMP-activated Na+ conductance in unaffected cells and the constitutively activated inward conductance in affected cells. Cytosolic addition of a peptide identical to the terminal 10 amino acids of the truncated beta-subunit normalized the cAMP-mediated but not the pertussis toxin-induced regulation of the mutant ASSC. The findings show that lymphocyte ASSC are constitutively activated in affected individuals, that a mutation of the beta-subunit alters ASSC responsiveness to specific regulatory effectors, and that the cellular mechanism responsible for the pathophysiology of Liddle's disease is abnormal regulation of Na+ channel activity. These findings have important diagnostic and therapeutic implications and provide a cellular phenotype for the diagnosis of pseudoaldosteronism.
Bubien
J K
JK
Department of Medicine, University of Alabama at Birmingham, USA.
Ismailov
I I
II
Berdiev
B K
BK
Cornwell
T
T
Lifton
R P
RP
Fuller
C M
CM
Achard
J M
JM
Benos
D J
DJ
Warnock
D G
DG
D000584:Amiloride / Q000494:pharmacology*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004594:Electrophysiology; D006801:Humans; D006929:Hyperaldosteronism / Q000503:physiopathology; D006973:Hypertension / Q000097:blood / Q000235:genetics* / Q000503:physiopathology*; D008214:Lymphocytes / Q000378:metabolism; D009154:Mutation; D018408:Patch-Clamp Techniques; D037342:Pertussis Toxin; D012083:Renin / Q000097:blood*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013873:Thionucleotides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D015222:Sodium Channels; D013873:Thionucleotides; D010566:Virulence Factors, Bordetella; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000584:Amiloride; D000242:Cyclic AMP; D037342:Pertussis Toxin; D012083:Renin