LIDDLES DISEASE - ABNORMAL REGULATION OF AMILORIDE-SENSITIVE NA-SUBUNIT MUTATION( CHANNELS BY BETA)

Liddle's disease is an autosomal dominant genetic disorder characteriz ed 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 indistinguis hable from those expressed by Na+-reabsorbing renal epithelial cells ( 3, 5). The amiloride-sensitive Na+ conductance in PBL from affected an d unaffected individuals from the original Liddle's pedigree was exami ned using whole cell patch clamp. Typically, the basal Na+ currents in cells from affected individuals were maximally activated. Basal Na+ c urrents in cells from unaffected individuals were minimal and could be maximally activated by superfusion with 8-(4-chlorophenylthio)adenosi ne 3',5'-cyclic monophosphate (CPT-cAMP). Affected cells could not be further stimulated with CPT-cAMP. Superfusion with a supermaximal conc entration of amiloride (2 mu M) inhibited both the cAMP-activated Naconductance in unaffected cells and the constitutively activated inwar d conductance in affected cells. Cytosolic addition of a peptide ident ical to the terminal 10 amino acids of the truncated beta-subunit norm alized the cAMP-mediated but not the pertussis toxin-induced regulatio n of the mutant ASSC. The findings show that lymphocyte ASSC are const itutively activated in affected individuals, that a mutation of the be ta-subunit alters ASSC responsiveness to specific regulatory effecters , and that the cellular mechanism responsible for the pathophysiology of Liddle's disease is abnormal regulation of Na+ channel activity. Th ese findings have important diagnostic and therapeutic implications an d provide a cellular phenotype for the diagnosis of pseudoaldosteronis m.