MECHANISM BY WHICH LIDDLES SYNDROME MUTATIONS INCREASE ACTIVITY OF A HUMAN EPITHELIAL NA+ CHANNEL

Liddle's syndrome is an inherited form of hypertension caused by mutat ions that truncate the C-terminus of human epithelial Na+ channel (hEN aC) subunits, Expression of truncated beta and gamma hENaC subunits in creased Na+ current, However, truncation did not alter single-channel conductance or open state probability, suggesting there were more chan nels in the plasma membrane. Moreover, truncation of the C-terminus of the beta subunit increased apical cell-surface expression of hENaC in a renal epithelium, We identified a conserved motif in the C-terminus of all three subunits that, when mutated, reproduced the effect of Li ddle's truncations. Further, both truncation of the C-terminus and mut ation of the conserved C-terminal motif increased surface expression o f chimeric proteins containing the C-terminus of beta hENaC, Thus, by deleting a conserved motif, Liddle's mutations increase the number of Na+ channels in the apical membrane, which increases renal Na+ absorpt ion and creates a predisposition to hypertension.