Peptide Inhibition of ENaC
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- 作者：Iskander I. Ismailov ; Vadim Gh. Shlyonsky ; Engin H. Serpersu ; Catherine M. Fuller ; Herbert C. Cheung ; Donald Muccio ; Bakhrom K. Berdiev ; and Dale J. Benos
- 刊名：Biochemistry
- 出版年：1999
- 出版时间：January 5, 1999
- 年：1999
- 卷：38
- 期：1
- 页码：354 - 363
- 全文大小：199K
- 年卷期：v.38,no.1(January 5, 1999)
- ISSN：1520-4995
文摘
Liddle's disease is an autosomal dominant form of human hypertension resulting from a basalactivation of amiloride-sensitive Na+ channels (ENaC). This channel activation is produced by mutationsin the 
- and/or 
-carboxy-terminal cytoplasmic tails, in many cases causing a truncation of the last45-76 amino acids. In this study, we tested two hypotheses; first, - and -ENaC C-terminal truncationmutants (
C and C), in combination with the wild-type 
-ENaC subunit, reproduce the Liddle'sphenotype at the single channel level, i.e., an increase in open probability (Po), and second, these C-terminalregions of - and -ENaC act as intrinsic blockers of this channel. Our results indicate that CC-rENaC, incorporated into planar lipid bilayers, has a significantly higher single channel Po compared tothe wild-type channel (0.85 vs 0.60, respectively), and that 30-mer synthetic peptides corresponding tothe C-terminal region of either - or -ENaC block the basal-activated channel in a concentration-dependentfashion. Moreover, there was a synergy between the peptides for channel inhibition when added together.We conclude that the increase in macroscopic Na+ reabsorption that occurs in Liddle's disease is at leastin part due to an increase in single channel Po and that the cytoplasmic tails of the - and -ENaC subunitsare important in the modulation of ENaC activity.
- and/or -carboxy-terminal cytoplasmic tails, in many cases causing a truncation of the last45-76 amino acids. In this study, we tested two hypotheses; first, - and -ENaC C-terminal truncationmutants (C and C), in combination with the wild-type -ENaC subunit, reproduce the Liddle'sphenotype at the single channel level, i.e., an increase in open probability (Po), and second, these C-terminalregions of - and -ENaC act as intrinsic blockers of this channel. Our results indicate that CC-rENaC, incorporated into planar lipid bilayers, has a significantly higher single channel Po compared tothe wild-type channel (0.85 vs 0.60, respectively), and that 30-mer synthetic peptides corresponding tothe C-terminal region of either - or -ENaC block the basal-activated channel in a concentration-dependentfashion. Moreover, there was a synergy between the peptides for channel inhibition when added together.We conclude that the increase in macroscopic Na+ reabsorption that occurs in Liddle's disease is at leastin part due to an increase in single channel Po and that the cytoplasmic tails of the - and -ENaC subunitsare important in the modulation of ENaC activity.