Gain-of-function variant of the human epithelial sodium channel.
Am J Physiol Renal Physiol
; 304(2): F207-13, 2013 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-23136006
ABSTRACT
Epithelial Na(+) channel (ENaC) mutations are associated with several human disorders, underscoring the importance of these channels in human health. Recent human genome sequencing projects have revealed a large number of ENaC gene variations, several of which have been found in individuals with salt-sensitive hypertension, cystic fibrosis, and other disorders. However, the functional consequences of most variants are unknown. In this study, we used the Xenopus oocyte expression system to examine the functional properties of a human ENaC variant. Oocytes expressing αßγL511Q human ENaCs showed 4.6-fold greater amiloride-sensitive currents than cells expressing wild-type channels. The γL511Q variant did not significantly alter channel surface expression. Single channel recordings revealed that the variant had fourfold higher open probability than wild type. In addition, γL511Q largely eliminated the Na(+) self-inhibition response, which reflects a downregulation of ENaC open probability by extracellular Na(+). Moreover, γL511Q diminished chymotrypsin-induced activation of the mutant channel. We conclude that γL511Q is a gain-of-function human ENaC variant. Our results suggest that γL511Q enhances ENaC activity by increasing channel open probability and dampens channel regulation by extracellular Na(+) and proteases.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sódio
/
Variação Genética
/
Regulação da Expressão Gênica
/
Canais Epiteliais de Sódio
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Am J Physiol Renal Physiol
Assunto da revista:
FISIOLOGIA
/
NEFROLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos