Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome.

摘要: Liddle syndrome is an autosomal dominant form of hypertension, resulting from mutations in the cytoplasmic C-terminus either beta or gamma subunits amiloride-sensitive epithelial Na channel (ENaC) which lead to constitutively increased activity. Most reported date result elimination 45-75 normal amino acids these segments, leaving open question identity precise mutation can enhanced To address this question, we have performed a systematic mutagenesis study C-termini alpha, and ENaC rat analyzed their function by expression Xenopus oocytes. The results demonstrate that short proline-rich segment present each subunit required for regulation Missense altering consensus PPPXY sequence reproduced increase activity found mutants entire are deleted. This sequence, referred as PY motif, known be site binding proteins bearing WW domain. These findings show three motifs involved activity, probably via protein-protein interactions. new regulatory mechanism critical maintenance reabsorption kidney Na+ balance blood pressure.