ENaC and its regulatory proteins as drug targets for blood pressure control.
Hypertension is a serious medical problem affecting millions of people worldwide. A key protein regulating blood pressure is the Epithelial Na(+) Channel (ENaC). In accord, loss of function mutations in ENaC (PHA1) cause hypotension, whereas gain of function mutations (Liddle syndrome) result in hypertension. The region mutated in Liddle syndrome, called the PY motif (L/PPxY), serves as a binding site for the ubiquitin ligase Nedd4-2, a C2-WW-Hect E3 ubiquitin ligase. Nedd4-2 binds the ENaC-PY motif via it WW domains, ubiquitylates the channel and targets it for endocytosis, a process impaired in Liddle syndrome due to poor binding of the channel to Nedd4-2. This leads to accumulation of active channels at the cell surface and increased Na(+) (and fluid) absorption in the distal nephron, resulting in elevated blood volume and blood pressure. Compounds that destabilize cell surface ENaC, or enhance Nedd4-2 activity in the kidney, could potentially serve as drug targets for hypertension. In addition, recent discoveries of regulation of activation of ENaC by proteases such as furin, prostasin and elastase, which cleave the extracellular domain of this channel leading to it activation, as well as the identification of inhibitors that block the activity of these proteases, provide further avenues for drug targeting of ENaC and the control of blood pressure.
Rotin
Daniela
D
Program in Cell Biology, The Hospital for Sick Children, TMDT-MaRS, Rm 11-305, 101 College St., Toronto, Ont., Canada. drotin@sickkids.ca
Schild
Laurent
L
D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D016503:Drug Delivery Systems; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects / Q000378:metabolism
D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D012964:Sodium; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases