THE AMILORIDE-SENSITIVE SODIUM-CHANNEL

The amiloride-sensitive epithelial Na+ channel is formed by the assemb ly of three homologous subunits alpha, beta and gamma. The channel is characterized by its sensitivity to amiloride and to some amiloride de rivatives, such as phenamil and benzamil, by its small unitary conduct ance (approximate to 5pS), by its high selectivity for lithium and sod ium, and by its slow kinetics. The alpha, beta, and gamma proteins sha re significant identity with degenerins, a family of proteins found in the mechanosensory neurons and interneurons of the nematode Caenorhab ditis elegans. They are also homolgous to FaNaCh, a protein from Helix aspersa nervous tissues, which corresponds to a neuronal ionotropic r eceptor for the Phe-Met-Arg-Phe-amide peptide. All these proteins cont ain a large extracellular loop, located between two transmembrane alph a-helices. The NH2 and COOH terminal segments are cytoplasmic, and con tain potential regulatory segments that are able to modulate the activ ity of the channel. In Liddle syndrom, in which patients develop a for m of genetic hypertension, mutations within the cytoplasmic COOH termi nal of the beta and gamma chains of the epithelial Na+ channel lead to a hyper-activity of the channel. Epithelial Na+ channel activity is t ightly controlled by several distinct hormonal systems, including cort icosteroids and vasopressin. In kidney and colon, aldosterone is the m ajor sodium-retaining hormonde, acting by stimulation of Na+ reabsorpt ion through the epithelium. In the distal colon from steroid-treated a nimals, a large increase of the beta and gamma subunits transcription is observed, whereas the alpha subunit remains constitutively transcri bed. In kidney, RNA rebels of the three subunits are not significantly altered by aldosterone, suggesting that other mechanisms control Nachannel activity in that tissue. In lung, the glucocorticoids are the positive regulators of the channel activity, especially around birth, and act via an increased transcription of the three subunits.