Regulation of the epithelial Na+ channel by aldosterone: Open questions and emerging answers

Regulation of the epithelial Na+ channel by aldosterone: Open questions and emerging answers. Aldosterone is the principal adrenal steroid controlling Na+ retention in amphibians and mammalians. It acts primarily by increasing the apical Na+ permeability through activation of the epithelial Na+ channel (ENaC). The cellular events mediating the hormonal action are mostly unknown. Early studies have provided evidence that the hormone functions to activate or translocate pre-existing channels by a yet undefined mechanism. In addition, enhanced de novo channel synthesis appears to take place as well. The molecular cloning of the three ENaC subunits has provided new powerful tools for testing and confirming this hypothesis, as well as for characterizing mechanisms by which ENaC is regulated. Another important development is the recent identification of several cDNAs corresponding to aldosterone-induced and suppressed mRNAs. The study of these genes and their putative interactions with ENaC is likely to provide important clues to the mechanisms by which aldosterone controls the apical Na+ permeability of tight epithelia. This article reviews recent developments in the field that may lead to the elucidation of the mechanisms by which the hormone controls Na+ transport

Specific Expression and Regulation of CHIF in Kidney and Colon

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CHIF, a member of the FXYD protein family, is a regulator of Na,K-ATPase distinct from the γ-subunit

The biological role of small membrane proteins of the new FXYD family is largely unknown. The best characterized FXYD protein is the γ-subunit of the Na,K-ATPase (NKA) that modulates the Na,K-pump function in the kidney. Here, we report that, similarly to γa and γb splice variants, the FXYD protein CHIF (corticosteroid-induced factor) is a type I membrane protein which is associated with NKA in renal tissue, and modulates the Na,K-pump transport when expressed in Xenopus oocytes. In contrast to γa and γb, which both decrease the apparent Na(+) affinity of the Na,K-pump, CHIF significantly increases the Na(+) affinity and decreases the apparent K(+) affinity due to an increased Na(+) competition at external binding sites. The extracytoplasmic FXYD motif is required for stable γ-subunit and CHIF interaction with NKA, while cytoplasmic, positively charged residues are necessary for the γ-subunit’s association efficiency and for CHIF’s functional effects. These data document that CHIF is a new tissue-specific regulator of NKA which probably plays a crucial role in aldosterone-responsive tissues responsible for the maintenance of body Na(+) and K(+) homeostasis

FXYD7 is a brain-specific regulator of Na,K-ATPase α1–β isozymes

Recently, corticosteroid hormone-induced factor (CHIF) and the γ-subunit, two members of the FXYD family of small proteins, have been identified as regulators of renal Na,K-ATPase. In this study, we have investigated the tissue distribution and the structural and functional properties of FXYD7, another family member which has not yet been characterized. Expressed exclusively in the brain, FXYD7 is a type I membrane protein bearing N-terminal, post-translationally added modifications on threonine residues, most probably O-glycosylations that are important for protein stabilization. Expressed in Xenopus oocytes, FXYD7 can interact with Na,K-ATPase α1–β1, α2–β1 and α3–β1 but not with α–β2 isozymes, whereas, in brain, it is only associated with α1–β isozymes. FXYD7 decreases the apparent K(+) affinity of α1–β1 and α2–β1, but not of α3–β1 isozymes. These data suggest that FXYD7 is a novel, tissue- and isoform-specific Na,K-ATPase regulator which could play an important role in neuronal excitability