Thirty years of the NaCl cotransporter: from cloning to physiology and structure

Abstract

The primary structure of the thiazide sensitive NaCl cotransporter (NCC) was resolved 30 years ago by the molecular identification of the cDNA encoding this cotransporter, from the winter's flounder urinary bladder, following a functional expression strategy. This review outlines some aspects of how the knowledge about thiazide diuretics and the NaCl cotransporter evolved, the history of the cloning process and the expansion of the SLC12 family of electroneutral cotransporters. The disease associated with activation or inactivation of NCC are discussed, as well as the molecular model by which the activity of NCC is regulated. The controversies in the field are discussed and the recent publication of the three-dimensional model of NCC obtained by Cryo-EM microscopy, revealing not only the amino acid residues critical for Na+ and Cl- translocation, but also, the residues critical for the polythiazide binding to the transporter, opening the possibility for a new era in thiazide diuretic therapy.