An important class of Na+ transport proteins is the cotransporters. They exist in bacteria and animal cells and are responsible for the "active" accumulation of sugars, amino acids, carboxylic acids and some ions, e.g., I-, Cl-, and PO-4, in cells. In the small intestine and renal proximal tubule the cotransporters play an important role in the transport of salt and water across the epithelia. The most well known and best characterized Na+ cotransporter is the intestinal brush border Na+/glucose cotransporter. We have cloned, sequenced, and expressed both the rabbit and human Na+/glucose cotransporters. The cDNAs code for 73kDa proteins with 662-664 residues (86% identity). Secondary structure analysis suggests a 12 membrane-spanning helical model with the N- and C-termini in the cytoplasm. A single N-linked glycosylation site is utilized at Asn248. These sugars are not required for function. Two essential residues for functional expression in oocytes have been identified, Asp28 and Arg300. In two sisters with glucose-galactose malabsorption the transport defect is caused by a missense mutation changing Asp28 to Asn28, and we have found that changing Arg300 to Cys300 eliminated transport. Current research is directed to finding residues and domains essential for ligand binding and transport, and we are using electrophysiological techniques to correlate structure and function.