NBCe1 as a model carrier for understanding the structure–function properties of Na+-coupled SLC4 transporters in health and disease

SLC4 transporters are membrane proteins that in general mediate the coupled transport of bicarbonate (carbonate) and share amino acid sequence homology. These proteins differ as to whether they also transport Na(+) and/or Cl(−), in addition to their charge transport stoichiometry, membrane targeting, substrate affinities, developmental expression, regulatory motifs, and protein-protein interactions. These differences account in part for the fact that functionally, SLC4 transporters have various physiological roles in mammals including transepithelial bicarbonate transport, intracellular pH regulation, transport of Na(+) and/or Cl(−), and possibly water. Bicarbonate transport is not unique to the SLC4 family since the structurally unrelated SLC26 family has at least three proteins that mediate Cl(−)-HCO(3)(−) exchange. The present review focuses on the first of the sodium-dependent SLC4 transporters that was identified whose structure has been most extensively studied: the electrogenic Na(+)-base cotransporter NBCe1. Mutations in NBCe1 cause proximal renal tubular acidosis (pRTA) with neurologic and ophthalmologic extrarenal manifestations. Recent studies have characterized important structure-function properties of the transporter and how they are perturbed as a result of mutations that cause pRTA. It has become increasingly apparent that the structure of NBCe1 differs in several key features from the SLC4 Cl(−)-HCO(3)(−) exchanger AE1 whose structural properties have been well-studied. In this review, the structure-function properties and regulation of NBCe1 will be highlighted and its role in health and disease will be reviewed in detail

Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology

Solute carriers form one of three major superfamilies of membrane transporters in humans, and include uniporters, exchangers and symporters. Following several decades of molecular characterisation, multiple solute carriers that form obligatory heteromers with unrelated subunits are emerging as a distinctive principle of membrane transporter assembly. Here we comprehensively review experimentally established heteromeric solute carriers: SLC3-SLC7 amino acid exchangers, SLC16 monocarboxylate/H+ symporters and basigin/embigin, SLC4A1 (AE1) and glycophorin A exchanger, SLC51 heteromer Ost α-Ost β uniporter, and SLC6 heteromeric symporters. The review covers the history of the heteromer discovery, transporter physiology, structure, disease associations and pharmacology - all with a focus on the heteromeric assembly. The cellular locations, requirements for complex formation, and the functional role of dimerization are extensively detailed, including analysis of the first complete heteromer structures, the SLC7-SLC3 family transporters LAT1-4F2hc, b0,+AT-rBAT and the SLC6 family heteromer B0AT1-ACE2. We present a systematic analysis of the structural and functional aspects of heteromeric solute carriers and conclude with common principles of their functional roles and structural architecture