The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

Abstract

The solute carrier family 10 (SLC10) comprises two sodium-dependent bile acid transporters, i.e. the Na + / taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). These carriers are essentially involved in the maintenance of the enterohepatic circulation of bile acids mediating the first step of active bile acid transport through the membrane barriers in the liver (NTCP) and intestine (ASBT). Recently, four new members of the SLC10 family were described and referred to as P3 (SLC10A3), P4 (SLC10A4), P5 (SLC10A5) and sodium-dependent organic anion transporter (SOAT; SLC10A6). Experimental data supporting carrier function of P3, P4, and P5 is currently not available. However, as demonstrated for SOAT, not all members of the SLC10 family are bile acid transporters. SOAT specifically transports steroid sulfates such as oestrone-3-sulfate and dehydroepiandrosterone sulfate in a sodium-dependent manner, and is considered to play an important role for the cellular delivery of these prohormones in testes, placenta, adrenal gland and probably other peripheral tissues. ASBT and SOAT are the most homologous members of the SLC10 family, with high sequence similarity (∼70%) and almost identical gene structures. Phylogenetic analyses of the SLC10 family revealed that ASBT and SOAT genes emerged from a common ancestor gene. Structure-activity relationships of NTCP, ASBT and SOAT are discussed at the amino acid sequence level.Based on the high structural homology between ASBT and SOAT, pharmacological inhibitors of the ASBT, which are currently being tested in clinical trials for cholesterollowering therapy, should be evaluated for their crossreactivity with SOAT.

The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation

“…The substrate specificity the cloned Ntcps has been studied to a great extent and has been covered and compared with data from in vivo systems in many reviews [8,57,96,179,180,214,215,309,318]. Table 2 gives an overview on these findings by listing Ntcp substrates different from taurocholate.…”

The Biological Roles of Steroid Sulfonation

“…Sulfonated steroids are moved through the plasma membrane of cells by several different transporter proteins, including the sodium-dependent organic anion transporter (aka SOAT) [75], the sodium-independent organic anion transporting polypeptides (aka OATPs) [76] and the ATP binding cassette (ABC) proteins [77] (Figure 1). ABC transporters are ubiquitously expressed and are mostly considered responsible for the efflux of steroid substrates, whereas SOAT and OATPs mediate tissue-specific bi-directional transport of steroid sulfates across the plasma membrane of cells.…”

Effects of Ala Substitution for Conserved Cys Residues in Mouse Ileal and Hepatic Na+-Dependent Bile Acid Transporters

“…[1][2][3][4][5][6][7] These transporters and their homologous transporters do not share structural similarities with other Na þ -dependent secondary transporters. Even though analysis of naturally occurring and artificially induced mutations has identified some residues critical for the function of these transporters, [8][9][10][11][12][13][14][15][16][17][18][19][20][21] the strict localization of functionally important regions, such as substrate binding sites, has not been decided yet, and the secondary structure of SLC10A1 and SLC10A2 is still controversial. Cys insertion scanning and chemical modification using thiol modifiers are useful methods to determine functionally important regions and the topology of membrane transporters.…”