J Physiol 586.17 (2008) pp 4061–4067 4061 Human solute carrier SLC6A14 is the β-alanine carrier Catriona M. H. Anderson1, Vadivel Ganapathy2 and David T. Thwaites1 1Epithelial Research Group, Institute for Cell & Molecular Biosciences, Faculty of Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK 2Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia, 30912, USA The β-alanine carrier was characterized functionally in the 1960s to 1980s at the luminal surface of the ileal mucosal wall and is a Na+- and Cl−-dependent transporter of a number of essential and non-essential cationic and dipolar amino acids including lysine, arginine and leucine. β-Alanine carrier-like function has not been demonstrated by any solute carrier transport system identiﬁed at the molecular level. A series of experiments were designed to determine whether solute carrier SLC6A14 is the molecular correlate of the intestinal β-alanine carrier, perhaps the last of the classical intestinal amino acid transport systems to be identiﬁed at the molecular level. Following expression of the human SLC6A14 transporter in Xenopus laevis oocytes, the key functional characteristics of the β-alanine carrier, identiﬁed previously in situ in ileum, were demonstrated for the ﬁrst time. The transport system is both Na+ and Cl− dependent, can transport non-α-amino acids such as β-alanine with low afﬁnity, and has a higher afﬁnity for dipolar and cationic amino acids such as leucine and lysine. N -methylation of its substrates reduces the afﬁnity for transport. These observations conﬁrm the hypothesis that the SLC6A14 gene encodes the transport protein known as the β-alanine carrier which, due to its broad substrate speciﬁcity, is likely to play an important role in absorption of essential nutrients and drugs in the distal regions of the human gastrointestinal tract. (Received 26 March 2008; accepted after revision 1 July 2008; ﬁrst published online 3 July 2008) Corresponding author D. T. Thwaites: Institute for Cell & Molecular Biosciences, Faculty of Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK. Email: d.t.thwaites@ncl.ac.uk Amino acids are required for many fundamental biological functions such as protein synthesis, neurotransmission, nitrogen metabolism, and cell growth. In humans and mammals the requirements for most amino acids are met by assimilation from diet. Transepithelial amino acid absorption across the intestinal wall is mediated by a number of amino acid transporters arranged in series and parallel at the luminal and serosal membranes of the intestinal epithelium (Ganapathy et al. 2006). Although amino acid transporters vary in substrate selectivity, ion dependency and substrate afﬁnity, the attribution of function to any particular transport system in intact tissues is often hampered by overlapping substrate speciﬁcity. One such amino acid transport system was described at the mucosal surface of rabbit ileum and named the β-alanine carrier (Munck & Schultz, 1969; Paterson et al. 1981; Munck, 1985; Anderson & Munck, 1987). This carrier system transports a range of both essential and non-essential amino acids and accepts non-α-amino acids such as β-alanine but has a higher afﬁnity for dipolar (e.g. leucine) and cationic (e.g. lysine) amino acids; is Na+ and Cl− dependent; is only moderately stereospeciﬁc; and has a much lower afﬁnity for the N -methylated derivatives of its dipolar amino acid substrates (Munck, 1985; Munck & Munck, 1990, 1992a,b, 1995). The β-alanine carrier is unusual in that, under normal circumstances, its small intestinal expression is limited to the ileum (Munck & Munck, 1992a,b). The cloning of transporter related genes over recent years has allowed molecular identiﬁcation of most of the ‘classical’ amino acid transport systems characterized functionally in speciﬁc cells and tissues during the 1960s to 1980s. The purpose of this investigation was to establish the molecular identity of the β-alanine carrier. The solute carrier SLC6A14 has been cloned from human mammary gland, mouse colon and rat lung (Sloan & Mager, 1999; Hatanaka et al. 2001; Nakanishi et al. 2001; Ugawa et al. 2001; Umapathy et al. 2004). SLC6A14 is the 14th member of solute carrier family 6, a family of Na+- and Cl−-dependent solute transport systems many of which are involved in transmembrane movement of neurotransmitters (Chen et al. 2004). SLC6A14 (also named ATB0,+) functions as a dipolar and cationic amino acid transporter with characteristics similar to C 2008 The Authors. Journal compilation C 2008 The Physiological Society DOI: 10.1113/jphysiol.2008.154500