J Physiol 586.17 SLC6A14 is the β-alanine carrier 4065 this distal intestinal site of absorption could be important in both nutrient and drug absorption. β-Alanine is a non-proteinogenic amino acid and is a component of the dipeptide carnosine (β-alanine–L-histidine), found at high concentrations in both vertebrate and non-vertebrate skeletal muscle. In humans, dietary supplementation with β-alanine (at concentrations relevant to diet) leads to an increase in skeletal muscle carnosine (Harris et al. 2006) which is associated with an improvement in performance during exercise, proposed to be due to the enhanced pH buffering effect of carnosine (Harris et al. 2006; Stout et al. 2007; Zoeller et al. 2007). In addition to cationic and dipolar amino acids, SLC6A14 transports carnitine, a range of nitric oxide synthase inhibitors, and the antiviral prodrugs valacyclovir and valganciclovir (Hatanaka et al. 2001, 2004; Nakanishi et al. 2001; Umapathy et al. 2004). Thus, SLC6A14 has great potential as a target for drug delivery programmes using slow release formulations or rectal suppositories. In addition, the colonic expression may have relevance for the absorption of bacterially derived D-amino acids as D-serine is transported by SLC6A14 (Hatanaka et al. 2002). Inter- estingly, the distribution pattern of SLC6A14 parallels the regions of the gastrointestinal tract that are generally colonized by bacteria. The hypothesis that SLC6A14 expression might be up-regulated following bacterial colonization is consistent with the recent demonstration of selective up-regulation of SLC6A14 mRNA and protein expression in acute cholera patients compared to convalescence such that SLC6A14 protein has been immunolocalized to the luminal surface of the human duodenum during acute infection (Flach et al. 2007). After induction, e.g. following infection with cholera, SLC6A14 could provide a highly concentrating mechanism (due to its Na+ and Cl− dependence) for absorption of essential amino acids such as lysine and leucine that could otherwise be lost during excess intestinal ﬂuid and electrolyte secretion. The SLC6A14 gene seems highly regulated being associated with obesity (Suviolahti et al. 2003; Durand et al. 2004), and being up-regulated in colorectal cancer (Gupta et al. 2005), cervical cancer (Gupta et al. 2006), and ulcerative colitis (Flach et al. 2006). Figure 6. The effects of substrate N-methylation on β-alanine carrier-like transport by SLC6A14 SLC6A14-mediated [3H]β-alanine (100 μM) uptake (measured in NaCl pH 7.4 solution) in the presence of various amino acids (ﬁlled squares) and their N-methylated analogues (open squares) at 0.1, 1 and 10 mM. Amino acids are: A, leucine and N-methyl-leucine (N-Me-Leu); B, glycine and sarcosine (Sar; N-methyl-glycine); C, alanine and N-methyl-alanine (N-Me-Ala); D, AIB (aminoisobutyric acid) and MeAIB (α-(methylamino)isobutyric acid). Data are expressed as percentage of control (absence of competing amino acids) after subtraction of uptake in water-injected oocytes under each condition (n = 18–20). C 2008 The Authors. Journal compilation C 2008 The Physiological Society