Although the transport of imino acids across the brush-border membrane of the mammalian small intestinal epithelium has been demonstrated in a large number of studies the identity and nature of the transport mechanism has remained controversial. From the 1960s onwards this transport system has been given a variety of names including the imino acid carrier, the sarcosine carrier, the methionine-insensitive ‘sarcosine-glycine-proline’ system, and more recently the IMINO system. Most studies demonstrate that this IMINO system is a Na⁺-dependent transporter of imino acids and small dipolar amino acids. However, an unusual feature of the IMINO system is that there are marked differences in the ion dependency and substrate specificity between studies using small intestinal tissues from rat, rabbit, hamster or guinea-pig intestine (Munck et al. 1994; Stevens & Wright, 1985). The IMINO system is perhaps the only ‘classical’ amino acid transport system yet to be identified at the molecular level. The IMINO transport system could be linked to the hereditary malabsorption syndrome iminoglycinuria, which is associated with a defect in proline, hydroxyproline and glycine transport (where defects can be observed in both renal transport and intestinal absorption).

To date there is no convincing evidence for the existence of a Na⁺-dependent IMINO system in human small intestine. However, a transport system with similar substrate specificity to the rat IMINO carrier has been identified functionally at the apical membrane of the human intestinal epithelial cell line Caco-2. This transport mechanism was named ‘system PAT’ (for Proton-coupled Amino-acid Transporter) as it functions in an H⁺-coupled, pH-dependent, Na⁺-independent manner (Thwaites et al. 1993; 1995). Substrates for this transporter include a range of small, unbranched, dipolar amino acids (including methylated analogues such as betaine and MeAIB), imino acids, beta amino acids, and potential neuromodulatory amino acids including D-amino acids (e.g. D-cycloserine and D-serine) and GABA (and analogues). The presence of a transport system with such a broad range of transported substrates provides a potential route for nutrient, osmolyte and drug transport across the luminal brush-border membrane.

Recently a cDNA has been isolated (using a probe specific for the LYAAT1 transporter originally identified in rat brain (Sagne et al. 2001)) from Caco-2 cells that (when expressed in HRPE cells) is able to induce H⁺-coupled amino acid transport (hPAT1, for human Proton-coupled Amino-acid Transporter 1) (Chen et al. 2003). hPAT1 has an identical substrate specificity to that measured for system PAT in Caco-2 cell monolayers and the IMINO system in rat small intestine. Immunocytochemistry demonstrates PAT1-like immunoreactivity (IR) localised solely to the apical membrane of Caco-2 cells and human and rat small intestinal enterocytes.

Is PAT1 the IMINO carrier? Despite the similarity in substrate specificity and substrate affinity, there is a clear difference in the apparent ion dependency between studies using the hPAT1 clone or measurements of IMINO transport in intact intestinal tissues. However, our recent studies using intact monolayers of the human intestinal cell line Caco-2 can account for this apparent anomaly (Anderson & Thwaites, 2003). In intact epithelia optimal H⁺-coupled PAT1 transport is dependent upon the maintenance of the driving force (H⁺-electrochemical gradient) during transport and this is achieved by functional activity of the apically-localised Na⁺/H⁺ exchanger NHE3. Inhibition of NHE3 (e.g. following Na⁺ removal) will thus lead to a reduction in PAT1 capacity and produce the partial Na⁺ dependency observed in studies using intact epithelia (e.g. Caco-2 cell monolayers and rat small intestine). In conclusion, the PAT1 clone is responsible for IMINO system transport in human and rat small intestine. The absolute requirement for Na⁺ and Cl^– and distinct substrate specificity of the IMINO system in rabbit small intestine suggest that the rabbit IMINO carrier is a non-PAT1 type transporter.