Programme Contents

Disorders of neutral amino acid resorption in epithelial cells

Recent successes in the molecular cloning and identification of apical neutral amino acid transporters have shed a new light on inherited neutral amino acidurias, such as Hartnup disorder and iminoglycinuria. Hartnup disorder is caused by mutations in the neutral amino acid transporter B⁰AT1 (SLC6A19) (Kleta et al., 2004; Seow et al., 2004). The transporter is found in kidney and intestine, where it is involved in the resorption of all neutral amino acids (Bröer et al., 2004). It belongs to the SLC6 family, comprising transporters for neurotransmitters, osmolytes and creatine. B⁰AT1 transports neutral amino acids together with 1 Na⁺-ion but in contrast to other members of the SLC6 family is chloride independent. The SLC6 family also contains a number of ‘orphan transporters’ the physiological function of which has remained elusive. Identification of SLC6A19 as a Na⁺-dependent amino acid transporter suggested that orphan neurotransmitter transporters might in fact be amino acid transporters. SLC6A20 turned out to be the long-sought IMINO system, a Na⁺ and Cl^--dependent proline transporter (Kowalczuk et al., 2005). SLC6A20 is highly expressed in the kidney and intestine and may play a role in iminoglycinuria, a disorder characterised by hypersecretion of proline and glycine in the urine. Although SLC6A20 transports proline but not glycine, it is considered a candidate for iminoglycinuria because excess of proline in the proximal tubule could compete for glycine uptake by the proline/glycine transporter PAT1 (SLC36A1). Further functional analysis of SLC6 orphan transporters demonstrated that SLC6A15 is a transporter for large neutral amino acids plus proline. The transporter is highly expressed in the brain and kidney. In the kidney it may serve as a high-affinity back-up transporter for selected amino acids in the distal parts of the proximal tubule. Functionally SLC6A15 is related to B⁰AT1 and was hence named B⁰AT2. It transports neutral amino acids together with 1 Na⁺ and is chloride independent. In summary, a new family of Na⁺-dependent amino acid transporters has been identified, the members of which are involved in the transport of amino acids in epithelial cells and the nervous system.

Bröer A., Klingel K., Kowalczuk S., Rasko J.E., Cavanaugh J. & Bröer S.. (2004) Journal of Biological Chemistry 279: 24467-24476.

Kleta, R., Romeo, E., Ristic, Z., Ohura, T., Stuart, C., Arcos-Burgos, M., Dave, M.H., Wagner, C.A., Camargo, S.R., Inoue, S., Matsuura, N., Helip-Wooley, A., Bockenhauer, D., Warth, R., Bernardini, I., Visser, G., Eggermann, T., Lee, P., Chairoungdua, A., Jutabha, P., Babu, E., Nilwarangkoon, S., Anzai, N., Kanai, Y., Verrey, F., Gahl, W.A. & Koizumi, A. (2004). Nature Genetics 36: 999-1002.

Kowalczuk, S., Bröer, A., Munzinger, M., Tietze, N., Klingel, K. & Bröer, S. (2005) Biochemcal Journal 386: 417-422.

Seow, H.F., Bröer, S., Bröer, A., Bailey, C.G., Potter, S.J., Cavanaugh, J.A. & Rasko, J.E. (2004) Nature Genetics 36: 1003-1007.