Amino acid derivatives are substrates or non-transported inhibitors of the amino acid transporter PAT2 (slc36a2)

Abstract

The H+-coupled amino acid transporter PAT2 (SLC36A2) transports the amino acids proline, glycine, alanine and hydroxyproline. A physiological role played by PAT2 in amino acid reabsorption in the renal proximal tubule is demonstrated by mutations in SLC36A2 that lead to an iminoglycinuric phenotype (imino acid and glycine uria) in humans. A number of proline, GABA and tryptophan derivatives were examined to determine if they function either as transported substrates or non-transported inhibitors of PAT2. The compounds were investigated following heterologous expression of rat PAT2 in Xenopus laevis oocytes. PAT2 function was characterised by: radiotracer uptake and competition (cis-inhibition) studies; radiotracer efflux and trans-stimulation; and measurement of substrate-induced positive inward current by two-electrode voltage-clamp. In general, the proline derivatives appeared to be transported substrates and the relative ability to induce current flow was closely related to the inhibitory effects on PAT2-mediated Research Highlights: ⠺PAT2 (SLC36A2) transports proline, glycine, alanine and hydroxyproline. ⠺Heterocyclic proline derivatives are transported substrates. ⠺Heterocyclic GABA derivatives are translocated slowly. ⠺Tryptophan derivatives (e.g. α-methyl- Abbreviations: 1-ACHC, 1-aminocyclohexanecarboxylic acid Keywords: PAT2