The SLC36 family: proton-coupled transporters for the absorption of selected amino acids from extracellular and intracellular proteolysis

Abstract

Whilst Na(+) has replaced H(+) as a major transport driving force at the plasma membrane of animal cells, the evolutionarily older H(+)-driven systems persist on endomembranes and at the plasma membrane of specialized cells. The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. In addition to LYAAT1/PAT1, the family comprises another characterized member, PAT2, and two orphan transporters. Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline. Their mRNAs are broadly and differentially expressed in mammalian tissues. The PAT1 protein localizes to lysosomes in brain neurons, but is also found in the apical membrane of intestinal epithelial cells with a role in the absorption of amino acids from luminal protein digestion. In both cases, protons supplied by the lysosomal H(+)-ATPase or by the acidic microclimate of the brush border membrane drive transport of the amino acids into the cytosol. The subcellular localization and physiological role of PAT2 have still to be determined. SLC36 transporters are related distantly to other proton-coupled amino acid transporters, such as the vesicular neurotransmitter transporter VIAAT/VGAT (SLC32) and system N transporters (SLC38 family).

Functional Characterization of Novel Human and Mouse Equilibrative Nucleoside Transporters (hENT3 and mENT3) Located in Intracellular Membranes

“…It is unclear whether such pH dependence reflects proton-nucleoside co-transport activity, such as is seen for kinetoplastid ENT family members (8). However, the optimum pH value corresponds to that of late endosomes/lysosomes and probably reflects an evolutionary adaptation to the acidic interior of these organelles: lysosomes are known to contain other proton-linked solute exporters, such as amino acid transporter LYAAT1/PAT1 (31). Previous studies of adenosine uptake into isolated rat liver lysosomes showed no similar dependence on the pH of the medium (29), but the dependence of activity on the intraorganelle pH was not studied.…”

Substrate specificity and transport mode of the proton‐dependent amino acid transporter mPAT2

“…The PAT1 mRNA shows widespread expression with high levels in brain, intestine and kidney whereas the PAT2 mRNA is highly abundant in lung, kidney and brain. PAT3 mRNA is found solely in testis, whereas PAT4 mRNA shows ubiquitous expression [8].…”

“…The PAT1 mRNA shows widespread expression with high levels in brain, intestine and kidney whereas the PAT2 mRNA is highly abundant in lung, kidney and brain. PAT3 mRNA is found solely in testis, whereas PAT4 mRNA shows ubiquitous expression [8].So far, only PAT1 and PAT2 have been characterized functionally. They have an exceptional position among the mammalian amino acid transporters, as they act as electrogenic amino acid/proton symporters.…”

“…PAT1 recognizes, besides L-a amino acids, a number of additional substrates, e.g. b-alanine, c-aminobutyrate (GABA), betaine, D-Ser, and D-Ala [1,2,5,6,9], whereas for the PAT2 transporter only sarcosine has been identified as an additional high affinity substrate beside the normal L-a amino acid substrates [2,10].Recent studies on PAT1 suggest it to play a dual role in mammalian cells [8]. Based on its localization in lysosomal membranes in neurons [1,6] it is considered to act as an export system for amino acids out of lysosomes after their intralysosomal release from proteolytic processes.…”

The Proton/Amino Acid Cotransporter PAT2 Is Expressed in Neurons with a Different Subcellular Localization than Its Paralog PAT1

“…PAT3 and PAT4 are orphan transporters, whereas PAT1 (also designated as LYAAT1) and PAT2 are characterized as electrogenic amino acid/proton co-transporters with a high selectivity for amino acids with apolar and small side chains (3,16). PAT1 was shown to transport glycine, L-alanine, and L-proline as well as GABA and D-serine (11,12,(17)(18)(19).…”