Affinage

SLC36A1

Proton-coupled amino acid transporter 1 · UniProt Q7Z2H8

Length
476 aa
Mass
53.1 kDa
Annotated
2026-06-10
18 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/8 claims corpus-supported (75%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC36A1 (PAT1/LYAAT-1) is a proton-coupled, Na+- and Cl--independent, low-affinity, high-capacity symporter for small zwitterionic amino acids and imino acids that operates across several membrane compartments (PMID:19074966, PMID:16373326). At the apical brush-border membrane of intestinal enterocytes and renal tubule it transports proline, glycine, L-alanine, taurine, beta-alanine and GABA, corresponding to the classical intestinal imino acid carrier, and its activity depends on an inwardly directed H+ electrochemical gradient maintained in cooperation with the Na+/H+ exchanger NHE3 (SLC9A3) (PMID:19074966, PMID:17123464, PMID:16373326). This coupling makes PAT1-mediated uptake indirectly subject to the cAMP/PKA pathway, which inhibits NHE3 and thereby collapses the proton driving force (PMID:15754324). Its broad substrate tolerance, limited by molecular size, extends to certain dipeptides (Gly-Sar, Gly-Gly) and to clinically relevant drug substrates including delta-/5-aminolevulinic acid, gaboxadol and vigabatrin, governing their intestinal and rectal absorption; tryptophan and proline act as competitive inhibitors (PMID:20128809, PMID:19594759, PMID:20880398, PMID:22234618). In neurons SLC36A1 localizes to lysosomal membranes (with secondary Golgi distribution), consistent with efflux of amino acids from the lysosomal lumen (PMID:12761825); at the lysosomal surface it physically associates with SLC38A9, the two transporters reinforcing each other's expression and localization as part of the leucine-responsive amino acid-sensing machinery that activates mTORC1 (PMID:34572527). Through this mTORC1-activating function elevated SLC36A1 promotes proliferation and drives acquired resistance to CDK4/6 inhibitors, with transcription controlled by E2F derepression upon Rb loss, by FMRP-dependent translation, and by the transcription factor TFE3 under glucose starvation (PMID:31555743, PMID:38599381). In smooth muscle cells, by contrast, PAT1 is directed to the nucleus by a 3'-UTR element and suppresses proliferation (PMID:24222668). A missense mutation (T63R) in SLC36A1 causes champagne coat-color dilution in horses (PMID:18802473).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Established the subcellular site of action of the protein, showing PAT1/LYAAT-1 is not merely a plasma-membrane transporter but resides on lysosomal membranes in neurons, framing a role in efflux of amino acids from degradative compartments.

    Evidence In situ hybridization, immunohistochemistry, confocal and electron microscopy, and subcellular fractionation in rat CNS neurons

    PMID:12761825

    Open questions at the time
    • Did not measure lysosomal efflux flux directly
    • Did not connect lysosomal localization to downstream signaling
  2. 2005 High

    Defined the transport mechanism by identifying PAT1 as a pH-dependent, Na+-independent symporter for proline, glycine and alanine and distinguishing it from the separate Na+-dependent IMINO carrier, resolving the long-standing low-affinity renal imino acid uptake activity.

    Evidence cDNA isolation and heterologous expression of rabbit PAT1 in mammalian cells plus renal brush-border membrane vesicle assays with ion substitution

    PMID:16373326

    Open questions at the time
    • Stoichiometry of H+ coupling not quantified
    • No structural basis for substrate selectivity
  3. 2005 Medium

    Explained how PAT1 activity is regulated despite lacking direct regulatory input, by showing PKA signaling inhibits transport indirectly through NHE3, collapsing the proton gradient that energizes the symporter.

    Evidence Caco-2 beta-alanine uptake, intracellular pH measurement, pharmacological PKA modulators and immunocytochemistry

    PMID:15754324

    Open questions at the time
    • Regulation shown in single epithelial model
    • No direct PAT1 post-translational modification demonstrated
  4. 2006 Medium

    Consolidated PAT1 as the molecular identity of the classical mammalian intestinal imino acid carrier functioning in concert with NHE3, with a broad D-/L-amino acid and drug substrate range.

    Evidence Functional characterization in Xenopus oocytes and Caco-2 cells integrated with prior biochemical data

    PMID:17123464

    Open questions at the time
    • Integrative synthesis rather than single decisive experiment
    • Physiological substrate priorities in vivo not ranked
  5. 2008 High

    Quantified the physiological substrate role at the intestinal apical membrane, defining PAT1 as the high-capacity bulk taurine/beta-alanine route operating alongside the high-affinity TauT transporter.

    Evidence Xenopus oocyte expression, Caco-2 monolayer uptake and real-time PCR of human intestinal biopsies

    PMID:19074966

    Open questions at the time
    • Relative in vivo flux at dietary concentrations not measured
    • Did not address other compartmental functions
  6. 2008 Medium

    Provided in vivo genetic evidence that SLC36A1 function affects a whole-organism phenotype, linking a T63R missense mutation to champagne coat-color dilution in horses.

    Evidence Genome scanning, candidate gene sequencing and complete genotype-phenotype association across 182 horses

    PMID:18802473

    Open questions at the time
    • Functional consequence of T63R on transport not tested in vitro
    • Mechanistic link between transport and pigmentation unestablished
  7. 2009 High

    Demonstrated pharmacological relevance by showing PAT1 mediates intestinal absorption of the drug gaboxadol, with competitive inhibition translating to altered in vivo pharmacokinetics.

    Evidence Caco-2 transport assays and in vivo pharmacokinetics in beagle dogs with PAT1 inhibitor co-administration

    PMID:19594759

    Open questions at the time
    • Contribution of other transporters not fully excluded in vivo
  8. 2010 High

    Extended the substrate repertoire to the photodynamic prodrug ALA and to selected small dipeptides, mapping the size limit of PAT1 recognition.

    Evidence COS-7 and Xenopus oocyte uptake/electrophysiology with substrate panels plus Caco-2 inhibition studies

    PMID:20128809 PMID:20880398

    Open questions at the time
    • Structural determinants of the size cutoff not resolved
    • Affinities are low (mM range), physiological dipeptide handling uncertain
  9. 2012 Medium

    Added vigabatrin as a transported drug and demonstrated PAT1 expression and function in rectal epithelium, broadening the absorptive sites relevant to oral and rectal drug delivery.

    Evidence Xenopus oocyte voltage clamp, Western blotting of rat rectal epithelium and in vivo rat pharmacokinetics with inhibitor co-administration

    PMID:22234618

    Open questions at the time
    • Single lab
    • Quantitative contribution of PAT1 to total rectal absorption not isolated
  10. 2013 Medium

    Revealed a non-canonical, compartment-specific function: in smooth muscle cells PAT1 is targeted to the nucleus via a 3'-UTR element and suppresses proliferation, contrasting with its membrane transport role.

    Evidence Immunolocalization, fractionation, 3'-UTR reporter constructs and siRNA knockdown with growth assays in A7r5 and primary SMCs

    PMID:24222668

    Open questions at the time
    • Mechanism of nuclear PAT1 action unknown
    • No transport-independent molecular activity defined
  11. 2019 Medium

    Connected SLC36A1 abundance to mTORC1-driven cancer drug resistance, showing elevated SLC36A1 reactivates mTORC1 and confers CDK4/6 inhibitor resistance, with transcriptional (Rb/E2F) and translational (FMRP) control.

    Evidence Cancer cell resistance models, Western blotting, mTORC1 assays, siRNA knockdown and in vivo mouse tumor models

    PMID:31555743

    Open questions at the time
    • Direct biochemical link from transport activity to mTORC1 not dissected
    • Single lab
  12. 2021 Medium

    Placed SLC36A1 mechanistically within the lysosomal amino acid-sensing apparatus by demonstrating a physical and functional partnership with SLC38A9 that supports leucine-induced mTORC1 activation.

    Evidence Co-immunoprecipitation, immunofluorescence co-localization and leucine stimulation in C2C12 cells

    PMID:34572527

    Open questions at the time
    • Co-IP without reciprocal or endogenous validation
    • Direct role of transport flux in sensing not separated from interaction
  13. 2024 Medium

    Identified an upstream transcriptional driver, showing glucose starvation stabilizes TFE3 via O-GlcNAcylation to induce SLC36A1 and sustain mTOR-dependent proliferation in kidney cancer.

    Evidence Functional genomic screen, TFE3/SLC36A1 siRNA knockdown, O-GlcNAcylation analysis and mTOR activity assays

    PMID:38599381

    Open questions at the time
    • Direct ChIP confirmation of TFE3 binding stated as inferred
    • Single lab
  14. 2026 Low

    Linked SLC36A1 to gut barrier physiology, indicating a microbiota metabolite (4-GBA) and the agonist sarcosine engage SLC36A1 to support intestinal stem cell function and attenuate colitis.

    Evidence Metabolomics, organoid co-culture, mouse colitis models and single-cell RNA sequencing

    PMID:41782409

    Open questions at the time
    • Mechanism not validated by SLC36A1 loss-of-function
    • Hedgehog activation link to SLC36A1 indirect
    • Single lab, newly published
  15. 2026 Medium

    Reinforced the prodrug-transport role in oncology, showing SLC36A1 mediates 5-ALA uptake that determines protoporphyrin IX accumulation and photodynamic therapy sensitivity in cisplatin-resistant cells.

    Evidence Tryptophan inhibition, mRNA expression, PpIX accumulation assays and post-PDT viability in cisplatin-resistant cell line pairs

    PMID:42009158

    Open questions at the time
    • Relies on pharmacological inhibition rather than genetic knockout
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single transporter executes opposing roles — proliferation-suppressing nuclear localization in smooth muscle versus mTORC1-activating lysosomal/membrane function in cancer — and what governs its compartmental targeting remain unresolved.
  • No structural model of the transporter
  • Mechanism of nuclear targeting versus membrane targeting unresolved
  • Whether transport flux per se versus protein abundance drives mTORC1 signaling not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140104 molecular carrier activity 3 GO:0140299 molecular sensor activity 1
Localization
GO:0005764 lysosome 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-382551 Transport of small molecules 4 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
SLC38A9SLC9A3TFE3

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 SLC36A1 (PAT1) functions as a H+-coupled, pH-dependent, Na+- and Cl--independent, low-affinity, high-capacity transporter for taurine and beta-alanine at the apical brush-border membrane of human intestinal enterocytes, coexpressed with TauT (SLC6A6). PAT1 mediates bulk taurine uptake at dietary concentrations while TauT predominates at low concentrations. Heterologous expression in Xenopus laevis oocytes, Caco-2 cell monolayer uptake assays, real-time PCR of human intestinal biopsies The Journal of physiology High 19074966
2005 hPAT1 (SLC36A1) function (H+/amino acid symport) is indirectly regulated by the cAMP/PKA pathway: PKA activation (via forskolin, 8-br-cAMP, VIP, PACAP) inhibits hPAT1-mediated beta-alanine uptake by inhibiting NHE3 activity, which collapses the H+ electrochemical gradient driving PAT1. NHERF1 localizes apically in Caco-2 cells and permits PKA-mediated NHE3 phosphorylation. Caco-2 cell monolayer beta-alanine uptake assays, intracellular pH measurements, pharmacological inhibitors, immunocytochemistry Journal of cellular physiology Medium 15754324
2006 SLC36A1 (PAT1) functions as a proton-coupled imino and amino acid symporter in cooperation with the Na+/H+ exchanger NHE3 (SLC9A3), corresponding to the classical imino acid carrier of mammalian small intestine. SLC36A1 transports D- and L-imino and amino acids, beta- and gamma-amino acids, and orally active neuromodulatory and antibacterial agents. Functional characterization in Xenopus oocytes and Caco-2 cells; integration of prior biochemical data with molecular transporter identification Biochimica et biophysica acta Medium 17123464
2005 Rabbit PAT1 (SLC36A1) mediates pH-dependent, Na+-independent uptake of proline, glycine, L-alanine, and alpha-(methylamino)isobutyric acid in mammalian cells and is identified as the low-affinity transporter of proline, glycine, and hydroxyproline in renal brush-border membrane vesicles; PAT1 is distinct from the IMINO transporter (a second Na+-dependent proline uptake system). Isolation and heterologous expression of rabbit PAT1 cDNA in mammalian cells; renal brush-border membrane vesicle transport assays with ion-substitution experiments Molecular membrane biology High 16373326
2003 LYAAT-1 (SLC36A1) localizes predominantly to lysosomal membranes in rat CNS neurons (co-localizing with cathepsin D) and also to Golgi apparatus and lateral saccules, consistent with a role in amino acid efflux from lysosomes; expression is widespread in neurons regardless of neurotransmitter type. In situ hybridization, immunohistochemistry, confocal microscopy, electron microscopy, subcellular fractionation The Journal of comparative neurology High 12761825
2010 Delta-aminolevulinic acid (ALA) is a substrate for SLC36A1 with saturable, pH-dependent, Na+-independent uptake (Km ~6.8 mM, Vmax ~96 pmol·cm-2·min-1) in SLC36A1-expressing COS-7 cells; ALA transport is inhibited by glycine, proline, and GABA. In Caco-2 cells, apical ALA uptake is mediated only by SLC36A1 and SLC15A1. Transient expression of SLC36A1 in COS-7 cells with radiolabeled uptake assays, membrane potential assay, Caco-2 inhibition studies British journal of pharmacology High 20128809
2009 Gaboxadol is a substrate of PAT1 (SLC36A1) and its intestinal absorption is mediated by PAT1: gaboxadol inhibits hPAT1-mediated L-[3H]proline uptake in Caco-2 cells (Ki ~6.6 mM); transepithelial transport is polarized apical-to-basolateral and pH-dependent. In vivo co-administration of L-tryptophan (a PAT1 inhibitor) decreased absorption rate and Cmax without affecting total absorption (AUC), consistent with competitive PAT1 inhibition. Caco-2 cell transport assays, in vivo pharmacokinetic study in beagle dogs with PAT1 inhibitor co-administration British journal of pharmacology High 19594759
2010 SLC36A1 transports Gly-Sar and Gly-Gly (but not most other dipeptides) as substrates; in SLC36A1-expressing Xenopus oocytes, Gly-Sar, Gly-Gly, ALA, beta-aminoethylglycine, GABA, Gly, and Pro evoked inward currents, while Val, Leu, Gly-Ala, Gly-Pro, and Gly-Phe did not, defining the structural size limit of dipeptide transport via SLC36A1. Two-electrode voltage clamp in SLC36A1 cRNA-injected Xenopus laevis oocytes; Caco-2 inhibition assays British journal of pharmacology High 20880398
2013 In rat smooth muscle cells (A7r5 line and primary aorta/colon SMCs), PAT1 (SLC36A1) protein localizes predominantly to the cell nucleus (not the plasma membrane), driven by a 3'-UTR element of the PAT1 transcript. Knockdown of PAT1 by siRNA increased cellular growth rate, indicating PAT1 suppresses proliferation in SMCs. Immunolocalization, cellular fractionation, 3'-UTR reporter constructs, siRNA knockdown with growth rate measurement in A7r5 and primary SMCs American journal of physiology. Endocrinology and metabolism Medium 24222668
2019 Increased SLC36A1 expression drives acquired resistance to CDK4/6 inhibitors by reactivating mTORC1 signaling. Two mechanisms elevate SLC36A1: (i) Rb loss reduces E2F suppression, increasing SLC36A1 transcription; (ii) FMRP1 overexpression promotes SLC36A1 translation. mTORC1 inhibition combined with CDK4/6 inhibition overcomes resistance in vivo. Cancer cell line models of acquired resistance, Western blotting, mTORC1 activity assays, siRNA knockdown, in vivo mouse tumor models Science advances Medium 31555743
2021 SLC38A9 and SLC36A1 interact physically on the lysosomal surface in C2C12 cells; they enhance each other's expression levels and lysosomal localization. This interaction is part of the amino acid sensing machinery that activates mTORC1. Leucine increases expression of both transporters, leading to mTORC1 activation. Co-immunoprecipitation, Western blotting, immunofluorescence co-localization, leucine stimulation experiments in C2C12 cells Biomolecules Medium 34572527
2024 TFE3 transcriptionally activates SLC36A1 in kidney cancer cells; glucose starvation stabilizes TFE3 protein via increased O-GlcNAcylation, which induces SLC36A1 expression, promoting mTOR activity and proliferation. SLC36A1 is identified as a TFE3 target gene in a functional genomic screen. Suppressing TFE3 or SLC36A1 increases sensitivity to GLUT1 inhibitor. Functional genomic screen, chromatin immunoprecipitation (inferred from TFE3 as transcription factor), siRNA knockdown of TFE3/SLC36A1, O-GlcNAcylation analysis, mTOR activity assays The Journal of biological chemistry Medium 38599381
2008 A missense mutation in exon 2 of SLC36A1 (T63R, threonine to arginine at position 63) causes champagne coat color dilution in horses; the SNP was perfectly associated with the phenotype across 85 champagne and 97 non-champagne horses, establishing SLC36A1 as the champagne dilution gene. Genome scanning, candidate gene sequencing, genotype-phenotype association in horse families PLoS genetics Medium 18802473
2026 SLC36A1 mediates 5-aminolevulinic acid (5-ALA) uptake in cisplatin-resistant cancer cells; SLC36A1 mRNA is upregulated in cisplatin-resistant sublines, and inhibition of SLC36A1 with tryptophan markedly reduced intracellular protoporphyrin IX accumulation and 5-ALA-PDT cytotoxicity, identifying SLC36A1 as a functional 5-ALA transporter contributing to PDT sensitivity. Inhibitor experiments (tryptophan as SLC36A1 inhibitor), mRNA expression analysis, PpIX accumulation assay, cell viability after PDT in cisplatin-resistant cancer cell lines Photodiagnosis and photodynamic therapy Medium 42009158
2026 4-Guanidinobutanoic acid (4-GBA), a gut microbiota metabolite, upregulates SLC36A1 and activates Hedgehog signaling to promote intestinal stem cell function and goblet cell differentiation. The SLC36A1 agonist sarcosine enhances barrier homeostasis and attenuates colitis in mice, and SLC36A1 expression inversely correlates with ulcerative colitis severity. Untargeted metabolomics, organoid co-culture, mouse colitis models, single-cell RNA sequencing, SLC36A1 agonist (sarcosine) treatment Gut microbes Low 41782409
2012 Vigabatrin is a substrate of PAT1 (SLC36A1) with Km ~5.2 mM in hPAT1-expressing Xenopus oocytes; transport is almost completely inhibited by tryptophan. PAT1 protein is expressed in rat rectal epithelium and participates in rectal vigabatrin absorption, as shown by altered pharmacokinetics upon proline or tryptophan co-administration. Two-electrode voltage clamp in Xenopus oocytes, Western blotting for PAT1 in rectal epithelium, in vivo rat pharmacokinetics with co-administration of PAT1 inhibitors Pharmaceutical research Medium 22234618

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Taurine uptake across the human intestinal brush-border membrane is via two transporters: H+-coupled PAT1 (SLC36A1) and Na+- and Cl(-)-dependent TauT (SLC6A6). The Journal of physiology 112 19074966
2006 Deciphering the mechanisms of intestinal imino (and amino) acid transport: the redemption of SLC36A1. Biochimica et biophysica acta 51 17123464
2010 Delta-aminolevulinic acid is a substrate for the amino acid transporter SLC36A1 (hPAT1). British journal of pharmacology 44 20128809
2008 Missense mutation in exon 2 of SLC36A1 responsible for champagne dilution in horses. PLoS genetics 41 18802473
2019 SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors. Science advances 38 31555743
2009 Intestinal gaboxadol absorption via PAT1 (SLC36A1): modified absorption in vivo following co-administration of L-tryptophan. British journal of pharmacology 32 19594759
2010 The proton-coupled amino acid transporter, SLC36A1 (hPAT1), transports Gly-Gly, Gly-Sar and other Gly-Gly mimetics. British journal of pharmacology 28 20880398
2003 Lysosomal amino acid transporter LYAAT-1 in the rat central nervous system: an in situ hybridization and immunohistochemical study. The Journal of comparative neurology 28 12761825
2005 Indirect regulation of the intestinal H+-coupled amino acid transporter hPAT1 (SLC36A1). Journal of cellular physiology 22 15754324
2013 PAT1 (SLC36A1) shows nuclear localization and affects growth of smooth muscle cells from rats. American journal of physiology. Endocrinology and metabolism 19 24222668
2005 Isolation and function of the amino acid transporter PAT1 (slc36a1) from rabbit and discrimination between transport via PAT1 and system IMINO in renal brush-border membrane vesicles. Molecular membrane biology 14 16373326
2012 Intestinal drug transport via the proton-coupled amino acid transporter PAT1 (SLC36A1) is inhibited by Gly-X(aa) dipeptides. Molecular pharmaceutics 11 22853447
2021 Insights into the Interaction of Lysosomal Amino Acid Transporters SLC38A9 and SLC36A1 Involved in mTORC1 Signaling in C2C12 Cells. Biomolecules 10 34572527
2012 Rectal absorption of vigabatrin, a substrate of the proton coupled amino acid transporter (PAT1, Slc36a1), in rats. Pharmaceutical research 10 22234618
2024 TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells. The Journal of biological chemistry 7 38599381
2010 Gaboxadol has affinity for the proton-coupled amino acid transporter 1, SLC36A1 (hPAT1)--A modelling approach to determine IC(50) values of the three ionic species of gaboxadol. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 5 21112392
2026 A 4-guanidinobutanoic acid-SLC36A1 axis drives a microbiota‒host feedback loop to regulate intestinal homeostasis. Gut microbes 0 41782409
2026 Enhanced accumulation of protoporphyrin IX via SLC6A6 and SLC36A1 sensitizes cisplatin-resistant cells to 5-aminolevulinic acid-based photodynamic therapy. Photodiagnosis and photodynamic therapy 0 42009158

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