Disease relevance of SLC36A1

• Together, these results suggest that ARA67/PAT1 may function as a novel repressor that can modulate AR function in prostate cancer [1].
• Genome analysis of Rickettsia felis highlighted the presence of three patatin-like protein (PLP) genes (pat1, pat2A, and pat2B), whereas only one PLP gene (pat1) is found in the other sequenced rickettsial genomes [2].

High impact information on SLC36A1

• In intact epithelia, PAT1-mediated amino acid influx is reduced under conditions in which NHE3 is inactive [3].
• METHODS: PAT1 function was measured in isolation ( Xenopus laevis oocytes) and in intact epithelia (Caco-2 cell monolayers and rat small intestine) by measurement of amino acid and/or H(+) influx [3].
• RESULTS: PAT1-specific immunofluorescence was localized exclusively to the luminal membrane of Caco-2 cells and human and rat small intestine [3].
• The substrate specificity of hPAT1 is identical to that of the imino acid carrier [3].
• Tissue and membrane expression of PAT1 were determined by reverse-transcription polymerase chain reaction and immunohistochemistry [3].

Biological context of SLC36A1

• In human Caco-2 cells, hPAT1 function (H(+)/amino acid symport) is associated with a decrease in intracellular pH (pH(i)), which selectively activates the Na(+)/H(+) exchanger NHE3, and thus maintains pH(i) and the driving force for hPAT1 function (the H(+) electrochemical gradient) [4].
• The Pat subspecies was grouped into Pat1-Pat3, based on restriction fragment length polymorphism (RFLP) and ribosomal DNA (rDNA) internal transcribed spacer (ITS) sequences in previous studies [5].
• Rather, axonal LYAAT1 colocalizes with the exocyst, suggesting a role for membranes expressing LYAAT1 in specifying sites for exocytosis [6].
• Homology searching in eukaryotic genomes suggests that LYAAT-1 defines a subgroup of lysosomal transporters in the amino acid/auxin permease family [7].
• Here we report the identification and characterization of ARA67/PAT1 as an AR coregulator from a prostate cDNA library [1].

Anatomical context of SLC36A1

• This review focuses on the physiological roles of transporters recently identified at the molecular level, in particular SLC36A1, by identifying how they relate to the classical epithelial imino and amino acid transporters characterised in mammalian small intestine in the 1960s-1990s [8].
• Vigabatrin transport across the human intestinal epithelial (Caco-2) brush-border membrane is via the H(+)-coupled amino-acid transporter hPAT1 [9].
• The human PAT1 and PAT2 transporters when functionally expressed in Xenopus laevis oocytes show characteristics similar to those of their mouse counterparts [10].
• The aim of this investigation was to determine if the human proton-coupled amino-acid transporter 1 (hPAT1 or SLC36A1) is responsible for the intestinal uptake of the orally-administered antiepileptic agent 4-amino-5-hexanoic acid (vigabatrin).The Caco-2 cell line was used as a model of the human small intestinal epithelium [9].
• Phenotypically, the PAT1 transporter possesses the same functional characteristics as the previously described proton-dependent amino acid transport process in apical membranes of intestinal and renal epithelial cells [11].

Associations of SLC36A1 with chemical compounds

• Activation of the cAMP/protein kinase A pathway in Caco-2 cell monolayers either using pharmacological tools (forskolin, 8-br-cAMP, [(11,22,28)Ala]VIP) or physiological activators (the neuropeptides VIP and PACAP) inhibited hPAT1 function (beta-alanine uptake) at the apical membrane [4].
• With serine and cysteine, though the L-isomers did not interact with hPAT1 to any significant extent, the corresponding D-isomers were recognized as substrates [12].
• Of the most recently cloned members of the solute carrier family, two are "proline transporters". The amino acid transporter PAT1, expressed in intestine, kidney, brain and other organs, mediates the uptake of proline and derivatives in a pH gradient-dependent manner [13].
• Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline [14].
• The functional characteristics of rabbit PAT1 in either mammalian cells or renal BBMV suggest that PAT1 is the low-affinity transporter of proline, glycine and hydroxyproline believed to be defective in patients with iminoglycinuria [15].
• Replacement of the two highly conserved cysteine residues Cys-180 and Cys-329 abolished the transport function of hPAT1 in Xenopus laevis oocytes [16].

Regulatory relationships of SLC36A1

• In conclusion, we have shown that amino acid uptake via hPAT1 is inhibited by activators of the cAMP pathway indirectly through inhibition of NHE3 activity [4].

Other interactions of SLC36A1

• This review summarises evidence for expression of SLC36A1 and SLC6A20 in human small intestine, highlights the differences in functional characteristics of the imino acid carrier and IMINO transporter, and explains the confusion surrounding these two distinct transport systems [8].
• We recently cloned and functionally characterized two novel proton/amino acid transporters (PAT1 and PAT2) from mouse [10].
• In contrast, SLC26A6 (CFEX, PAT1) is expressed on the brush border of proximal tubule cells [17].

Analytical, diagnostic and therapeutic context of SLC36A1

• Among the various human tissues examined by Northern blot, PAT1 mRNA was expressed most predominantly in the intestinal tract [12].
• Further mechanism dissection reveals that the interrupted AR cytoplasmic-nuclear shuttling may play a major role in ARA67/PAT1 mediated suppression on AR [1].
• By using the Xenopus laevis oocytes as an expression system and by combining the two-electron voltage clamp technique with radiotracer flux studies, it was demonstrated that the aliphatic side chain of L-alpha-amino acids substrates can consist maximally of only one CH2-unit for high affinity interaction with PAT1 [18].

References