SLC22A6 Membrane Protein Introduction

Introduction of SLC22A6

Solute carrier family 22 member 6 (SLC22A6), also known as organic anion transporter 1 (OAT1), is a protein that in humans is encoded by the SLC22A6 gene. SLC22A6 is a transmembrane protein that is widely expressed in the brain, the placenta, the eyes, smooth muscles, and the basolateral membrane of proximal tubular cells of the kidneys. SLC22A6 mediates the uptake of a wide range of relatively small and hydrophilic organic anions from plasma into the cytoplasm of the proximal tubular cells of the kidneys.

Basic Information of SLC22A6
Protein Name	Solute carrier family 22 member 6
Gene Name	SLC22A6
Aliases	Organic anion transporter 1, hOAT1, PAH transporter, hPAHT, Renal organic anion transporter 1, hROAT1
Organism	Homo sapiens (Human)
UniProt ID	Q4U2R8
Transmembrane Times	12
Length (aa)	563
Sequence	MAFNDLLQQVGGVGRFQQIQVTLVVLPLLLMASHNTLQNFTAAIPTHHCRPPADANLSKNGGLEVWLPRDRQGQPESCLRFTSPQWGLPFLNGTEANGTGATEPCTDGWIYDNSTFPSTIVTEWDLVCSHRALRQLAQSLYMVGVLLGAMVFGYLADRLGRRKVLILNYLQTAVSGTCAAFAPNFPIYCAFRLLSGMALAGISLNCMTLNVEWMPIHTRACVGTLIGYVYSLGQFLLAGVAYAVPHWRHLQLLVSAPFFAFFIYSWFFIESARWHSSSGRLDLTLRALQRVARINGKREEGAKLSMEVLRASLQKELTMGKGQASAMELLRCPTLRHLFLCLSMLWFATSFAYYGLVMDLQGFGVSIYLIQVIFGAVDLPAKLVGFLVINSLGRRPAQMAALLLAGICILLNGVIPQDQSIVRTSLAVLGKGCLAASFNCIFLYTGELYPTMIRQTGMGMGSTMARVGSIVSPLVSMTAELYPSMPLFIYGAVPVAASAVTVLLPETLGQPLPDTVQDLESRWAPTQKEAGIYPRKGKQTRQQQEHQKYMVPLQASAQEKNGL

Function of SLC22A6 Membrane Protein

SLC22A6 is a classical Na⁺-dependent transporter and a typical p-aminopurine (PAH) transporter, which is a multispecific and inverse potential difference dicarboxylic acid exchange transporter. SLC22A6 operates as anion exchangers, which couple the uptake of an organic anion into the cell to the release of another organic anion from the cell. SLC22A6 shows remarkably broad substrate specificity and has been reported to be actively involved in the tubular uptake of various small, negatively charged molecules, such as endogenous metabolites, toxicants, and numerous clinically used therapeutics. As toxins and cytotoxic drugs are taken up by SLC22A6 and SLC22A8, these toxic substances may exert toxic effects on the proximal tubule cells and cause renal injury. In vitro studies with SLC22A6-transfected cells showed that SLC22A6 over-expression sensitizes the cytotoxicity caused by antiviral drugs.

Fig.1 The pathway of tenofovir (TFV) transport in proximal tubular epithelial cells. (Tun-Yong, 2017)

Application of SLC22A6 Membrane Protein in Literature

Hsueh C.H., et al. Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3. Mol Pharm. 2016, 13(9): 3130-3140. PubMed ID: 27467266

Authors in this article found that through inhibition of OAT1 and OAT3, uremic solutes contributed to the decline in renal drug clearance in patients with CKD.
Liu H.C., et al. An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network. J Biol Chem. 2016, 291(37): 19474-19486. PubMed ID: 27440044

This article indicated an important role for OAT1 in metabolism involving: the TCA cycle, tryptophan and other amino acids, fatty acids, prostaglandins, cyclic nucleotides, odorants, polyamines, and vitamins, providing novel mechanistic insights into the role of OAT1 and other drug transporters implicated in metabolic diseases like gout, diabetes, and chronic kidney disease.
Liu Q., et al. MDR1 and OAT1/OAT3 mediate the drug-drug interaction between puerarin and methotrexate. Pharm Res. 2014, 31(5): 1120-1132. PubMed ID: 24242937

Aided by in vivo and in vitro MTX absorption experiments in rats, the authors found that methotrexate (MTX) absorption was enhanced in combination with puerarin (PUR). Co-administration of PUR enhanced MTX exposure by inhibition of intestinal MDR1 and renal OAT1/3.
Hagos Y., et al. Human organic anion transporter OAT1 is not responsible for glutathione transport but mediates transport of glutamate derivatives. Am J Physiol Renal Physiol. 2013, 304(4): F403-409. PubMed ID: 23255614

The authors revealed that human OAT3 and OAT1 cannot be involved in renal GSH extraction from the blood. However, OAT1 could support intracellular GSH synthesis by taking up cysteinyl glycine.
Zeng Y., et al. Organic anion transporter 1 (OAT1) involved in renal cell transport of aristolochic acid I. Hum Exp Toxicol. 2012, 31(8): 759-770. PubMed ID: 22027505

This article demonstrated that AAI was taken up by OAT1, and then exerted its intracellular toxic effects on renal proximal tubule cells, which in turn damaged functional OAT1 and may further disturb the transport of its substrates.

SLC22A6 Preparation Options

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Reference

Tun-Yhong W, et al. (2017). Tenofovir Disoproxil Fumarate Is a New Substrate of ATP-Binding Cassette Subfamily C Member 11. Antimicrob Agents Chemother. 61(4): e01725-16.

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