SLC22A4 Membrane Protein Introduction

Introduction of SLC22A4

Solute carrier family 22 member 4 (SLC22A4), also known as organic cation/carnitine transporter 1 (OCTN1), Ergothioneine transporter, is encoded by the gene SLC22A4. SLC22A4 was cloned from the fetal liver in 1997 and comprises of 551 amino acid residues. SLC22A4 contains 11 transmembrane regions and 1 nucleotide binding site. SLC22A4 is an uptake transporter expressed in immature erythrocytes and in the K562 erythroid cell line. SLC22A4 is ubiquitously expressed in the body including the brain, small intestine, liver, and kidney. In the brain, SLC22A4 is functionally expressed in neurons and neural stem cells.

Function of SLC22A4 Membrane Protein

Carnitine /organic cation transporters (OCTNs) are important membrane proteins that mediate the transcellular transport of endogenous compounds and drugs. OCTNs are also called a new type of organic cation transporters because of their similar properties to the previously discovered organic cation transporters (OCTs). SLC22A4 (OCTN1) and SLC22A5 (OCTN2) are responsible for the transport of ergothioneine (ERGO) and carnitine in the body, respectively. SLC22A4 is the main transporter in the process of intestinal absorption and renal elimination of ergothioneine, and its transport process is pH and sodium concentration dependent. SLC22A4 expressed in brain neuronal cells can also participate in cell differentiation by regulating oxidative stress. Systemically administered ERGO is taken up by neurons via SLC22A4 in vivo. Interestingly, the expression of the SLC22A4 gene product is increased in inflammatory tissues of peripheral organs. Thus, SLC22A4 may be induced as a system to delete reactive oxygen species, which are produced at high levels in inflammatory tissues, because ERGO (SLC22A4 substrate) is a potent food-derived antioxidant. Although it has not yet been clarified whether SLC22A4 is induced in neurons during cellular toxicity, the expression of SLC22A4 is increased in neuronal maturation.

Fig.1 UVA-induced ROS, mitochondrial dysfunction, DNA damage was reversed by EGT pretreatment via Nrf2/ARE-mediated antioxidant status in human keratinocytes. (Hseu, 2015)

Application of SLC22A4 Membrane Protein in Literature

1. Dickens D., et al. Cellular Uptake of the Atypical Antipsychotic Clozapine Is a Carrier-Mediated Process. Mol Pharm. 2018, 15(8):3557-3572. PubMed ID: 29944835
   
   

   This article showed that clozapine was not a substrate of OCT1 (SLC22A1), OCT3 (SLC22A3), OCTN1 (SLC22A4), OCTN2 (SLC22A5), ENT1 (SLC29A1), ENT2 (SLC29A2), and ENT4/PMAT (SLC29A4), indicating that cellular clozapine uptake was independent of currently known drug transporters.

2. Ishimoto T., et al. Carnitine/Organic Cation Transporter OCTN1 Negatively Regulates Activation in Murine Cultured Microglial Cells. Neurochem Res. 2018, 43(1): 107-119. PubMed ID: 28688036
   
   

   This article demonstrated that OCTN1 negatively regulated the induction of inflammatory cytokine IL-1β, at least in part, via the transport of unidentified substrates other than ERGO in microglial cells.

3. Noritaka N., et al. Physiological Roles of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Neural Cells. Biol Pharm Bull. 2017, 40(8): 1146-1152. PubMed ID: 28768995
   
   

   This article revealed that OCTN1 might contribute to the alleviation of oxidative stress and the promotion of neuronal differentiation via the uptake of ERGO in the brain, perhaps abating symptoms of neurological disorders.

4. Drenberg C.D., et al. OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues. Cancer Res. 2017, 77(8): 2102-2111. PubMed ID: 28209616
   
   

   This article revealed that OCTN1-mediated transport of cytarabine and various structurally related cytidine analogues, such as 2' deoxycytidine and gemcitabine, occurred through a saturable process that was highly sensitive to inhibition by the classic nucleoside transporter inhibitors dipyridamole and nitrobenzylmercaptopurine ribonucleoside.

5. Walker A.L., et al. Sustained enhancement of OCTN1 transporter expression in association with hydroxyurea induced γ-globin expression in erythroid progenitors. Exp Hematol. 2018, 45: 69-72. PubMed ID: 27616638
   
   

   The authors verified that HU-induced OCTN1 expression was correlated positively with γ-globin level and was sustained throughout the period of induction.

SLC22A4 Preparation Options

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Reference

1. Hseu Y C, et al. (2015). Ergothioneine prevent UVA-induced skin damage through its potent antioxidant property. Free Radic Biol Med.

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