Physiological Roles of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Neural Cells

Abstract

Dysfunction in neurotransmission mediated by neurotransmitters causes various neurological disorders.Therefore, receptors and reuptake transporters of neurotransmitters have been focused on as a therapeutic target in neurological disorders. These membrane proteins have high affinity for a specific neurotransmitter and are highly expressed on synaptic membranes. In contrast, xenobiotic transporters have relatively lower affinity for neurotransmitters but widely recognize various organic cations and/or anions and are also expressed in brain neurons. However, it has been largely unknown why such xenobiotic transporters are expressed in neurons that play a key role in signal transduction. We have therefore attempted to clarify the physiological roles of one such xenobiotic organic cation transporter (OCT) in neural cells with the aim of obtaining new insight into the treatment of neurological disorders. Carnitine/organic cation transporter OCTN1/SLC22A4 is functionally expressed in neurons and neural stem cells. In particular, OCTN1 is expressed at much higher levels compared with other OCTs in neural stem cells and positively regulates their differentiation into neurons. OCTN1 accepts the naturally occurring food-derived antioxidant ergothioneine (ERGO) as a good in vivo substrate. Because ERGO is highly distributed into the brain after oral ingestion, OCTN1 may contribute to the alleviation of oxidative stress and promotion of neuronal differentiation via the uptake of ERGO in the brain, perhaps abating symptoms of neurological disorders. In this review, we introduce current topics on the physiological roles of OCTs with a focus on OCTN1 in neural cells and discuss its possible application to the treatment of neurological disorders.

OCTN: A Small Transporter Subfamily with Great Relevance to Human Pathophysiology, Drug Discovery, and Diagnostics

“…We may suppose that metabolic alterations arise only after medium-/long-time ablation of the transporter and/or exposure to stress conditions. Very interestingly, a role for OCTN1 is proposed in the nervous system after confirming the neuronal expression of this transporter 26,28,29,143 that was not described in the first reports. 11 Taking into consideration that many neurological diseases are caused by oxidative stress, the ergothioneine transport mediated by OCTN1 is plausibly linked to the antioxidant property of the mushroom metabolite ( Fig.…”

“…16,[23][24][25] Despite the uncertainties, correlations between OCTN1 expression and neural tissue development have been recently reported. [26][27][28][29] Thus, the status artis on the role of the two transporters in cell metabolism is quite different. A clear and common aspect of the two transporters is the involvement in drug delivery and interaction.…”

Therapeutic potential of glutathione-enhancers in stress-related psychopathologies

“…OCTN1 shows high selectivity for ergothioneine and is expressed in different cell types and tissues, including brain neurons (Kato, Kubo et al 2010;Nakamichi and Kato 2017;Tang, Cheah et al 2018;Tschirka, Kreisor et al 2018). High levels of ergothioneine may help maintain a higher GSH/GSSG ratio (Song, Lin et al 2014), suggesting higher availability of reduced GSH to exert its antioxidant activity.…”

Effect of Cholesterol on the Organic Cation Transporter OCTN1 (SLC22A4)

“…To this aim, CHS, a widely used cholesterol analogue which is more suitable than free cholesterol for incorporating into membranes [35], was added to the phospholipid mixture. In these experiments, besides TEA, transport of acetylcholine was also measured, that is a physiological substrate of OCTN1 [5,15,20,42]. Figure 3a,b show the time courses of TEA and acetylcholine uptake, respectively, in the presence of increasing CHS concentrations.…”

“…Then, studies performed using a metabolomic approach, highlighted transport competence for ergothioneine, a fungi 2 of 17 metabolite [12]. Even though the high affinity towards this molecule was documented, the physiological significance of this function still remains uncertain [13][14][15]. To further investigate the function of this transporter on the single protein, the human OCTN1 was over-expressed in E. coli and its transport activity was assayed in proteoliposomes harboring the recombinant transporter.…”