Structure and Function of Renal Organic Cation Transporters

Polyspecific transport systems in the kidney mediate the excretion and reabsorption of organic cations. Electrogenic import systems and electroneutral export systems in the basolateral and luminal plasma membranes of proximal renal tubules are involved. Two subtypes of electrogenic import systems have been cloned from rats and humans and functionally characterized.

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Hepatocellular uptake of organic cations by the organic anion transporting polypeptides (Oatp1, Oatp2 and OATP-A) and the organic cation transporters (rOCT1 and hOCT1)

Journal of Hepatology ◽

10.1016/s0168-8278(00)80786-2 ◽

2000 ◽

Vol 32 ◽

pp. 118

Author(s):

J.E. van Montfoort ◽

B. Stieger ◽

H. Koepsell ◽

M. Müller ◽

G.M.M. Groothuis ◽

...

Keyword(s):

Organic Cation ◽

Organic Anion ◽

Organic Cations ◽

Organic Cation Transporters ◽

Organic Anion Transporting Polypeptides ◽

Cation Transporters

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Deficiency in the Organic Cation Transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in Mice Abolishes Renal Secretion of Organic Cations

Molecular and Cellular Biology ◽

10.1128/mcb.23.21.7902-7908.2003 ◽

2003 ◽

Vol 23 (21) ◽

pp. 7902-7908 ◽

Cited By ~ 177

Author(s):

Johan W. Jonker ◽

Els Wagenaar ◽

Sven van Eijl ◽

Alfred H. Schinkel

Keyword(s):

Organic Cation ◽

Basolateral Membrane ◽

Hepatic Uptake ◽

The Body ◽

Organic Cations ◽

Organic Cation Transporters ◽

Renal Secretion ◽

Double Knockout ◽

Intestinal Excretion ◽

Cation Transporters

ABSTRACT The polyspecific organic cation transporters 1 and 2 (Oct1 and -2) transport a broad range of substrates, including drugs, toxins, and endogenous compounds. Their strategic localization in the basolateral membrane of epithelial cells in the liver, intestine (Oct1), and kidney (Oct1 and Oct2) suggests that they play an essential role in removing noxious compounds from the body. We previously showed that in Oct1 −/− mice, the hepatic uptake and intestinal excretion of organic cations are greatly reduced. Since Oct1 and Oct2 have extensively overlapping substrate specificities, they might be functionally redundant. To investigate the pharmacologic and physiologic roles of these proteins, we generated Oct2 single-knockout and Oct1/2 double-knockout mice. Oct2 −/− and Oct1/2 −/− mice are viable and fertile and display no obvious phenotypic abnormalities. Absence of Oct2 in itself had little effect on the pharmacokinetics of tetraethylammonium (TEA), but in Oct1/2 −/− mice, renal secretion of this compound was completely abolished, leaving only glomerular filtration as a TEA clearance mechanism. As a consequence, levels of TEA were substantially increased in the plasma of Oct1/2 −/− mice. This study shows that Oct1 and Oct2 together are essential for renal secretion of (small) organic cations. A deficiency in these proteins may thus result in increased drug sensitivity and toxicity.

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Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology

International Journal of Molecular Sciences ◽

10.3390/ijms21217890 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7890 ◽

Cited By ~ 2

Author(s):

Sophia L. Samodelov ◽

Gerd A. Kullak-Ublick ◽

Zhibo Gai ◽

Michele Visentin

Keyword(s):

Plasma Membrane ◽

Organic Cation ◽

Chemical Exchange ◽

Therapeutic Index ◽

Organic Cation Transporter ◽

Organic Cation Transporters ◽

Waste Products ◽

Carnitine Transporter ◽

Cation Transporters ◽

And Function

Individual cells and epithelia control the chemical exchange with the surrounding environment by the fine-tuned expression, localization, and function of an array of transmembrane proteins that dictate the selective permeability of the lipid bilayer to small molecules, as actual gatekeepers to the interface with the extracellular space. Among the variety of channels, transporters, and pumps that localize to cell membrane, organic cation transporters (OCTs) are considered to be extremely relevant in the transport across the plasma membrane of the majority of the endogenous substances and drugs that are positively charged near or at physiological pH. In humans, the following six organic cation transporters have been characterized in regards to their respective substrates, all belonging to the solute carrier 22 (SLC22) family: the organic cation transporters 1, 2, and 3 (OCT1–3); the organic cation/carnitine transporter novel 1 and 2 (OCTN1 and N2); and the organic cation transporter 6 (OCT6). OCTs are highly expressed on the plasma membrane of polarized epithelia, thus, playing a key role in intestinal absorption and renal reabsorption of nutrients (e.g., choline and carnitine), in the elimination of waste products (e.g., trimethylamine and trimethylamine N-oxide), and in the kinetic profile and therapeutic index of several drugs (e.g., metformin and platinum derivatives). As part of the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations, this article critically presents the physio-pathological, pharmacological, and toxicological roles of OCTs in the tissues in which they are primarily expressed.

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Identification of the Tetraspanin CD9 as an Interaction Partner of Organic Cation Transporters 1 and 2

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555219859837 ◽

2019 ◽

Vol 24 (9) ◽

pp. 904-914

Author(s):

Beatrice Snieder ◽

Sabine Brast ◽

Alexander Grabner ◽

Sven Buchholz ◽

Rita Schröter ◽

...

Keyword(s):

Cellular Localization ◽

Organic Cation ◽

Resonance Energy Transfer ◽

Resonance Energy ◽

Potential Interaction ◽

Organic Cation Transporters ◽

Neurotransmitter Activity ◽

Cation Transporters ◽

Split Ubiquitin ◽

And Function

Organic cation transporters (OCTs) are membrane proteins with relevant physiological (because they accept neurotransmitters as substrate) and pharmacological (because of their interaction with drugs) roles. The human OCTs hOCT1 ( SLC22A1/hOCT1) and hOCT2 ( SLC22A2/hOCT2) are highly expressed in hepatic (hOCT1) and in renal and neuronal tissue (hOCT2), suggesting a possible role in modulating neurotransmitter activity in the liver, kidney, and brain, and their clearance from the blood. Even though there are several data demonstrating that OCTs are regulated under various patho-physiological conditions, it remains largely unknown which proteins directly interact with OCTs and thereby influence their cellular processing, localization, and function. In this work, using a mating-based split-ubiquitin yeast two-hybrid system, we characterized the potential interactome of hOCT1 and 2. It became evident that these OCTs share some potential interaction partners, such as the tetraspanins CD63 and CD9. Moreover, we confirmed interaction of hOCT2 with CD9 by fluorescence-activated cell sorting coupled with Förster resonance energy transfer analysis. Together with other proteins, tetraspanins build “tetraspanins webs” in the plasma membrane, which are able to regulate cellular trafficking and compartmentalization of interacting partners. While CD63 was demonstrated to mediate the localization of the hOCT2 to the endosomal system, we show here that co-expression of hOCT2 and CD9 led to strong cell surface localization of the transporter. These data suggest that tetraspanins regulate the cellular localization and function of OCTs. Co-localization of CD9 and hOCT was confirmed in tissues endogenously expressing proteins, highlighting the potential biological relevance of this interaction.

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