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

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.

scholarly journals Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology

2020 ◽  
Vol 21 (21) ◽  
pp. 7890 ◽  
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.

Structure and Function of Renal Organic Cation Transporters

Physiology ◽  
1998 ◽  
Vol 13 (1) ◽  
pp. 11-16 ◽  
Author(s):  
Hermann Koepsell ◽  
Andreas Busch ◽  
Valentin Gorboulev ◽  
Petra Arndt
Keyword(s):  
Plasma Membranes ◽  
Organic Cation ◽  
Structure And Function ◽  
Transport Systems ◽  
Organic Cations ◽  
Renal Tubules ◽  
Organic Cation Transporters ◽  
Cation Transporters ◽  
And Function

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.

Transport of Dicationic Drugs Pentamidine and Furamidine by Human Organic Cation Transporters

2008 ◽  
Vol 37 (2) ◽  
pp. 424-430 ◽  
Author(s):  
Xin Ming ◽  
Wujian Ju ◽  
Huali Wu ◽  
Richard R. Tidwell ◽  
James E. Hall ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters

Role of organic cation transporters in the ocular disposition of its intravenously injected substrate in rabbits: Implications for ocular drug therapy

2013 ◽  
Vol 116 ◽  
pp. 27-35 ◽  
Author(s):  
Jayabalan Nirmal ◽  
Anju Sirohiwal ◽  
Sundararajan Baskar Singh ◽  
Nihar Ranjan Biswas ◽  
Vasantha Thavaraj ◽  
...  
Keyword(s):  
Drug Therapy ◽  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters

The role of organic cation transporters (OCTs) in the transfer of metformin in the dually perfused human placenta

2010 ◽  
Vol 39 (1-3) ◽  
pp. 76-81 ◽  
Author(s):  
Kristiina Tertti ◽  
Ulla Ekblad ◽  
Tuija Heikkinen ◽  
Melissa Rahi ◽  
Tapani Rönnemaa ◽  
...  
Keyword(s):  
Human Placenta ◽  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters

Abstract 14035: Renal Tubular Secretion and Cardiac Distribution of Dofetilide is Dependent on MATE1 Function

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Muhammad Erfan Uddin ◽  
Yan Jin ◽  
Alice A Gibson ◽  
Ingrid M Bonilla ◽  
Cynthia A Carnes ◽  
...  
Keyword(s):  
Organic Cation ◽  
Tubular Secretion ◽  
Hek293 Cells ◽  
Delayed Rectifier ◽  
Organic Cation Transporters ◽  
Wild Type ◽  
Renal Tubular Secretion ◽  
Cation Transporters ◽  
Renal Tubular

Introduction: Dofetilide is a delayed rectifier potassium channel inhibitor used to treat patients with atrial fibrillation and flutter, and its use is associated with a risk of QT prolongation and Torsades de Pointes . The mechanisms involved in dofetilide’s renal tubular secretion and its uptake into cardiomyocytes remain unknown. Previously reported drug-drug interaction (DDI) studies suggest the involvement of organic cation transporters. Here, we investigated the contribution of organic cation transporters (OCT2 and MATE1) to the pharmacokinetics of dofetilide to gain insight into its DDI potential. Hypothesis: Based on known DDIs with dofetilide, we hypothesize that OCT2 and/or MATE1 play a key role in the inter-individual variability in pharmacokinetics and pharmacodynamics of dofetilide. Methods: In vitro and ex vivo transport kinetics of dofetilide were determined in HEK293 cells stably transfected with OCT2 or MATE1, and in isolated cardiomyocytes, respectively. In vivo studies were performed in wild-type, OCT2-, and MATE1-deficient mice (n=5) receiving dofetilide (5 mg/kg, p.o., 2.5 mg/kg, i.v.), with or without several contraindicated drugs. Dofetilide concentrations in plasma and urine were determined by UPLC-MS/MS. Results: In vitro studies demonstrated that dofetilide is a good substrate of MATE1 but not OCT2. Deficiency of MATE1 was associated with increased plasma concentrations of dofetilide and with a significantly reduced urinary excretion (3-fold in females and 5-fold in males, respectively). Dofetilide accumulation in cardiomyocytes was increased by 2-fold in MATE1-deficient females, and pre-incubation with the MATE1 inhibitor cimetidine significantly reduced dofetilide uptake in wild-type cardiomyocytes. Several contraindicated drugs listed in the dofetilide prescribing information, including cimetidine, ketoconazole, increased dofetilide plasma exposure in wild-type mice by >2.8-fold. Conclusion: Renal secretion of dofetilide is mediated by MATE1 and is highly sensitive to inhibition by many widely used prescription drugs that can cause clinically relevant DDIs. Deficiency of MATE1 also increases accumulation in the heart which may contribute to individual variation in response to dofetilide.

scholarly journals Lipid Bilayer Composition Affects Transmembrane Protein Orientation and Function

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Katie D. Hickey ◽  
Mary M. Buhr
Keyword(s):  
Lipid Bilayer ◽  
Lipid Composition ◽  
Protein Function ◽  
Transmembrane Protein ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Outer Leaflet ◽  
Lipid Environment ◽  
Protein Incorporation ◽  
And Function

Sperm membranes change in structure and composition upon ejaculation to undergo capacitation, a molecular transformation which enables spermatozoa to undergo the acrosome reaction and be capable of fertilization. Changes to the membrane environment including lipid composition, specifically lipid microdomains, may be responsible for enabling capacitation. To study the effect of lipid environment on proteins, liposomes were created using lipids extracted from bull sperm membranes, with or without a protein (Na+K+-ATPase or -amylase). Protein incorporation, function, and orientation were determined. Fluorescence resonance energy transfer (FRET) confirmed protein inclusion in the lipid bilayer, and protein function was confirmed using a colourometric assay of phosphate production from ATP cleavage. In the native lipid liposomes, ATPase was oriented with the subunit facing the outer leaflet, while changing the lipid composition to 50% native lipids and 50% exogenous lipids significantly altered this orientation of Na+K+-ATPase within the membranes.

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