Abstract
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.
Highlights
The organic cation transporters are primarily members of the solute carrier 22 (SLC22) family, which itself belongs to the solute carrier (SLC) superfamily, the largest group of membrane transporters comprising 65 SLC families (SLC1–65) with more than 400 identified genes far [1]
The recognition of organic cation transporters (OCTs) as low affinity transporters of frequently prescribed drugs, such as several antibiotics and metformin, the flourishing of pharmacogenetics, and the development of rigorous drug–drug interaction studies for marketing approval have decisively contributed to elucidating the impact of the organ-specific and interorgan functions of these transporters and, in conjunction, their high pharmacological impact
With the exception of OCTN2, the understanding of the physio-pathological roles played by OCTs in humans is not fully understood
Summary
The organic cation transporters are primarily members of the solute carrier 22 (SLC22) family, which itself belongs to the solute carrier (SLC) superfamily, the largest group of membrane transporters comprising 65 SLC families (SLC1–65) with more than 400 identified genes far (for details on the SLC classification, we refer to the curated BioParadigms.org online SLC table) [1]. In the human SLC22 family, six organic cation transporters have been characterized in regard to their respective substrates. The SLC22A15 transporter that clusters with the other organic cation transporters has not been functionally characterized yet. This phylogeny was generated using the open access software Phylogeny.fr [9,10,11]. Prediction was generated with the Protter open access software from input transporters (OCTs).
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