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OCT1–3 function as uniporters (Fig. 2.2b), facilitating diffusion of substrates across the plasma membrane. Transport can be bidirectional, depending on substrate, and is driven by electrochemical gradients. The OCTs share several common features related to transport mechanism. First, modeling and mutational analysis suggest that OCTs follow an alternating‐access transport model. The substrate binds to the outward‐open conformation of the transporter, which induces a conformational change. Then the substrate–transporter complex passes a transient occluded state to the inward‐open conformation. Lastly, the substrate is released to the cytoplasm and the transporter returns to the outward open conformation [12] (Fig. 2.2a). The structural changes of OCTs during the transport cycle require a rigid body movement of the six N‐terminal TMDs against the six C‐terminal TMDs, and a hinge domain in TMD 11 is crucial for this movement [11, 14]. Second, the translocation of organic cations by OCTs is electrogenic and independent of sodium and chloride ions [11]. The net transport of organic cations is driven by the intracellular negative membrane potential and the concentration gradient. Positively charged cations are taken up into cells according to the electrochemical gradient, and this process is membrane sensitive. Artificially modulating the membrane potential by replacement of extracellular Na⁺ with K⁺ changes the rate of transport by OCTs [15]. Third, the transport direction of OCTs is bidirectional, and as noted, net transmembrane flux is dependent on the electrochemical gradient. In addition to cation influx, OCTs acting as efflux transporters have been demonstrated in multiple studies [1]. Fourth, OCT1‐3, defined as “poly‐specific” OCTs, can transport a variety of substrates with diverse molecular structures. As such, their substrates tend to have higher K _m values than those of the substrates for the more specific transporters, such as the neurotransmitter transporters (SLC6). In addition, OCT1–3 can be inhibited by a large number of compounds that are not transported. Common substrates of all OCTs are relatively low molecular mass (below 500 g/mol) and hydrophilic organic cations such as the prototypical cation tetraethylammonium (TEA), the neurotoxin MPP⁺, and the endogenous compound N‐methylnicotinamide (NMN). Several clinically important drugs have been shown to interact with all of the OCTs, including the antidiabetic drug metformin. Besides this, endogenous compounds such as the biogenic amine neurotransmitters (i.e., dopamine, epinephrine, norepinephrine, histamine, and serotonin) have been shown to interact with one or more OCT transporters [1]. Although the OCT family shows broad overlap in substrate specificity, there are examples of relatively isoform‐specific and species‐specific substrates and inhibitors. More details will be provided in the next section.