Functional Properties of Organic Cation Transporter OCT1, Binding of Substrates and Inhibitors, and Presumed Transport Mechanism

Organic cation transporters (OCTs) of the SLC22 family mediate absorption, distribution and excretion of cationic drugs. The OCTs belong to the major facilitator superfamily (MFS) containing transporters with 12 pseudosymmetrically arranged transmembrane α-helices. Whereas most transporters of the MFS are substrate selective and secondary active, most transporters of the SLC22 family are polyspecifi c facilitative diffusion systems. Recently resolved crystal structures of MFS transporters indicate translocation via alternating access surpassing a state with substrate occlusion. After cloning of the rat transporters rOCT1 and rOCT2, the functional properties of these transporters have been investigated employing tracer uptake measurements, electrical measurements, voltage clamp fl uorometry, and substrate binding measurements. Extensive mutagenesis studies in rOCT1 were interpreted in frame of tertiary structures that were modeled according to lactose permease which belongs to the MFS. Considering rOCT1 and rOCT2 as OCT prototypes, and assuming that all transporters of the MFS undergo similar interhelical movements during transport, a model for the translocation mechanism of OCTs is proposed. The model suggests that two small organic cations bind to the innermost cleft of the outward-facing conformation of OCTs and that translocation can be performed when either one or two cations are loaded per transporter monomer. With this model recent experimental recent results concerning interaction of ligands at OCTs can be explained that have high biomedical impact for in vitro testing.