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Cationic compounds undergo transepithelial secretion through a two‐step process: entry across the basolateral membrane followed by exit across the apical surface [1, 2]. In 1994, the organic cation transporter 1 (Oct1) was cloned from rat kidneys, which provided initial insight into how positively charged molecules gain access into cells [3]. By 1999, the bacterial NorM transporter was classified as a “multidrug and toxic compound extrusion (MATE)” protein due to its ability to mediate resistance to cationic dyes and antibacterial drugs [4]. The sequence of NorM did not align with the three previously recognized classes of bacterial multidrug efflux proteins leading to the designation of a new family of MATE transporters.

By 2005, the human and mouse orthologs of the prokaryotic MATE transporters were first identified and characterized as the final step in the excretion of organic cations [5]. Screening the human genome yielded two orthologs on chromosome 17, denoted as hMATE1 (SLC47A1) and hMATE2 (SLC47A2) that were approximately 20% identical to the NorM antiporter. This discovery opened the field to exploring how cationic compounds exit mammalian cells through a multispecific transporter.