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3 MULTIDRUG AND TOXIN EXTRUSION PROTEINS
Lauren M. Aleksunes1, Victoria Woo1, and Melanie S. Joy2
1 Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA
2 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
3.1 INTRODUCTION
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.
3.2 TISSUE AND SUBCELLULAR DISTRIBUTION
3.2.1 Tissue Distribution
Human MATE1 (denoted as hMATE1) is enriched in the kidneys, liver, adrenal glands, choroid plexus, and skeletal muscle [5–7]. Similarly, hMATE1 has been detected in salivary glands [8], adipocytes [9], retinal pigment epithelial cells [10], lung bronchial and bronchiolar epithelial cells [11], and dermal fibroblasts [12]. Within the brain, hMATE1 mRNA localizes to capillary endothelial cells [13]. Initial studies of the tissue distribution of mouse Mate1 (denoted as mMate1) revealed predominant expression in kidneys and liver [5, 14]. Additional profiling across mouse tissues extended the distribution of mMate1 protein to include heart, stomach, small intestine, bladder, thyroid, gland, testes, and adrenal gland [15]. Rat Mate1 (denoted as rMate1) was cloned in 2006 and shown to be highly expressed in kidneys, as well as liver, placenta, pancreas, and spleen [16–19].
In contrast, hMATE2 is largely restricted to the kidneys [5]. An alternative kidney splice variant (denoted as hMATE2‐K) was cloned and shown to lack 108 bp [6]. This region codes for an additional 36 amino acids within a predicted intracellular loop—a region that is not observed in mMate2 or rabbit Mate2‐K [20]. Overall, there is 94% identity between hMATE2 and hMATE2‐K and ~50% amino acid identity with hMATE1. Both hMATE2 and hMATE2‐K are expressed within human kidneys [21]. When purified and reconstituted in proteoliposomes, hMATE2 and hMATE2‐K exhibit similar kinetic properties [21]. In addition, a lesser described hMATE2‐B variant has been found in the brain, but this isoform appears to lack transport activity [6].
While there is moderate‐to‐high sequence identity among MATE1/Mate1 orthologs, there appears to be greater divergence for MATE2 with low sequence identity between hMATE2 and mMate2 (38%) [22]. This becomes more evident when viewing the phylogenetic tree for mammalian MATE‐type transporters [22](Fig. 3.1). MATE1 isoforms are found in Class I, whereas primate MATE2 and dog Mate2 are considered members of Class II. Mouse and rat Mate2 are found in Class III [22].
3.2.2 Subcellular Localization
In polarized cells, Mate/MATE transporters localize to apical surfaces including hepatic canalicular and tubular brush border membranes (Fig. 3.2) [5, 6, 23]. This localization coupled with the lower pH of luminal spaces leads to the secretion of organic cations in vivo. Sequestration of organic cations in intracellular vesicles or endosomes can also be accomplished by MATE1 working in concert with the V‐type H+‐ATPase [24]. While these MATE1‐expressing endosomes may alter the intracellular distribution of organic cations, they do not appear to influence the subsequent apical efflux. In other cell types, such as serous and mucous acinar