CommentaryPhysiological and pharmacokinetic roles of H+/organic cation antiporters (MATE/SLC47A)☆
Introduction
The secretion of drugs and xenobiotics is an important physiological function of the renal proximal tubules. Transport studies using isolated membrane vesicles and cultured renal epithelial cells have suggested that the renal tubular secretion of cationic substances involves the concerted actions of two distinct classes of organic cation transporters: one facilitated by the transmembrane potential difference at the basolateral membranes and the other driven by the transmembrane H+ gradient (H+/organic cation antiporter) at the brush-border membranes [1], [2], [3]. A prototype substrate, tetraethylammonium (TEA), has been used for the functional characterization of these organic cation transport systems in the kidney.
The first membrane potential-dependent organic cation transporter (OCT1) was isolated from the rat kidney in 1994 [4]. Subsequently, we isolated rat (r) OCT2 cDNA [5]. Currently, there are three isoforms (OCT1-3/SLC22A1-3), and the physiological and pharmacokinetic roles of these transporters have been characterized from various standpoints. There are several excellent reviews documenting the historical developments and recent progress in the understanding of OCT families [6], [7], [8], [9], [10].
On the other hand, the molecular identification of H+/organic cation antiport systems has not been progressed. Although several candidates for H+/organic cation antiporters such as OCT2p [11], OCTN1 (SLC22A4) [12], [13], and OCTN2 (SLC22A5) [14] have been proposed, all reports lacked direct and enough evidences to support the biochemical and physiological characteristics of H+/organic cation antiport systems. For example, Tamai et al. [12] reported that OCTN1 may serve as a H+/organic cation antiporter, because it can mediate the pH-dependent transport of TEA, and is localized at the brush-border membranes of renal proximal tubules. However, the following findings may not support that OCTN1 functions as classical H+/organic cation antiport systems: (i) TEA transport by OCTN1 is electrogenic [13], whereas TEA transport by classical H+/organic cation antiport systems is electroneutral [15], (ii) the renal expression level of OCTN1 is relatively weak [16], and (iii) OCTN1 has been demonstrated to mediate the Na+-dependent transport of the fungal antioxidant, ergothioneine with much greater catalytic efficiency than for TEA [17], [18]. Thus, no candidate fully satisfies the characteristics of H+/organic cation antiport systems, and the true molecular nature of this transporter has been veiled for a long time.
Section snippets
Cloning of MATE/SLC47
In 1998, Tsuchiya and his colleagues [19] identified a novel multidrug transporter in Vibrio parahaemolyticus and its homolog in Escherichia coli, named NorM and YdhE, respectively. These two transporters were assigned to a new family of transporters designated as the multidrug and toxin extrusion (MATE) family [20]. Although the overall properties of the MATE family in bacteria have not been elucidated, some transporters mediated the H+- or Na+-coupled export of cationic drugs [20], [21], [22].
hMATE2, hMATE2-K, and hMATE2-B
During the course of our cloning process, the original hMATE2 cDNA could not be isolated, alternatively cDNAs for hMATE2-K and hMATE2-B were isolated [24]. As compared to the original hMATE2 cDNA, the hMATE2-K cDNA lacked 108 base pair (bp) in exon 7, and the hMATE2-B cDNA contained an insertion of 46 bp in exon 7. The open reading frame of the hMATE2-K cDNA was 1698 bp long, coding for a 566-amino acid protein. That of hMATE2-B was 660 bp long and encoded a 220-amino acid protein. hMATE2-K, but
Structure
Human, mouse, rat, and rabbit MATE1 consists of 570, 532, 566, and 568 amino acid residues, respectively [23], [25], [26], [27]. Phylogenetic trees of MATE1 and MATE2-K from various species are shown in Fig. 1A. A comparison of the multiple alignments of these MATE1 sequences revealed a similar overall homology except for the C-terminus of mMATE1 (Fig. 1B). Instead of the original mMATE1 (AAH31436, mMATE1a), another protein with 567 amino acid residues was registered in the NCBI database
Tissue distribution and membrane localization
hMATE1 mRNA is primarily expressed in the kidney, and is also expressed in the adrenal grand, testis, skeletal muscle and liver [23], [24]. Immunohistochemical analyses showed the hMATE1 protein to be localized at the apical region of the proximal [23], [24] and distal convoluted tubules [23] of the kidney.
rMATE1 is also strongly expressed in the kidney by Northern blot analyses [25], [26]. Real-time PCR analyses revealed that rMATE1 mRNA is highly expressed in the kidney and placenta, and
Driving force
MATE1 exhibited the pH-dependent transport of TEA in cellular uptake and efflux studies, and intracellular acidification through pretreatment with NH4Cl stimulated TEA transport [23], [25], [26], [27], [28], [31], [32], suggesting that MATE1 utilized an oppositely directed H+ gradient as a driving force. Uptake studies using plasma membrane vesicles from rMATE1-stably expressing cells definitively indicated that an oppositely directed H+ gradient serves as a driving force for rMATE1 [34].
Comparison with OCTs
In the case of the basolateral organic cation transporters (OCTs), it has been reported that various factors such as development [44], gender [45], [46], chronic renal failure after 5/6 nephrectomy [47], and diabetes [48] affected the expression of OCTs in the kidney. For example, the expression level of rat OCT2, but not OCT1 or OCT3, in the kidney was much higher in males than females [45]. The treatment of male and female rats with testosterone significantly increased rOCT2 expression in the
Pharmacokinetic and toxicological roles
In general, efficient renal secretion of organic cations could be achieved by the efficient interplay between OCT2 and MATE1 and/or MATE2-K in human renal tubular epithelial cells. Cationic drugs such as cimetidine, metformin, and procainamide, and endogenous organic cations such as NMN recognized by both transporters were mainly excreted into the urine (Fig. 3A). These transporters also control the exposure of renal cells to nephrotoxic drugs and thereby are responsible for xenobiotic-induced
Summary and perspective
In this commentary, we described recent findings about the MATE/SLC47A family regarding their structure, expression, transport function, and regulation (Table 1). Most of the molecular characteristics of MATEs are consistent with the biochemical properties of renal H+/organic cation antiport systems assessed by classical assays using in vitro brush-border membrane vesicles and cultured renal epithelial cells. With respect to the roles of MATEs, their pharmacokinetic significance including renal
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This work was supported in part by the 21st Century Center of Excellence (COE) program “Knowledge Information Infrastructure for Genome Science”, a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a Grant-in-Aid for Research on Advanced Medical Technology from the Ministry of Health, Labor and Welfare of Japan.