Am J Physiol Cell Physiol Journal of Neurophysiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Cell Physiol 294: C1074-C1078, 2008. First published February 27, 2008; doi:10.1152/ajpcell.00504.2007
0363-6143/08 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/4/C1074    most recent
00504.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Matsumoto, T.
Right arrow Articles by Moriyama, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Matsumoto, T.
Right arrow Articles by Moriyama, Y.

MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Role of glutamate residues in substrate recognition by human MATE1 polyspecific H+/organic cation exporter

Takuya Matsumoto, Takuji Kanamoto, Masato Otsuka, Hiroshi Omote, and Yoshinori Moriyama

Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Submitted 25 October 2007 ; accepted in final form 25 February 2008


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Human multidrug and toxic compound extrusion 1 (hMATE1) is an electroneutral H+/organic cation exchanger responsible for the final excretion step of structurally unrelated toxic organic cations in kidney and liver. To elucidate the molecular basis of the substrate recognition by hMATE1, we substituted the glutamate residues Glu273, Glu278, Glu300, and Glu389, which are conserved in the transmembrane regions, for alanine or aspartate and examined the transport activities of the resulting mutant proteins using tetraethylammonium (TEA) and cimetidine as substrates after expression in human embryonic kidney 293 (HEK-293) cells. All of these mutants except Glu273Ala were fully expressed and present in the plasma membrane of the HEK-293 cells. TEA transport activity in the mutant Glu278Ala was completely absent. Both Glu300Ala and Glu389Ala and all aspartate mutants exhibited significantly decreased activity. Glu273Asp showed higher affinity for cimetidine, whereas it has reduced affinity to TEA. Glu278Asp showed decreased affinity to cimetidine. Both Glu300Asp and Glu389Asp had lowered affinity to TEA, whereas the affinity of Glu389Asp to cimetidine was fourfold higher than that of the wild-type transporter with about a fourfold decrease in Vmax value. Both Glu273Asp and Glu300Asp had altered pH dependence for TEA uptake. These results suggest that all of these glutamate residues are involved in binding and/or transport of TEA and cimetidine but that their individual roles are different.

multidrug and toxic compound extrusion; mutagenesis

THE EXPORT OF ORGANIC ELECTROLYTES with extremely diverse chemical structures into the urine and bile plays an essential role in elimination of toxic substances of exogenous and endogenous origin from the body. The export occurs through transepithelial transport across the basolateral and luminal membranes of renal tubular cells and across the sinusoidal membranes and bile canaliculi of hepatocytes (17, 19, 21). Metabolic organic cations (OCs) or xenobiotic OCs in the blood are taken up by organic cation transporter 2 (OCT2) at basolateral membrane of renal tubular cells and by OCT1 at sinusoidal membranes and are then released at luminal membranes or canaliculi through an electroneutral H+/OC exchanger(s). Recently, the transporter corresponding to an electroneutral H+/OC exchanger was identified as a multidrug and toxic compound extrusion (MATE)-type transporter (11, 15, 16).

The MATE transporter family is the most recently identified multidrug resistance-conferring protein family in bacteria, and it mediates polyspecific H+- or Na+/cationic drug exchange (2, 5, 11, 15). We have cloned the cDNA encoding two human orthologues of the bacterial MATE-type transporter and named them hMATE1 (SLC47A1) and hMATE2 (SLC47A2) (11, 16). hMATE1 is predominantly expressed in luminal membranes of renal tubular cells and bile canaliculi (11, 15, 16). In contrast, hMATE2 and its splicing variant hMATE2K are more specific to kidney (10, 11, 16). MATE transporters from other mammalian species have been also identified and characterized (3, 4, 8, 14, 19, 24). Overall, these mammalian MATE-type transporters have been shown to act as H+/OC exporters and are regarded as novel drug exporters.

One of the most significant properties of the mammalian MATE transporters is their great ability to recognize compounds with diverse molecular masses, structures, and hydrophobicity as substrates (11, 15). However, little is known about the molecular mechanism of substrate recognition. When the glutamate residue at position 273 of hMATE1, the only amino acid residue conserved in all eukaryotic MATE families (11, 15), was changed to glutamine, the resultant mutant hMATE1 completely lacked TEA transport activity, suggesting the importance of this residue in transport and/or substrate binding (16). Since the preferred substrates of MATE transporters are cationic in nature, the negatively charged form of this acidic residue may form ionic interactions with OCs. Involvement of acidic amino acid residues is also suggested in chemical modification experiments on brush border membrane vesicles using dicyclohexylcarbodiimide (7). Since several glutamate residues are conserved in the transmembrane domains of mammalian MATE-transporters, we introduced mutations in these residues and investigated the transport activity of the resulting mutant proteins. Here we show that mutation of these glutamate residues altered substrate recognition and pH dependence, providing evidence for the involvement of these glutamate residues in binding and/or transport of OCs.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Construction of mutant hMATE1. Point mutations were introduced into the wild-type hMATE1 by means of the overlap extension method (6). The following oligonucleotides were used for generating the mutants: Glu273Ala, 5'-GGCCCACCACGCCATGCACAGCATGAGC-3'; Glu273Asp, 5'-GGCCCACCAGTC CATGCACAGCATGAGC-3'; Glu278Ala, 5'-GGAAGCTCCCGAC CGCATAGGCCCACCAC-3'; Glu278Asp, 5'-GGAAGCTCCCGA CATCATAGGCCCACCAC-3'; Glu300Ala, 5'-GGCCAGTGCATACACGATGGACTGAGCG-3'; Glu300Asp, 5'-GGCCAGATCATACACGATGGACTGAGCG-3'; Glu389Ala, 5'-GCAAGCAAGAGCGGCAAAGAGGTGGGAA-3'; and Glu389Asp, 5'-GCAAGCAAGAGCGTCAAAGAGGTGGGAA-3'.

Expression and transport assay. cDNA encoding wild-type or mutant hMATE1 was subcloned into the expression vector pcDNA3.1(+) (Invitrogen). These plasmids, pcDNA3.1/hMATE1-wild or pcDNA3.1/hMATE1-mutant, were used to transfect HEK-293 cells by lipofection using TransIT reagent (Mirus). HEK-293 cells (1.0 x 105 cells/well) were grown on 24-well plates containing DMEM supplemented with 10% fetal calf serum, 100 µg/ml penicillin, and 0.25 µg/ml streptomycin at 37°C under 5% CO2, as described previously (3). Twenty-four hours later, 0.5 µg of pcDNA3.1/hMATE1-wild, pcDNA3.1/hMATE1-mutant, or pcDNA3.1 was used for transfection. The cells were grown for a further 2 days, harvested, and suspended in transport assay medium containing 125 mM NaCl, 4.8 mM KCl, 5.6 mM D-glucose, 1.2 mM CaCl2, 1.2 mM KH2PO4, 1.2 mM MgSO4, and 25 mM Tricine (pH 8.0). The cells were incubated at 37°C for 5 min; the transport assay was initiated by adding [1-14C]TEA (0.5 MBq/µmol) (3.7 kBq/assay; Perkin Elmer Life Science) to a final concentration of 50 µM. N-methyl-[3H]MPP (1.85 MBq/µmol; PerkinElmer Life Science) and N-methyl-[3H]cimetidine (18.5 MBq/µmol; GE Healthcare,) were also used as substrates for the transport assay; the final concentrations used were 10 and 1 µM, respectively. After 5–20 min incubation at 37°C, the cells were washed twice with 500 µl ice-cold assay medium. The cells were lysed with 400 µl 0.5 N NaOH, and the radioactivity was counted.

Immunohistochemistry. Immunohistochemical analysis was performed by indirect immunofluorescence microscopy as described previously (3, 4). In brief, cultured cells on poly-L-lysine-coated coverslips were fixed with 4% paraformaldehyde in phosphate-buffered saline (PBS) for 30 min. After being washed with PBS, the specimens were incubated for 20 min each in PBS containing 0.1% Triton X-100 followed by PBS containing 2% goat serum and 0.5% bovine serum albumin. The specimens were incubated with anti-hMATE1 antiserum (16) diluted 1,000-fold with PBS containing 0.5% bovine serum albumin for 1 h at room temperature. Samples were washed four times with PBS and then reacted with Alexa Fluor488-labeled anti-rabbit IgG (2 µg/ml) for 1 h at room temperature. Finally, the immunoreactivity was examined under either an Olympus BX60 microscope or an Olympus FV300 confocal laser microscope.

Preparation of membrane samples. Membranes of HEK-293 cells were isolated as follows. Cultured cells (2.0 x 107 cells) were suspended in ice-cold 20 mM MOPS-Tris (pH 7.0) containing 0.3 M sucrose, 5 mM EDTA, and protease inhibitors (pepstatin A and leupeptin at 5 µg/ml each), homogenized, and centrifuged at 800 g for 8 min at 4°C. The postnuclear supernatant was centrifuged at 100,000 g for 1 h at 4°C. The pellet was suspended in the same buffer, solubilized with dissociation buffer containing SDS, and used for polyacrylamide gel electrophoresis in the presence of SDS.

Miscellaneous procedures. Polyacrylamide gel electrophoresis in the presence of SDS and Western blotting were performed as described previously (3, 16). Protein concentration was determined with the Bio-Rad protein assay using bovine serum albumin as a standard.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
hMATE1 has four conserved glutamate residues in the transmembrane (TM) helices 7, 8, and 10 (Fig. 1A) . Glu273 in TM7 is the only amino acid residue conserved among all eukaryotic and some prokaryotic members of the MATE family. Glu278 in TM7 is conserved in the most of eukaryotes with the exception of subfamily in plant MATEs. Glu300 in TM8 is conserved in most vertebrates. Glu389 in TM10 is well conserved as Glu or Asp in eukaryotes but not in subfamily in plant MATEs.


Figure 1
View larger version (42K):
[in this window]
[in a new window]

  		Fig. 1. Preparation and expression of human multidrug and toxic compound extrusion 1 (hMATE1) mutants. A: conserved amino acid residues (*) in the transmembrane domains of the MATE1 subfamily. The positions of mutations are indicated. B: expression and localization of hMATE1 in human embryonic kidney 293 (HEK-293) cells were examined by indirect immunofluorescence microscopy using anti-hMATE1 antibody. Bar, 10 µm. C: expression of mutant hMATE1s as revealed by Western blotting. Membranes of HEK-293 cells expressing wild-type and mutant hMATE1 were subjected to electrophoresis on an 11% polyacrylamide gel. After the proteins were transferred to nitrocellulose membrane and incubated with anti-hMATE1 antibody, the immunoreactive proteins were visualized using an ECL detection kit (Amersham Biosciences).

 
We replaced all of these glutamate residues with alanine and aspartate and expressed the mutant hMATE1 in HEK-293 cells to evaluate functional roles in substrate recognition and transport. Immunofluorescence microscopy with anti-hMATE1 antibody revealed that all mutants except for Glu273 mutated to Ala (Glu273Ala) were expressed and localized to the plasma membrane in HEK-293 cells (Fig. 1B). Western blot analysis of the membrane fractions from HEK-293 cells confirmed the expression of the mutant hMATE1 as a ~62-kDa polypeptide in the cells (Fig. 1C). In contrast, Glu273Ala mutant was not expressed or was expressed at levels below the detection limit of our experimental system (Fig. 1, B and C).

TEA uptake by HEK-293 cells expressing mutant hMATE1 was measured. TEA uptake activity was completely absent from the Glu278Ala mutant (Fig. 2A). No uptake activity was also observed in Glu273Ala mutant (Fig. 2A), but this is because of undetectable expression of the mutant (Fig. 1, B and C). The Glu300Ala and Glu389Ala mutants showed around 48% and 16% of the activity of the wild-type transporter, respectively (Fig. 2A). Substitution of the glutamate to aspartate changed the position of the carboxyl group while retaining the net negative charge. As shown in Fig. 2B, all Glu-to-Asp substitution mutants exhibited significantly decreased activity with the order being Glu273 < Glu389 < Glu278 < Glu300. These results suggested that all Glu residues tested were somehow involved in TEA uptake, and, in particular, Glu273 and Glu278 had critical roles in TEA uptake.


Figure 2
View larger version (16K):
[in this window]
[in a new window]

  		Fig. 2. Time course of TEA uptake by wild-type and mutant hMATE1. A: tetraethylammonium (TEA; 50 µM) uptake by HEK-293 cells expressing wild-type and Ala mutants was measured at pH 8.0. Reactions were started by the addition of radiolabeled TEA, and the amount of TEA taken up by HEK-293 cells was measured. TEA uptake by HEK-293 cells transfected with a control plasmid (pcDNA3.1) was subtracted. B: TEA uptake by Asp mutants was measured as in A. Error bars are SDs of 3–6 samples.

 
The substrate specificity of the four aspartate substitution mutants was measured using TEA, methylphenylpyridinium (MPP), and cimetidine because of their different hydrophobicities, mode of interactions, and affinity to MATE transporters (9, 22). As shown in Fig. 3, the Glu273Asp mutant showed the lowest transport activity for all three substrates, suggesting functional importance of this residue. In the case of the Glu278Asp mutant, cimetidine and MPP uptakes were very low, whereas TEA uptake was less affected in this mutant. We determined the kinetic parameters for TEA and cimetidine uptake in both the Glu273Asp and Glu278Asp mutants (Table 1). The apparent Km for TEA uptake by Glu273Asp mutant significantly increased, and its Vmax value decreased to 41% of that of the wild-type protein. The Km was not significantly altered by the Glu278Asp mutant, but the Vmax for TEA uptake decreased to 49% of that of the wild-type protein. When cimetidine was used as a substrate, the corresponding Km of the Glu273Asp mutant decreased by almost sevenfold, with a dramatic loss of Vmax value, which was only 2.5% of that of the wild-type hMATE1. The Km of the Glu278Asp mutant increased about threefold, with a Vmax equivalent to 39% of that of the wild-type hMATE1. Thus its substrate selectivity toward TEA and cimetidine was significantly changed in comparison to that of the wild-type transporter, suggesting a critical role of Glu273 and Glu278 in the transport of TEA and cimetidine.


Figure 3
View larger version (16K):
[in this window]
[in a new window]

  		Fig. 3. Effect of mutations on substrate preference. TEA (50 µM), cimetidine (1 µM), and methylphenylpyridinium (MPP; 10 µM) uptakes were measured at pH 8.0. Activity relative to that of the wild type (WT) is shown. TEA, cimetidine, and MPP uptakes by HEK-293 cells expressing the wild-type protein were 1.30 nmol/mg, 58.6 pmol/mg, and 0.89 nmol/mg, respectively. Data are means ± SD; n = 3–6. Significant differences between TEA uptake and other substrates were calculated: *P < 0.1, **P < 0.01, ***P < 0.001.

 

View this table:
[in this window]
[in a new window]

  		Table 1. Kinetic parameters of TEA and cimetidine uptake by wild-type and mutant hMATE1

 
Substrate selectivity was also significantly altered in the Glu300Asp and Glu389Asp mutants; the uptake of cimetidine and MPP was higher than that of the Glu278Asp mutant (Fig. 3). Kinetic studies indicated that the Km for TEA of the Glu300Asp and Glu389Asp mutants increased about fourfold (Table 1). The Vmax for TEA uptake of these two mutants decreased to 48% and 70% of that of the wild-type protein, respectively (Table 1). These results suggest that both amino acid residues contribute to the binding and/or transport of TEA. In contrast, Glu389Asp mutant exhibited a decreased Km for cimetidine, with decreased Vmax values, suggesting a distinct interaction of the mutant to cimetidine.

Finally, we tested the pH dependence of TEA uptake, since the protonation status of these glutamate residues would be important for substrate recognition and transport. TEA uptake by wild-type MATE1 was markedly stimulated between pH 7.0 and 8.0, as reported previously (Fig. 4; see also ref. 16). A similar tendency was observed in the Glu278Asp, Glu389Ala, and Glu389Asp mutants, although these mutants were less sensitive to inhibition by pH values >8.0 (Fig. 4). Glu273Asp mutant had altered pH dependence. This mutant did not show any significant TEA uptake below pH 7.5 and exhibited little activity at alkaline pH with shifted pH optimum. The Glu278Ala mutant did not exhibit any activity at various pH conditions tested. The Glu300Ala mutant exhibited altered pH profile. In this case, pH optimum was shifted to 8.5, and activity was slightly lower at further alkaline pH. The Glu300Asp mutant also showed altered pH dependence. It retained wild-type activity up to pH 7.0, but in contrast with that of the wild-type MATE1, the uptake rate remained relatively constant up to approximately pH 8.0. Above pH 8.0, the uptake decreased sharply.


Figure 4
View larger version (12K):
[in this window]
[in a new window]

  		Fig. 4. pH dependence of TEA uptake by wild-type and mutant hMATE1. A: TEA (50 µM) uptake by wild-type and alanine mutants was measured at the indicated pH as described in MATERIALS AND METHODS. B: TEA uptake by Asp mutants was measured as in A. Data are means ± SD; n = 3–6.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Human MATE1 is principally involved in the excretion of structurally unrelated OCs and xenobiotics as metabolic waste products through OC/H+ exchange in the liver and kidney. Since the polyspecific nature of this transporter is of primary importance to excretion, systematic mutational analysis was carried out to determine functional contribution of specific amino acid residues to substrate recognition and transport in the present study. We focused on glutamate residues conserved in transmembrane region of hMATE1, because such acidic residues can be expected to interact with various OCs as transport substrates.

Our results clearly indicated that Glu273, Glu278, Glu300, and Glu389 are important for substrate recognition and/or transport. Although Glu273Ala mutant was not expressed in HEK-293 cells, our previous study showed that Glu273Gln mutant completely lost TEA transport activity without affecting expression in HEK-293 cells (16). Deleterious effect of glutamine and aspartate mutants showed functional importance of Glu273. The Asp mutations had different effects on TEA and cimetidine uptake. The Km for TEA was increased in the Glu273Asp, Glu300Asp, and Glu389Asp mutants, and the Km for cimetidine was increased in the Glu278Asp mutant. The apparent decrease in substrate affinity caused by the Asp replacements suggests that the glutamate residues at these positions are required for high-affinity binding, that Glu278 contributes to the recognition of cimetidine, and that Glu273, Glu300, and Glu389 contribute to TEA recognition. It is reasonable to suppose that these glutamate residues are located in the substrate binding pocket of hMATE1 and that substrate- and amino acid residue-dependent multiple interaction may explain how MATE transporter recognizes structurally unrelated OCs as substrates. Of course, the possibility that mutation-derived conformational change of hMATE1 affected their transport activity could not be excluded. It is noteworthy that the bacterial multidrug transporter AcrB uses a similar strategy to recognize the diverse structures of drugs: minocycline interacts with Asn274, Phe178, and Phe615, and doxorubicin interacts with Gln176, Phe615, and Phe617 (12).

Since hMATE1 is an electroneutral OC/H+ exchanger, an amino acid residue(s) that participates in H+ translocation during transport of OCs should exist. Identification of such amino acid residues(s) must be another important issue, and the four glutamate residues should be candidates. Among the four glutamate residues in the transmembrane region, however, Glu300 and Glu389 are not involved in H+ transport, since the respective alanine mutants retained substantial TEA transport activity. Because Glu273 is conserved in all MATE members and its mutation severely affected transport activity irrespective of type substrate (16) (Figs. 2 and 3), this residue could be a candidate for the H+ carrier. It is also possible that Glu278 is involved in the H+ translocation, since Glu278Ala mutant lost the transport activity at any pH condition tested (Fig. 4A).

It is noteworthy that the bacterial multidrug transporter EmrE contains only one charged residue in the transmembrane region, Glu14, and that this glutamate residue is essential for H+ translocation and substrate binding (13). An Asp mutation at this position in EmrE resulted in the altered pH dependence of tetraphenyl phosphonium binding and transport (13, 18, 23). The properties of Glu273Asp and Glu278Asp mutants of hMATE1 are similar to those of the Glu14Asp mutant of EmrE, supporting the idea for participation of these residues in H+ translocation.

Besides glutamate residues, histidine residues, namely, His139 and His386, located in the transmembrane region are also candidates for the site(s) of H+ translocation. However, His139 is not conserved at all, and His386 is conserved only in the mammalian and chicken MATE families. Furthermore, TEA transport activity was still present after replacement of the His386 counterpart in rat MATE1 with glutamine (1). Thus these histidine residues are most likely not proton carriers. Of course, the possibility that these histidine residues form a salt bridge with the four Glu residues and are involved in the substrate transport cannot be excluded.

In conclusion, the present study is the first systematic attempt to reveal the molecular basis for transport mechanism of hMATE-type transporters. We presented that Glu273, Glu278, Glu300, and Glu389 form a part of substrate binding site for TEA and cimetidine and that their roles in substrate binding seem to differ from one another. It seems likely that the concerted action of four glutamate residues in hMATE1 is the equivalent to Glu14 in EmrE. We speculate that these evolutionally unrelated bacterial multidrug transporters employ a similar mechanism for OC recognition and transport, which may be a fundamental strategy for the polyspecific nature of the transporters. Further studies, particularly with purified transporters combined with mutagenesis, will be necessary to identify the amino acid residues(s) involved in substrate binding and proton translocation.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
T. Matsumoto was supported by a Research Fellowship from the Japan Society for the Promotion of Science for Young Scientists. This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan to H. Omote, M. Otsuka and Y. Moriyama and the Smoking Research Foundation to Y. Moriyama.


   ACKNOWLEDGMENTS
 
We thank M. Hiasa for kind help with immunohistochemistry and C. Hina and N. Kaneko for constructing the plasmids for the mutant hMATE1.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Y. Moriyama, Dept. of Membrane Biochemistry, Okayama Univ. Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8530, Japan (e-mail: moriyama{at}pharm.okayama-u.ac.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
1. Asaka J, Terada T, Tsuda M, Katsura T, Inui K. Identification of essential histidine and cysteine residues of the H+/organic cation antiporter multidrug and toxin extrusion (MATE). Mol Pharmacol 71: 1487–1493, 2007.[Abstract/Free Full Text]

2. Brown MH, Paulsen IT, Skurray RA. The multidrug efflux protein NorM is a prototype of a new family of transporters. Mol Microbiol 31: 394–395, 1999.[CrossRef][Web of Science][Medline]

3. Hiasa M, Matsumoto T, Komatsu T, Moriyama Y. Wide variety of locations for rodent MATE1, a transporter protein that mediates the final excretion step for toxic organic cations. Am J Physiol Cell Physiol 291: C678–C686, 2006.[Abstract/Free Full Text]

4. Hiasa M, Matsumoto T, Komatsu T, Omote H, Moriyama Y. Functional characterization and localization of rodent multidrug and toxic compound extrusion 2, a class III MATE-type polyspecific H+/organic cation exporter. Am J Physiol Cell Physiol 293: C1437–C1444, 2007.[Abstract/Free Full Text]

5. Hvorup RN, Winnen B, Chang AB, Jiang Y, Zhou XF, Saier MH Jr. The multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) exporter superfamily. Eur J Biochem 270: 799–813, 2003.[Web of Science][Medline]

6. Ito W, Ishiguro H, Kurosawa Y. A general method for introducing a series of mutations into cloned DNA using the polymerase chain reaction. Gene 102: 67–70, 1991.[CrossRef][Web of Science][Medline]

7. Kim YK, Kim TI, Jung DK, Jung JS, Lee SH. Inhibition of H+/organic cation antiport by carboxyl reagents in rabbit renal brush-border membrane vesicles. J Pharmacol Exp Ther 266: 500–505, 1993.[Abstract/Free Full Text]

8. Kobara A, Hiasa M, Matsumoto T, Otsuka M, Omote H, Moriyama Y. A novel variant of mouse H+/organic cation antiporter with a long hydrophobic tail. Arch Biochem Biophys 469: 195–199, 2008.[CrossRef][Web of Science]

9. Koepsell H, Lips K, Volk C. Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24: 1227–1251, 2007.[CrossRef][Web of Science][Medline]

10. Masuda S, Terada T, Yonezawa A, Tanihara Y, Kishimoto K, Katsura T, Ogawa O, Inui K. Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol 17: 2127–2135, 2006.[Abstract/Free Full Text]

11. Moriyama Y, Hiasa M, Matsumoto T, Omote H. MATE-type proteins as anchor transporters for excretion of metabolic waste products and xenobiotics. Xenobiotica. In press.

12. Murakami S, Nakashima R, Yamashita E, Matsumoto T, Yamaguchi A. Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 443: 173–179, 2006.[CrossRef][Medline]

13. Muth TR, Schuldiner S. A membrane-embedded glutamate is required for ligand binding to the multidrug transporter EmrE. EMBO J 19: 234–240, 2000.[CrossRef][Web of Science][Medline]

14. Ohta KY, Inoue K, Hayashi Y, Yuasa H. Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H+ antiporter in the kidney. Drug Metab Dispos 34: 1868–1874, 2006.[Abstract/Free Full Text]

15. Omote H, Hiasa M, Matsumoto T, Otsuka M, Moriyama Y. The MATE proteins as fundamental transporters of metabolic and xenobiotic organic cations. Trends Pharmacol Sci 27: 587–593, 2006.[CrossRef][Medline]

16. Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y. A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci USA 102: 17923–17928, 2005.[Abstract/Free Full Text]

17. Pritchard JB, Miller DS. Mechanisms mediating renal secretion of organic anions and cations. Physiol Rev 73: 765–796, 1993.[Free Full Text]

18. Soskine M, Adam Y, Schuldiner S. Direct evidence for substrate-induced proton release in detergent-solubilized EmrE, a multidrug transporter. J Biol Chem 279: 9951–9955, 2004.[Abstract/Free Full Text]

19. Terada T, Masuda S, Asaka J, Tsuda M, Katsura T, Inui K. Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res 23: 1696–1701, 2006.[CrossRef][Web of Science][Medline]

20. Ullrich KJ. Specificity of transporters for ‘organic anions’ and ‘organic cations’ in the kidney. Biochim Biophys Acta 1197: 45–62, 1994.[Medline]

21. Wright SH, Dantzler WH. Molecular and cellular physiology of renal organic cation and anion transport. Physiol Rev 84: 987–1049, 2004.[Abstract/Free Full Text]

22. Wright SH, Wunz TM. Influence of substrate structure on turnover of the organic cation/H+ exchanger of the renal luminal membrane. Pflügers Arch 436: 469–477, 1998.[CrossRef][Web of Science][Medline]

23. Yerushalmi H, Schuldiner S. An essential glutamyl residue in EmrE, a multidrug antiporter from Escherichia coli. J Biol Chem 275: 5264–5269, 2000.[Abstract/Free Full Text]

24. Zhang X, Cherrington NJ, Wright SH. Molecular identification and functional characterization of rabbit MATE1 and MATE2-K. Am J Physiol Renal Physiol 293: F360–F370, 2007.[Abstract/Free Full Text]




This article has been cited by other articles:


Home page
 DiabetesHome page
M. L. Becker, L. E. Visser, R. H.N. van Schaik, A. Hofman, A. G. Uitterlinden, and B. H.Ch. Stricker
Genetic Variation in the Multidrug and Toxin Extrusion 1 Transporter Protein Influences the Glucose-Lowering Effect of Metformin in Patients With Diabetes: A Preliminary Study
Diabetes, March 1, 2009; 58(3): 745 - 749.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/4/C1074    most recent
00504.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Matsumoto, T.
Right arrow Articles by Moriyama, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Matsumoto, T.
Right arrow Articles by Moriyama, Y.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.