Faculty Profiles - HIASA Miki

Papers - HIASA Miki

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Suppression of increased blood glucose levels in mice by Awa-ban tea following oral administration of mono- and disaccharides Reviewed

Miki Hiasa, Megumi Kurokawa, Hiroshi Akita, Masatomo Harada, Kengo Niki, Kana Ohta, Masaki Shoji, Noriko Echigo, Takashi Kuzuhara

Journal of Functional Foods 8 ( 1 ) 188 - 192 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Ltd

Awa-ban tea is a uniquely flavored, pickled and anaerobically fermented tea found only in the Tokushima prefecture in the Shikoku region of Japan. Diabetes is a major health problem worldwide. Here, we report that Awa-ban tea suppressed the increase in blood glucose levels after oral administration of maltose, sucrose, or glucose in mice (n = 9-54). Awa-ban tea suppressed the area under the curve (AUC) of blood glucose by 72-83%. Thus, we propose that Awa-ban tea can be used as an alternative functional beverage for diabetes prevention. © 2014 Elsevier Ltd.

DOI： 10.1016/j.jff.2014.03.012

Inhibition of MAO-A and stimulation of behavioural activities in mice by the inactive prodrug form of the anti-influenza agent oseltamivir Reviewed

Miki Hiasa, Yumiko Isoda, Yasushi Kishimoto, Kenta Saitoh, Yasuaki Kimura, Motomu Kanai, Masakatsu Shibasaki, Dai Hatakeyama, Yutaka Kirino, Takashi Kuzuhara

British Journal of Pharmacology 169 ( 1 ) 115 - 129 2013.5

Language：English Publishing type：Research paper (scientific journal)

Background and Purpose Oseltamivir is the most widely prescribed anti-influenza medication. However, in rare instances, it has been reported to stimulate behavioural activities in adolescents. The goal of this study was to determine the molecular mechanism responsible for these behavioural activities. Experimental Approach We performed an in vitro assay of MAO-A, the enzyme responsible for neurotransmitter degradation, using either the active form - oseltamivir carboxylate (OC) or the inactive prodrug - oseltamivir ethyl ester (OEE). We also analysed the docking of MAO-A with OEE or OC in silico. Mouse behaviours after OEE or OC administration were monitored using automated video and computer analysis. Key Results OEE, but not OC, competitively and selectively inhibited human MAO-A. The estimated Ki value was comparable with the Km values of native substrates of MAO-A. Docking simulations in silico based on the tertiary structure of MAO-A suggested that OEE could fit into the inner pocket of the enzyme. Behavioural monitoring using automated video analysis further revealed that OEE, not OC, significantly enhanced spontaneous behavioural activities in mice, such as jumping, rearing, sniffing, turning and walking. Conclusions and Implications Our multilevel analyses suggested OEE to be the cause of the side effects associated with oseltamivir and revealed the molecular mechanism underlying the stimulated behaviours induced by oseltamivir in some circumstances. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

DOI： 10.1111/bph.12102

Vesicular nucleotide transporter regulates the nucleotide content in airway epithelial mucin granules Reviewed

Juliana I. Sesma, Silvia M. Kreda, Seiko F. Okada, Catharina van Heusden, Lama Moussa, Lisa C. Jones, Wanda K. O'Neal, Natsuko Togawa, Miki Hiasa, Yoshinori Moriyama, Eduardo R. Lazarowski

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 304 ( 10 ) C976 - C984 2013.5

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

Nucleotides within the airway surface liquid promote fluid secretion via activation of airway epithelial purinergic receptors. ATP is stored within and released from mucin granules as co-cargo with mucins, but the mechanism by which ATP, and potentially other nucleotides, enter the lumen of mucin granules is not known. We assessed the contribution of the recently identified SLC17A9 vesicle nucleotide transporter (VNUT) to the nucleotide availability within isolated mucin granules and further examined the involvement of VNUT in mucin granule secretion-associated nucleotide release. RT-PCR and Western blot analyses indicated that VNUT is abundantly expressed in airway epithelial goblet-like Calu-3 cells, migrating as a duplex with apparent mobility of 55 and 60 kDa. Subcellular fractionation studies indicated that VNUT55 was associated with high-density mucin granules, whereas VNUT60 was associated with low-density organelles. Immunofluorescence studies showed that recombinant VNUT localized to mucin granules and other organelles. Mucin granules isolated from VNUT short hairpin RNA-expressing cells exhibited a marked reduction of ATP, ADP, AMP, and UTP levels within granules. Ca2+ regulated vesicular ATP release was markedly reduced in these cells, but mucin secretion was not affected. These results suggest that VNUT is the relevant nucleotide transporter responsible for the uptake of cytosolic nucleotides into mucin granules. By controlling the entry of nucleotides into mucin granules, VNUT contributes to the release of purinergic signaling molecules necessary for the proper hydration of co-released mucins.

DOI： 10.1152/ajpcell.00371.2012

Identification and purification of resorcinol, an antioxidant specific to Awa-ban (pickled and anaerobically fermented) tea Reviewed

Miki Hiasa, Megumi Kurokawa, Kana Ohta, Tomoyuki Esumi, Hiroshi Akita, Kengo Niki, Yasuyuki Yagi, Noriko Echigo, Dai Hatakeyama, Takashi Kuzuhara

Food Res Int. 54 ( 1 ) 72 - 80 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Awa-ban tea (Awa, Tokushima prefecture in Japan; ban, "evening" in Japanese) is a type of tea exclusive to the Tokushima area. Awa-ban tea leaves are unique in that they are produced via pickling and anaerobic fermentation. Here, we report the identification and purification of an antioxidant that is specifically present in Awa-ban tea but is absent in green and black tea. The molecule, identified as resorcinol, was found to exhibit radical-scavenging activity in vitro at levels equivalent to those of (-)-epigallocatechin gallate in green tea. Fluorescence microscopy and flow cytometry results further showed that resorcinol decreased the levels of reactive oxygen species in HEK293T cells, human umbilical vein endothelial cells, and Jurkat cells in a concentration-dependent manner. Moreover, the 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated that treatment with 10 mM resorcinol did not affect cell viability. Our results indicate that Awa-ban tea has properties that are quite distinct from those of green and black tea and is therefore a unique antioxidant beverage. We also suggest that resorcinol is a novel tea-based antioxidant. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.foodres.2013.05.036

Functional and Anatomical Identification of a Vesicular Transporter Mediating Neuronal ATP Release Reviewed

Max Larsson, Keisuke Sawada, Cecilie Morland, Miki Hiasa, Lasse Ormel, Yoshinori Moriyama, Vidar Gundersen

CEREBRAL CORTEX 22 ( 5 ) 1203 - 1214 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

ATP is known to be coreleased with glutamate at certain central synapses. However, the nature of its release is controversial. Here, we demonstrate that ATP release from cultured rat hippocampal neurons is sensitive to RNAi-mediated knockdown of the recently identified vesicular nucleotide transporter (VNUT or SLC17A9). In the intact brain, light microscopy showed particularly strong VNUT immunoreactivity in the cerebellar cortex, the olfactory bulb, and the hippocampus. Using immunoelectron microscopy, we found VNUT immunoreactivity colocalized with synaptic vesicles in excitatory and inhibitory terminals in the hippocampal formation. Moreover, VNUT immunolabeling, unlike that of the vesicular glutamate transporter VGLUT1, was enriched in preterminal axons and present in postsynaptic dendritic spines. Immunoisolation of synaptic vesicles indicated presence of VNUT in a subset of VGLUT1-containing vesicles. Thus, we conclude that VNUT mediates transport of ATP into synaptic vesicles of hippocampal neurons, thereby conferring a purinergic phenotype to these cells.

DOI： 10.1093/cercor/bhr203

Characterization of the human MATE2 proton-coupled polyspecific organic cation exporter Reviewed

Toshinori Komatsu, Miki Hiasa, Takaaki Miyaji, Takuji Kanamoto, Takuya Matsumoto, Masato Otsuka, Yoshinori Moriyama, Hiroshi Omote

INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 43 ( 6 ) 913 - 918 2011.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Human multidrug and toxic compound extrusion 2 (hMATE2) is a kidney-specific isoform of hMATE1, an exporter of toxic organic cations (OCs) of exogenous and endogenous origins at the final excretion step in the kidneys and liver (Otsuka et al., 2005), and contains a splicing variant, MATE2K, that has an exon of hMATE2 deleted (Masuda et al., 2006). In the present study, we characterized the degree of expression and the transport properties of hMATE2. Quantitative PCR analysis with probes specific for hMATE2 indicated the presence of hMATE2 mRNA in the kidneys, which corresponded to 39% of total mRNA encoding both hMATE2 and hMATE2K. hMATE2-specific antibodies immunostained the renal urinary tubules. Upon expression in HEK293 cells, hMATE2 was localized in intracellular vesicular structures, and thus transport activity of tetraethylammonium (TEA), a typical substrate for MATE transporters, by the cells was not detected. The hMATE2 protein was purified and reconstituted into liposomes. An artificially imposed pH gradient (Delta pH) across the proteoliposomal membrane drove the uptake of TEA. Dissipation of Delta pH by ammonium sulfate effectively inhibited the TEA uptake, while that of the membrane potential by valinomycin had little effect. The profiles of cis-inhibition of TEA transport by hMATE2 and hMATE2K are similar to each other. Thus, both hMATE2 and hMATE2K equally operate in the human kidneys to extrude OCs into the urine. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.biocel.2011.03.005

Type 1 Sodium-dependent Phosphate Transporter (SLC17A1 Protein) Is a Cl--dependent Urate Exporter Reviewed

Masafumi Iharada, Takaaki Miyaji, Takahiro Fujimoto, Miki Hiasa, Naohiko Anzai, Hiroshi Omote, Yoshinori Moriyama

JOURNAL OF BIOLOGICAL CHEMISTRY 285 ( 34 ) 26107 - 26113 2010.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

SLC17A1 protein (NPT1) is the first identified member of the SLC17 phosphate transporter family and mediates the transmembrane cotransport of Na+/P-i in oocytes. Although this protein is believed to be a renal polyspecific anion exporter, its transport properties are not well characterized. Here, we show that proteoliposomes containing purified SLC17A1 transport various organic anions such as p-aminohippuric acid and acetylsalicylic acid (aspirin) in an inside positive membrane potential (Delta psi)-dependent manner. We found that NPT1 also transported urate. The uptake characteristics were similar to that of SLC17 members in its Cl- dependence and inhibitor sensitivity. When arginine 138, an essential amino acid residue for members of the SLC17 family such as the vesicular glutamate transporter, was specifically mutated to alanine, the resulting mutant protein was inactive in Delta psi-dependent anion transport. Heterologously expressed and purified human NPT1 carrying the single nucleotide polymorphism mutation that is associated with increased risk of gout in humans exhibited 32% lower urate transport activity compared with the wild type protein. These results strongly suggested that NPT1 is a Cl--dependent polyspecific anion exporter involved in urate excretion under physiological conditions.

DOI： 10.1074/jbc.M110.122721

Vesicular Inhibitory Amino Acid Transporter Is a Cl-/gamma-Aminobutyrate Co-transporter Reviewed

Narinobu Juge, Akiko Muroyama, Miki Hiasa, Hiroshi Omote, Yoshinori Moriyama

JOURNAL OF BIOLOGICAL CHEMISTRY 284 ( 50 ) 35073 - 35078 2009.12

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

The vesicular inhibitory amino acid transporter (VIAAT) is a synaptic vesicle protein responsible for the vesicular storage of gamma-aminobutyrate (GABA) and glycine which plays an essential role in GABAergic and glycinergic neurotransmission. The transport mechanism of VIAAT remains largely unknown. Here, we show that proteoliposomes containing purified VIAAT actively took up GABA upon formation of membrane potential (Delta psi) (positive inside) but not Delta pH. VIAAT-mediated GABA uptake had an absolute requirement for Cl- and actually accompanied Cl- movement. Kinetic analysis indicated that one GABA molecule and two Cl- equivalents were transported during one transport cycle. VIAAT in which Glu(213) was specifically mutated to alanine completely lost the ability to take up both GABA and Cl-. Essentially the same results were obtained with glycine, another substrate of VIAAT. These results demonstrated that VIAAT is a vesicular Cl- transporter that co-transports Cl- with GABA or glycine in a Delta psi dependent manner. It is concluded that Cl- plays an essential role in vesicular storage of GABA and glycine.

DOI： 10.1074/jbc.M109.062414

Identification of the vesicular nucleotide transporter (VNUT) in taste cells Reviewed

Ken Iwatsuki, Reiko Ichikawa, Miki Hiasa, Yoshinori Moriyama, Kunio Torii, Hisayuki Uneyama

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 388 ( 1 ) 1 - 5 2009.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Taste cells are chemosensory epithelial cells that sense distinct taste qualities. It is the type II taste cell that express G-protein coupled receptors to sense either umami, sweet, or bitter compounds. Whereas several reports have suggested involvement of ATP in taste signal transduction, there is a paucity of molecular information about how ATP is stored and being released. The recent discovery of a novel vesicular nucleotide transporter (VNUT) led us to examine whether VNUT exist in the taste tissue where ATP is to be released for taste signal transmission. Here, we report that VNUT is selectively expressed in type II cell but not in type III taste cell. In addition, we show that during taste bud development VNUT expression is always accompanied by the expression of type II taste cell markers. Our results, together with previous studies, strongly suggest that VNUT plays a role in type II taste cell. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2009.07.069

Expression and function of TETRAN, a new type of membrane transporter Reviewed

Hironori Ushijima, Miki Hiasa, Takushi Namba, Hyun-Jung Hwang, Tatsuya Hoshino, Shinji Mima, Tomofusa Tsuchiya, Yoshinori Moriyama, Tohru Mizushima

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 374 ( 2 ) 325 - 330 2008.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

In contrast to transport across basolateral membranes, the mechanism governing transport Of Organic anions across the luminal membranes Of proximal tubules has remained Unclear. We recently found Tet-racycline transporter-like protein (TETRAN), a human ortholog of yeast Tpo1p that can transport anionic Non-steroidal anti-inflammatory drugs (NSAIDs). In this study, we examine the expression and function of TETRAN. TETRAN mRNA is expressed in various human tissues, including kidney. When overexpressed in Cultured cells, TETRAN was predominantly localized on cytoplasmic membranes. immunohistochemical analysis of human and mouse kidney tissue showed that TETRAN was expressed at the luminal membranes of proximal tubules. overexpression of TETRAN in cultured cells facilitated the Uptake of organic anions Such as indomethacin (a NSAID) and fluorescein. The results suggest that TETPAN is a novel human organic anion transporter, and that it serves as a transporter for some NSAIDs and various other organic anions at the final excretion step. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2008.07.034

Identification of a vesicular aspartate transporter Reviewed

Takaaki Miyaji, Noriko Echigo, Miki Hiasa, Shigenori Senoh, Hiroshi Omote, Yoshinori Moriyama

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 105 ( 33 ) 11720 - 11724 2008.8

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Aspartate is an excitatory amino acid that is costored with glutamate in synaptic vesicles of hippocampal neurons and synaptic-like microvesicles (SLMVs) of pinealocytes and is exocytosed and stimulates neighboring cells by binding to specific cell receptors. Although evidence increasingly supports the occurrence of aspartergic neurotransmission, this process is still debated because the mechanism for the vesicular storage of aspartate is unknown. Here, we show that sialin, a lysosomal H+/sialic acid cotransporter, is present in hippocampal synaptic vesicles and pineal SLMVs. RNA interference of sialin expression decreased exocytosis of aspartate and glutamate in pinealocytes. Proteoliposomes containing purified sialin actively accumulated aspartate and glutamate to a similar extent when inside positive membrane potential is imposed as the driving force. Sialin carrying a mutation found in people suffering from Salla disease (R39C) was completely devoid of aspartate and glutamate transport activity, although it retained appreciable H+/sialic acid cotransport activity. These results strongly suggest that sialin possesses dual physiological functions and acts as a vesicular aspartate/glutamate transporter. It is possible that people with Salla disease lose aspartergic (and also the associated glutamatergic) neurotransmission, and this could provide an explanation for why Salla disease causes severe neurological defects.

DOI： 10.1073/pnas.0804015105

A novel variant of mouse MATE-1 H+/organic cation antiporter with a long hydrophobic tall Reviewed

Ayumi Kobara, Miki Hiasa, Takuya Matsumoto, Masato Otsuka, Hiroshi Omote, Yoshinori Moriyama

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 469 ( 2 ) 195 - 199 2008.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Mammalian multidrug and toxic compound extrusion 1 (MATE1) are polyspecific H+-coupled exporters of organic cations (OCs) and responsible for excretion of metabolic waste products and xenobiotics. Here, we report a novel variant of mouse MATE1, mMATE1b, that has a long carboxyl terminal hydrophobic tail homologous to other MATE1 transporter proteins. Mouse MATE1b mediates tetraethylammonium (TEA) uptake with properties similar to that of mMATE1 and is localized in renal brush border membranes. Thus, mMATE1b is a functional variant of mMATE1 and seems to be the true counterpart to other MATE1 transporters. (C) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.abb.2007.10.010

[Identification, structure and function of a drug transporter at the final step of extrusion]. Reviewed

Hiasa M, Omote H, Moriyama Y

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 53 ( 1 ) 52 - 58 2008.1

Multidrug and toxic compound extrusion (MATE)-type proteins as anchor transporters for the excretion of metabolic waste products and xenobiotics Reviewed

Y. Moriyama, M. Hiasa, T. Matsumoto, H. Omote

XENOBIOTICA 38 ( 7-8 ) 1107 - 1118 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

1. Multidrug and toxic compound extrusion (MATE)-type transporters, which were first identified as a bacterial drug transporter family, are present in almost all prokaryotes and eukaryotes, and are thus one of the mostly conserved transporter families in nature.
2. Recently, a mammalian MATE transporter was shown to be a long hypothesized electroneutral H(+)/organic cation exporter that is responsible for the excretion of metabolic waste products and xenobiotics at renal brush border membranes and bile canaliculi. Plant MATE-type transporters are involved in the detoxification of metals and secondary metabolites such as phenols through their vesicular storage or extrusion at the plasma membrane.
3. Thus, MATE transporters are involved in one of the basic mechanisms that maintain homeostasis through the excretion of metabolic waste products and xenobiotics in nature.

DOI： 10.1080/00498250701883753

Functional characterization of testis-specific rodent multidrug and toxic compound extrusion 2, a class III MATE-type polyspecific H+/organic cation exporter Reviewed

Miki Hiasa, Takuya Matsumoto, Toshinori Komatsu, Hiroshi Omote, Yoshinori Moriyama

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 293 ( 5 ) C1437 - C1444 2007.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

Mammalian multidrug and toxic compound extrusion ( MATE) proteins are classified into three subfamilies: classes I, II, and III. We previously showed that two of these families act as polyspecific H+-coupled transporters of organic cations (OCs) at final excretion steps in liver and kidney ( Otsuka et al. Proc Natl Acad Sci USA 102: 17923-17928, 2005; Omote et al. Trends Pharmacol Sci 27: 587-593, 2006). Rodent MATE2 proteins are class III MATE transporters, the molecular nature, as well as transport properties, of which remain to be characterized. In the present study, we investigated the transport properties and localization of mouse MATE2 (mMATE2). On expression in human embryonic kidney (HEK)-293 cells, mMATE2 localized to the intracellular organelles and plasma membrane. mMATE2 mediated pH-dependent TEA transport with substrate specificity similar to, but distinct from, that of mMATE1, which prefers N-methylnicotinamide and guanidine as substrates. mMATE2 expressed in insect cells was solubilized and reconstituted with bacterial H+-ATPase into liposomes. The resultant proteoliposomes exhibited ATP-dependent uptake of TEA that was sensitive to carbonyl cyanide 3-chlorophenylhydrazone but unaffected by valinomycin in the presence of K+. Immunologic techniques using specific antibodies revealed that mMATE2 was specifically expressed in testicular Leydig cells. Thus mMATE2 appears to act as a polyspecific H+/OC exporter in Leydig cells. It is concluded that all classes of mammalian MATE proteins act as polyspecific and electroneutral transporters of organic cations.

DOI： 10.1152/ajpcell.00280.2007

Exocytosis of D-aspartate from INS-1E clonal beta cells Reviewed

Masafumi Iharada, Miki Hiasa, Ayumi Kobara, Yoshinori Moriyama

BIOLOGICAL & PHARMACEUTICAL BULLETIN 30 ( 7 ) 1329 - 1331 2007.7

Language：English Publishing type：Research paper (scientific journal) Publisher：PHARMACEUTICAL SOC JAPAN

D-Aspartate is present in the central nervous system and various endocrine organs, and modulates their neuroendocrine function. In islets of Langerhans, alpha and beta cells contain D-aspartate. Here we show that INS-1E clonal beta cells contain the highest amount Of D-aspartate. Immunohistochemical analysis with specific antibodies against D-aspartate indicated that D-aspartate is co-localized with insulin. Upon the addition of K+, both D-aspartate and insulin are secreted from the cells in a Ca2+-dependent manner. A Ca2+ ionophore, A23187, also triggers the release Of D-aspartate and insulin in the presence of Ca2+. Bafilomycin A, a specific inhibitor of V-ATPase and V-ATPase-linked secondary transport, inhibits the secretion of D-aspartate. These results support the idea that D-aspartate is present in insulin-containing secretory granules and co-secreted with insulin through exocytosis.

DOI： 10.1248/bpb.30.1329

The MATE proteins as fundamental transporters of metabolic and xenobiotic organic cations Reviewed

Hiroshi Omote, Miki Hiasa, Takuya Matsumoto, Masato Otsuka, Yoshinori Moriyama

TRENDS IN PHARMACOLOGICAL SCIENCES 27 ( 11 ) 587 - 593 2006.11

Language：English Publisher：ELSEVIER SCIENCE LONDON

Multidrug and toxic compound extrusion (MATE) proteins, comprising the most recently designated family of multidrug transporter proteins, are widely distributed in all kingdoms of living organisms, although their function is far from understood. The bacterial MATE-type transporters that have been characterized function as exporters of cationic drugs, such as norfloxacin and ethidium, through H+ or Na+ exchange. Plant MATE-type transporters are involved in the detoxification of secondary metabolites, including alkaloids. Mammalian MATE-type transporters are responsible for the final step in the excretion of metabolic waste and xenobiotic organic cations in the kidney and liver through electroneutral exchange of H+. Thus, we propose that members of the MATE family are organic cation exporters that excrete metabolic or xenobiotic organic cations from the body.

DOI： 10.1016/j.tips.2006.09.001

Wide variety of locations for rodent MATE1, a transporter protein that mediates the final excretion step for toxic organic cations Reviewed

Miki Hiasa, Takuya Matsumoto, Toshinori Komatsu, Yoshinori Moriyama

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 291 ( 4 ) C678 - C686 2006.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

MATE1 was the first mammalian example of the multidrug and toxin extrusion (MATE) protein family to be identified. Human MATE1 (hMATE1) is predominantly expressed and localized to the luminal membranes of the urinary tubules and bile canaliculi and mediates H+-coupled electroneutral excretion of toxic organic cations (OCs) into urine and bile (Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, and Moriyama Y. Proc Natl Acad Sci USA 102: 17923-17928, 2005). mMATE1, a mouse MATE ortholog, is also predominantly expressed in kidney and liver, although its transport properties are not yet characterized. In the present study, we investigated the transport properties and localization of mMATE1. Upon expression of this protein in HEK-293 cells, mMATE1 mediated electroneutral H+/ tetraethylammonium exchange and showed a substrate specificity similar to that of hMATE1. Immunological techniques with specific antibodies against mMATE1 combined with RT-PCR revealed that mMATE1 is also expressed in various cells, including brain glia-like cells and capillaries, pancreatic duct cells, urinary bladder epithelium, adrenal gland cortex, alpha cells of the islets of Langerhans, Leydig cells, and vitamin A-storing Ito cells. These results indicate that mMATE1 is a polyspecific H+/OC exchanger. The unexpectedly wide distribution of mMATE1 suggests involvement of this transporter protein in diverse biological functions other than excretion of OCs from the body.

DOI： 10.1152/ajpcell.00090.2006

Immunohistochemical localization of D-aspartate in islets of Langerhans Reviewed

Miki Hiasa, Yoshinori Moriyama

BIOLOGICAL & PHARMACEUTICAL BULLETIN 29 ( 6 ) 1251 - 1253 2006.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PHARMACEUTICAL SOC JAPAN

D-Aspartate is a putative modulator of neuroendocrine functions, and is present in various neuroendocrine cells as well as the central nervous system. Here we show that the islet of Langerhans is a D-aspartate-containing endocrine organ. Immunohistochemical analysis with specific antibodies against D-aspartate indicated that D-aspartate is present in all islet cells, and predominantly present in a cells and a subpopulation of F-cells. Since these cells are glutamatergic in nature, it is possible that D-aspartate is involved in the glutamate signaling pathways in the islets.

DOI： 10.1248/bpb.29.1251

Vesicular storage and secretion of L-glutamate from glucagon-like peptide 1-secreting clonal intestinal L cells Reviewed

S Uehara, SK Jung, R Morimoto, S Arioka, T Miyaji, N Juge, M Hiasa, K Shimizu, A Ishimura, M Otsuka, A Yamamoto, P Maechler, Y Moriyama

JOURNAL OF NEUROCHEMISTRY 96 ( 2 ) 550 - 560 2006.1

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Vesicular glutamate transporter (VGLUT) is responsible for the vesicular storage of (L)-glutamate, and plays an essential role in glutamate-mediated intercellular signal transmission in the CNS and in some neuroendocrine cells. Intestinal L cells are the glucose-responsive neuroendocrine cells responsible for the secretion of glucagon-like peptide 1 (GLP-1). We have shown that intestinal L cells express VGLUT2, a VGLUT isoform, which suggests that L cells secrete (L)-glutamate. In the present study, we investigated this possibility using GLUTag mouse clonal L cells. RT-PCR and northern blot analyses revealed expression of the VGLUT1 and VGLUT2 genes, but not of the VGLUT3 gene. Western blot analysis revealed immunological counterparts for VGLUT2, whereas an immunological counterpart of VGLUT1 was not detected. Indirect immunofluorescence microscopy revealed a punctate distribution of VGLUT2 immunoreactivity throughout the cells, which co-localized with GLP-1. Double-labeling immunoelectronmicroscopy confirmed the association of VGLUT2 with GLP-1-containing secretory granules. The membrane fraction exhibited ATP-dependent (L)-glutamate uptake, which was sensitive to bafilomycin A1 (a vacuolar proton ATPase inhibitor) and Evans blue (a VGLUT inhibitor) but insensitive to (D,L)-aspartate. Upon depolarization with KCl, GLUTag cells secreted appreciable amounts of (L)-glutamate and GLP-1. (D)-Glucose and methyl-alpha-(D)-glucopyranoside, stimulators of exocytosis of GLP-1, also triggered the secretion of (L)-glutamate. The (L)-glutamate secretion was partially dependent on Ca2+ and sensitive to bafilomycin A1. These results demonstrated that GLUTag cells stored (L)-glutamate in secretory granules and secreted it with GLP-1 by exocytosis. As GLUTag cells and intestinal L cells express kainate receptors and plasma membrane glutamate transporters, these results support the concept of (L)-glutamate-mediated intercellular signaling in the vicinity of intestinal L cells.

DOI： 10.1111/j.1471-4159.2005.03575.x

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