Identification of a mammalian H+-myo-inositol symporter expressed predominantly in the brain

Uldry, Marc; Ibberson, Mark; Horisberger, Jean‐Daniel; Chatton, Jean–Yves; Riederer, Beat M.; Thorens, Bernard

doi:10.1093/emboj/20.16.4467

Cited by 207 publications

(202 citation statements)

References 43 publications

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“…The substrate specificity of SMIT2 does match that of a transporter that has been observed in renal proximal tubule apical membranes (47). Because the RNAs coding for SMIT1, SMIT2, and HMIT appear to be absent from small intestine (2,23,41), the identification of the intestinal MI transporter remains to be determined. The presence of three distinct MI cotransporters in brain tissues complicates the issue of MI metabolism in the central nervous system, which has gained prominence with the recent identification of MI depletion as the mechanism of action of three drugs commonly used to treat bipolar affective disorder (48).…”

Section: Fig 7 Presteady-state Currents Of Smit2-expressing Oocytesmentioning

confidence: 94%

“…A number of other orphan proteins have not displayed significant currents after exposure to a battery of possible substrates, and there are examples where this has occurred because the protein was not expressed at the cell surface during heterologous expression in oocytes (23). The presteady-state currents displayed by SMIT2 are large and long-lived, enabling us to easily observe them and giving us confidence that the orphan protein was correctly expressed at the cell surface.…”

Section: Fig 6 Phlorizin Inhibition Of MI Currentmentioning

confidence: 99%

“…In particular, one transporter that exhibits similar affinities for MI and for its epimer D-chiro-inositol has been demonstrated in the hepatic cell culture line HepG2 (18); in contrast, transport of D-chiro-inositol is not observed with the SMIT transporter (18). The proteins known to transport MI in mammals are SMIT and HMIT, a H ϩ /MI cotransporter from a completely different protein family (23).…”

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confidence: 99%

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Identification of a Novel Na+/myo-Inositol Cotransporter

Coady

Wallendorff

Gagnon

et al. 2002

Journal of Biological Chemistry

147

141

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rkST1, an orphan cDNA of the SLC5 family (43% identical in sequence to the sodium myo-inositol cotransporter SMIT), was expressed in Xenopus laevis oocytes that were subsequently voltage-clamped and exposed to likely substrates. Whereas superfusion with glucose and other sugars produced a small inward current, the largest current was observed with myo-inositol. The expressed protein, which we have named SMIT2, cotransports myo-inositol with a K m of 120 M and displays a current-voltage relationship similar to that seen with SMIT (now called SMIT1). The transport is Na ؉ -dependent, with a K m of 13 mM. SMIT2 exhibits phlorizin-inhibitable presteady-state currents and substrate-independent "Na ؉ leak" currents similar to those of related cotransporters. The steady-state cotransport current is also phlorizin-inhibitable with a K i of 76 M. SMIT2 exhibits stereospecific cotransport of both D-glucose and D-xylose but does not transport fucose. In addition, SMIT2 (but not SMIT1) transports D-chiro-inositol. Based on previous publications, the tissue distribution of SMIT2 is different from that of SMIT1, and the existence of this second cotransporter may explain much of the heterogeneity that has been reported for inositol transport.The first members of the vertebrate cotransporter protein family SLC5, which includes the high affinity Na ϩ /glucose cotransporter (SGLT1) and the Na ϩ /myo-inositol cotransporter (SMIT), were isolated over a decade ago based on expression of the proteins in Xenopus laevis oocytes (1, 2). Although substrates as diverse as proline, iodide, and vitamins (3) are transported by this family of proteins, the best characterized transporters remain SGLT1 and SMIT. There are also several "orphan" transporters whose cDNA has been cloned either by using labeled cDNA from members of the SLC5 family as biochemical probes or by comparing SLC5 sequence information in silico to data stored in DNA data bases (3); the newly discovered sequences are orphans in that they have no known function. Some of the orphan protein sequences are particularly similar to the protein sequences for SGLT1 and SMIT (4, 5) and presumably transport substrates similar or identical to either glucose or its isomer myo-inositol. The SLC5 proteins with known functions have generally been studied by voltageclamp experiments because these proteins are electrogenic. Also, presteady-state currents are associated with expression of these proteins at the cell surface, and some (but not all, e.g.

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Section: Fig 7 Presteady-state Currents Of Smit2-expressing Oocytesmentioning

confidence: 94%

Section: Fig 6 Phlorizin Inhibition Of MI Currentmentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of a Novel Na+/myo-Inositol Cotransporter

Coady

Wallendorff

Gagnon

et al. 2002

Journal of Biological Chemistry

147

141

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“…24,25 A second transporter of unrelated sequence is activated as the pH lowers, and is known as the H þ /myoinositol transporter (HMIT). 26 Following depolarization and protein kinase C (PKC) activation HMIT translocates to the plasma membrane at growth cones, leading to increased myo-inositol uptake. 27 SMIT inhibition may present an additional mechanism for inositol-depletion.…”

Section: Inositol Uptake and Mood Stabilizersmentioning

confidence: 99%

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

2004

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Inositol, a simple six-carbon sugar, forms the basis of a number of important intracellular signaling molecules. Over the last 35 years, a series of biochemical and cell biological experiments have shown that lithium (Li þ ) reduces the cellular concentration of myo-inositol and as a consequence attenuates signaling within the cell. Based on these observations, inositol-depletion was proposed as a therapeutic mechanism in the treatment of bipolar mood disorder. Recent results have added significant new dimensions to the original hypothesis. However, despite a number of clinical studies, this hypothesis still remains to be either proven or refuted. In this review of our current knowledge, I will consider where the inositol-depletion hypothesis stands today and how it may be further investigated in the future.

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“…However, based on sequence characteristics and phylogenetic alignments, three subclasses in the family can be distinguished (7). This suggests a broader range of possible substrates and transport characteristics among these new isoforms that is not restricted to hexoses, as shown by the cloning of the H ϩ /myoinositol transporter isoform or GLUT13 (8). Here, we describe the characterization of human GLUT9 (9) and demonstrate that alternative splicing leads to differential targeting, suggesting possible new mechanisms in the regulation of hexose transport in mammalian cells.…”

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confidence: 99%

Identification and Characterization of Human Glucose Transporter-like Protein-9 (GLUT9)

Augustin

Carayannopoulos

Dowd

et al. 2004

Journal of Biological Chemistry

256

254

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The recently cloned human GLUT9 gene, which maps to chromosome 4p15.3-p16, consists of 12 exons coding for a 540-amino acid protein. Based on a sequence entry (NCBI accession number BC018897) and screening of expressed sequence tags, we have cloned an alternative splice variant of GLUT9 from human kidney cDNA. The RNA of this splice variant consists of 13 exons and codes for a putative protein of 512 amino acids (GLUT9⌬N). The predicted proteins differ only in their N terminus, suggesting a different subcellular localization and possible physiological role. Screening human tissue RNA by reverse transcription-PCR showed that GLUT9 is expressed mainly in kidney, liver, placenta, and leukocytes, whereas GLUT9⌬N was detected only in kidney and placenta. The GLUT9 protein localized by immunohistochemistry to human kidney proximal tubules, and subcellular fractionation of human kidney revealed the GLUT9 protein in plasma membranes and high density microsomal membranes. Treatment of kidney membrane proteins with peptide Nglycosidase F showed that GLUT9 and GLUT9⌬N are expressed in vivo. Localization of GLUT9 and GLUT9⌬N in three kidney-derived cell lines revealed a plasma membrane distribution for GLUT9 in COS-7 and HEK293 cells, whereas GLUT9⌬N showed a perinuclear pattern and plasma membrane staining in COS-7 and HEK293 cells, respectively. In polarized Madin-Darby canine kidney cells, GLUT9 trafficked to the basolateral membrane, whereas GLUT9⌬N localized to the apical membrane. Using heterologous expression of GLUT9 in Xenopus oocytes, GLUT9 appears to be a functional isoform with low affinity for deoxyglucose. Deoxyglucose transport mediated by GLUT9 was not inhibited by cytochalasin B. GLUT9 did not bind cytochalasin B as shown by a cytochalasin B binding assay, indicating a similar behavior of GLUT9 compared with GLUT5.

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Identification of a mammalian H+-myo-inositol symporter expressed predominantly in the brain

Cited by 207 publications

References 43 publications

Identification of a Novel Na+/myo-Inositol Cotransporter

Identification of a Novel Na+/myo-Inositol Cotransporter

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

Identification and Characterization of Human Glucose Transporter-like Protein-9 (GLUT9)

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