Organic anion transport is the primary function of the SLC17/type I phosphate transporter family

Reimer, Richard J.; Edwards, Robert H.

doi:10.1007/s00424-003-1087-y

Cited by 157 publications

(135 citation statements)

References 48 publications

(97 reference statements)

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“…SLC17 is a type I phosphate transporter family consisting of eight genes that are classified into three distinct subfamilies: (i) SLC17A1-4 (NPT1, NPT3, NPT4, and Na ϩ /PO4 2Ϫ cotransporter homologue), Na ϩ and inorganic phosphate cotransporters, (ii) SLC17A5 (sialin), a lysosomal H ϩ /sialic acid cotransporter, and (iii) SLC17A6-8, VGLUT (5). We found that a fourth subfamily, tentatively designated SLC17A9, was identified in a genome data bank screening (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of a vesicular nucleotide transporter

Sawada

Echigo

Juge

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

374

457

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ATP is a major chemical transmitter in purinergic signal transmission. Before secretion, ATP is stored in secretory vesicles found in purinergic cells. Although the presence of active transport mechanisms for ATP has been postulated for a long time, the proteins responsible for its vesicular accumulation remains unknown. The transporter encoded by the human and mouse SLC17A9 gene, a novel member of an anion transporter family, was predominantly expressed in the brain and adrenal gland. The mouse and bovine counterparts were associated with adrenal chromaffin granules. Proteoliposomes containing purified transporter actively took up ATP, ADP, and GTP by using membrane potential as the driving force. The uptake properties of the reconstituted transporter were similar to that of the ATP uptake by synaptic vesicles and chromaffin granules. Suppression of endogenous SLC17A9 expression in PC12 cells decreased exocytosis of ATP. These findings strongly suggest that SLC17A9 protein is a vesicular nucleotide transporter and should lead to the elucidation of the molecular mechanism of ATP secretion in purinergic signal transmission.ATP ͉ chromaffin granule ͉ purinergic signaling ͉ storage and exocytosis ͉ synaptic vesicle V esicular storage and subsequent exocytosis of neurotransmitters is essential for chemical transmission in neurons and endocrine cells. Thus far four distinct classes of transporters are known to participate in the uptake of neurotransmitters into neuronal synaptic vesicles and secretory granules in endocrine cells. These are vesicular monoamine transporters, vesicular acetylcholine transporters, vesicular inhibitory amino acid transporters, and vesicular glutamate transporters (VGLUTs) (1-7). These vesicular transporters mediate the active accumulation of their respective neurotransmitters through an electrochemical gradient of protons across the membrane generated by vacuolar proton-ATPase. ATP is stored in secretory vesicles and subsequently exocytosed, which leads to the various purinergic responses, such as central control of autonomic functions, pain and mechanosensory transduction, neural-glial interactions, control of vessel tone and angiogenesis, and platelet aggregation through purinoceptors, thus establishing its role as a chemical transmitter (8)(9)(10)(11)(12). Because the concentration of nucleotides in the vesicles was maintained at Ϸ0.1-1 M, an active transport mechanisms to accumulate nucleotides has been postulated (8-18). Although evidence increasingly supports the presence of a vesicular ATP transporters in secretory vesicles such as synaptic vesicles and adrenal chromaffin granules (13-19), the protein responsible for the ATP accumulation has not yet been identified.Here, we report the expression and function of human and mouse SLC17A9, an isoform of the SLC17 phosphate transporter family. We present evidence that the SLC17A9 protein acts as a vesicular nucleotide transporter (VNUT) and that it plays an essential role in vesicular storage of ATP in the ATP-secreting cells. Results a...

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Section: Resultsmentioning

confidence: 99%

Identification of a vesicular nucleotide transporter

Sawada

Echigo

Juge

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

374

457

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“…In glutamatergic neurons, glutamate is loaded into synaptic vesicles before its release into the synaptic cleft. This essential process is carried out by the VGLUTs, and inactivation of VGLUTs ablates glutamate release and neurotransmission (10)(11)(12)(13)(14)(15). Three distinct VGLUTs have been described, and anatomical studies have established that VGLUT1, 2, and 3 are expressed by largely nonoverlapping and functionally distinct populations of glutamatergic neurons in the nervous system (16).…”

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confidence: 99%

VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

Scherrer

Low

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

102

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Dorsal root ganglia (DRG) neurons, including the nociceptors that detect painful thermal, mechanical, and chemical stimuli, transmit information to spinal cord neurons via glutamatergic and peptidergic neurotransmitters. However, the specific contribution of glutamate to pain generated by distinct sensory modalities or injuries is not known. Here we generated mice in which the vesicular glutamate transporter 2 (VGLUT2) is ablated selectively from DRG neurons. We report that conditional knockout (cKO) of the Slc17a6 gene encoding VGLUT2 from the great majority of nociceptors profoundly decreased VGLUT2 mRNA and protein in these neurons, and reduced firing of lamina I spinal cord neurons in response to noxious heat and mechanical stimulation. In behavioral assays, cKO mice showed decreased responsiveness to acute noxious heat, mechanical, and chemical (capsaicin) stimuli, but responded normally to cold stimulation and in the formalin test. Strikingly, although tissue injury-induced heat hyperalgesia was lost in the cKO mice, mechanical hypersensitivity developed normally. In a model of nerve injuryinduced neuropathic pain, the magnitude of heat hypersensitivity was diminished in cKO mice, but both the mechanical allodynia and the microgliosis generated by nerve injury were intact. These findings suggest that VGLUT2 expression in nociceptors is essential for normal perception of acute pain and heat hyperalgesia, and that heat and mechanical hypersensitivity induced by peripheral injury rely on distinct (VGLUT2 dependent and VGLUT2 independent, respectively) primary afferent mechanisms and pathways.nociceptor | inflammatory pain | electrophysiology | neuroanatomy P rimary afferent neurons of the dorsal root ganglia (DRG) detect a wide range of stimulus modalities and intensities (1). This is particularly true for nociceptors, which are the neurons specialized to detect noxious stimuli. Not only do subsets of nociceptors express different repertoires of neuropeptides, receptors, and ion channels, but they also project to different laminae in the spinal cord where they engage different CNS circuits (2-4). Importantly, studies in rodents in which different nociceptor populations have been deleted revealed remarkably selective behavioral deficits (e.g., heat, mechanical, or chemical pain), demonstrating the existence of behaviorally relevant peripheral-labeled lines for different modalities of pain (5-8).Whether the modality-specific contribution of sensory neurons to acute pain and to injury-induced hypersensitivity states is also manifest at the level of the different neurotransmitters expressed by these neurons is still not known. Interestingly, previous pharmacological and genetic studies that disrupted neuropeptide function did not find a modality-specific loss of pain processing (9). Here we turned our attention to glutamate, which is presumed to be released by all DRG neurons to activate second-order spinal cord neurons.Because pharmacological blockade of glutamate signaling would nonselectively inhibit the centr...

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“…Vesicular storage and subsequent exocytosis of L-glutamate is the major pathway for excitatory signal transmission in the central nervous system (1)(2)(3). Vesicular glutamate transporters (VGLUTs) 2 are essential for the vesicular storage of L-glutamate through active transport of L-glutamate into synaptic vesicles at the expense of ⌬H ϩ established by vacuolar H ϩ -ATPase (V-ATPase) (1).…”

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confidence: 99%

“…Vesicular glutamate transporters (VGLUTs) 2 are essential for the vesicular storage of L-glutamate through active transport of L-glutamate into synaptic vesicles at the expense of ⌬H ϩ established by vacuolar H ϩ -ATPase (V-ATPase) (1). There are three isoforms of VGLUT, denoted VGLUT1, VGLUT2, and VGLUT3 on the basis of the order of their discovery (2, 4 -6).…”

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confidence: 99%

“…VGLUTs belong to the SLC17/type I anion transport family, one of the major facilitator superfamilies (MFS), and are not related to other neurotransmitter transporters such as vesicular acetylcholine transporter and vesicular monoamine transporter (2,14). VGLUT exhibits unique transport properties when compared with other vesicular neurotransmitter transporters.…”

mentioning

confidence: 99%

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Vesicular Glutamate Transporter Contains Two Independent Transport Machineries

Juge

Yoshida

Yatsushiro

et al. 2006

Journal of Biological Chemistry

109

193

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Vesicular glutamate transporters (VGLUTs) are responsible for the vesicular storage of L-glutamate and play an essential role in glutamatergic signal transmission in the central nervous system. The molecular mechanism of the transport remains unknown. Here, we established a novel in vitro assay procedure, which includes purification of wild and mutant VGLUT2 and their reconstitution with purified bacterial F o F 1 -ATPase (F-ATPase) into liposomes. Upon the addition of ATP, the proteoliposomes facilitated L-glutamate uptake in a membrane potential (⌬)-dependent fashion. The ATP-dependent L-glutamate uptake exhibited an absolute requirement for ϳ4 mM Cl ؊ , was sensitive to Evans blue, but was insensitive to D,L-aspartate. VGLUT2s with mutations in the transmembrane-located residues Arg 184 , His 128 , and Glu 191 showed a dramatic loss in L-glutamate transport activity, whereas Na ؉ -dependent inorganic phosphate (P i ) uptake remained comparable to that of the wild type. Furthermore, P i transport did not require Cl ؊ and was not inhibited by Evans blue. Thus, VGLUT2 appears to possess two intrinsic transport machineries that are independent of each other: a ⌬-dependent L-glutamate uptake and a Na ؉ -dependent P i uptake.Vesicular storage and subsequent exocytosis of L-glutamate is the major pathway for excitatory signal transmission in the central nervous system (1-3). Vesicular glutamate transporters (VGLUTs) 2 are essential for the vesicular storage of L-glutamate through active transport of L-glutamate into synaptic vesicles at the expense of ⌬H ϩ established by vacuolar H ϩ -ATPase (V-ATPase) (1). There are three isoforms of VGLUT, denoted VGLUT1, VGLUT2, and VGLUT3 on the basis of the order of their discovery (2, 4 -6). VGLUT1 and VGLUT2 show a complementary expression pattern in essentially all known glutamatergic neurons, suggesting that the two VGLUTs are involved in glutamatergic neurotransmission (7-9). In fact, VGLUT1 knock-out mice exhibit a loss of secretion of L-glutamate and glutamatergic neurotransmission in neurons that normally express VGLUT1 (4, 10). In contrast, VGLUT3 is expressed in neurons that are usually classified as non-glutamatergic neurons and astrocytes suggesting the involvement of VGLUT3 in a novel mode of L-glutamate signaling (11-13). VGLUTs are also expressed in peripheral nonneuronal cells, associated with a wide variety of secretory vesicles and are responsible for glutamate-mediated regulation in various cellular processes (5).VGLUTs belong to the SLC17/type I anion transport family, one of the major facilitator superfamilies (MFS), and are not related to other neurotransmitter transporters such as vesicular acetylcholine transporter and vesicular monoamine transporter (2, 14). VGLUT exhibits unique transport properties when compared with other vesicular neurotransmitter transporters. For one, VGLUT is activated by low concentrations of Cl Ϫ (ϳ4 mM) through a putative Cl Ϫ binding site (15-18). Furthermore, VGLUT requires membrane potential (positive inside) as a driving...

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Organic anion transport is the primary function of the SLC17/type I phosphate transporter family

Cited by 157 publications

References 48 publications

Identification of a vesicular nucleotide transporter

Identification of a vesicular nucleotide transporter

VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

Vesicular Glutamate Transporter Contains Two Independent Transport Machineries

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