The Experts below are selected from a list of 1023 Experts worldwide ranked by ideXlab platform
Matthias A Hediger - One of the best experts on this subject based on the ideXlab platform.
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the slc1 high affinity glutamate and neutral amino acid transporter family
Molecular Aspects of Medicine, 2013Co-Authors: Yoshikatsu Kanai, Benjamin Clemencon, Alexandre Simonin, Michele Leuenberger, Martin Lochner, Martin Weisstanner, Matthias A HedigerAbstract:Glutamate transporters play important roles in the termination of excitatory neurotransmission and in providing cells throughout the body with glutamate for metabolic purposes. The high-affinity glutamate transporters EAAC1 (SLC1A1), GLT1 (SLC1A2), GLAST (SLC1A3), EAAT4 (SLC1A6), and EAAT5 (SLC1A7) mediate the cellular uptake of glutamate by the co-transport of three sodium ions (Na(+)) and one proton (H(+)), with the counter-transport of one potassium ion (K(+)). Thereby, they protect the CNS from glutamate-induced neurotoxicity. Loss of function of glutamate transporters has been implicated in the pathogenesis of several diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. In addition, glutamate transporters play a role in glutamate excitotoxicity following an ischemic stroke, due to reversed glutamate transport. Besides glutamate transporters, the SLC1 family encompasses two transporters of neutral amino acids, ASCT1 (SLC1A4) and ASCT2 (SLC1A5). Both transporters facilitate electroneutral exchange of amino acids in neurons and/or cells of the peripheral tissues. Some years ago, a high resolution structure of an archaeal homologue of the SLC1 family was determined, followed by the elucidation of its structure in the presence of the substrate aspartate and the inhibitor d,l-threo-benzyloxy aspartate (d,l-TBOA). Historically, the first few known inhibitors of SLC1 transporters were based on constrained glutamate analogs which were active in the high micromolar range but often also showed off-target activity at glutamate receptors. Further development led to the discovery of l-threo-β-hydroxyaspartate derivatives, some of which effectively inhibited SLC1 transporters at nanomolar concentrations. More recently, small molecule inhibitors have been identified whose structures are not based on amino acids. Activators of SLC1 family members have also been discovered but there are only a few examples known.
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Distribution of the glutamate transporters GLT-1 (SLC1A2) and GLAST (SLC1A3) in peripheral organs
Anatomy and Embryology, 2006Co-Authors: Urs V Berger, Matthias A HedigerAbstract:The glutamate transporters GLT-1 and GLAST are widely expressed in astrocytes in the brain where they fulfill important functions during glutamatergic neurotransmission. The present study examines their distribution in peripheral organs using in situ hybridization (ISH) and immunocytochemistry. GLAST was found to be more widely distributed than GLT-1. GLAST was expressed primarily in epithelial cells, cells of the macrophage-lineage, lymphocytes, fat cells, interstitial cells, and salivary gland acini. GLT-1 was primarily expressed in glandular tissue, including mammary gland, lacrimal gland, and ducts and acini in salivary glands, but also by perivenous hepatocytes and follicular dendritic cells in spleen and lymph nodes. The findings demonstrate that, although expressed by the same cells in the brain, these two glutamate transporters have different distribution patterns in peripheral tissues and that they fulfill glutamate transport functions apart from glutamatergic neurotransmission in these areas.
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The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects
Pflügers Archiv, 2004Co-Authors: Yoshikatsu Kanai, Matthias A HedigerAbstract:The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l -Glu, l -Asp and d -Asp, accompanied by the cotransport of 3 Na^+ and 1 H^+, and the countertransport of 1 K^+, whereas ASC transporters mediate Na^+-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to “reversed glutamate transport”, which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS.
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the glutamate neutral amino acid transporter family slc1 molecular physiological and pharmacological aspects
Pflügers Archiv: European Journal of Physiology, 2004Co-Authors: Yoshikatsu Kanai, Matthias A HedigerAbstract:The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l-Glu, l-Asp and d-Asp, accompanied by the cotransport of 3 Na+ and 1 H+, and the countertransport of 1 K+, whereas ASC transporters mediate Na+-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to “reversed glutamate transport”, which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS.
Fuller W Bazer - One of the best experts on this subject based on the ideXlab platform.
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select nutrients in the ovine uterine lumen iv expression of neutral and acidic amino acid transporters in ovine uteri and peri implantation conceptuses
Biology of Reproduction, 2009Co-Authors: Haijun Gao, Gregory A. Johnson, Thomas E Spencer, Fuller W BazerAbstract:The availability of specific neutral and acidic amino acids in the uterine lumen of ewes increased significantly during the peri-implantation period, but mechanisms for their transport into the uterine lumen and uptake by conceptuses are not established in any species. In this study, effects of pregnancy, progesterone (P4), and interferon tau (IFNT) on expression of neutral and acidic amino acid transporters in uteri of cyclic and pregnant ewes and conceptuses were studied. SLC1A2, SLC1A3, SLC3A1, SLC6A14, SLC6A19, SLC7A6, SLC38A3, and SLC38A6 mRNAs were only weakly expressed in the ovine endometrium. However, SLC1A4, SLC1A5, SLC7A8, and SLC43A2 mRNAs were detectable in uterine luminal epithelia (LE), superficial glandular epithelia (sGE), and/or glandular epithelia (GE). SLC1A1 and SLC7A5 mRNAs were most abundant in LE/sGE and GE. SLC1A3 and SLC38A4 mRNAs were most abundant in uterine stroma. SLC38A6 mRNA was detected only in cells with a stromal distribution suggesting immune lineage. SLC1A5 mRNA was expressed primarily in LE/sGE and stromal cells, and it was more abundant in uteri of pregnant ewes (day x status interaction; P < 0.05). Furthermore, P4 induced and IFNT further stimulated SLC1A5 expression in LE/sGE. Endometrial SLC1A1, SLC7A5, and SLC43A2 mRNAs demonstrated both temporal and cellSLC-specific changes. Several mRNAs were detectable in trophectoderm (SLC6A19, SLC7A5, SLC7A6, and SLC43A2), while others were more abundant in endoderm (SLC1A4, SLC1A5, SLC6A19, SLC7A5, SLC7A6, SLC7A8, and SLC43A2) of conceptuses. These results document coordinate changes in expression of transporters that are likely responsible for increases in amounts of neutral and acidic amino acids in the uterine lumen to support conceptus growth, development, and survival.
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Select Nutrients in the Ovine Uterine Lumen. IV. Expression of Neutral and Acidic Amino Acid Transporters in Ovine Uteri and Peri-Implantation Conceptuses
Biology of Reproduction, 2009Co-Authors: Guoyao Wu, Gregory A. Johnson, Thomas E Spencer, Fuller W BazerAbstract:Abstract The availability of specific neutral and acidic amino acids in the uterine lumen of ewes increased significantly during the peri-implantation period, but mechanisms for their transport into the uterine lumen and uptake by conceptuses are not established in any species. In this study, effects of pregnancy, progesterone (P4), and interferon tau (IFNT) on expression of neutral and acidic amino acid transporters in uteri of cyclic and pregnant ewes and conceptuses were studied. SLC1A2, SLC1A3, SLC3A1, SLC6A14, SLC6A19, SLC7A6, SLC38A3, and SLC38A6 mRNAs were only weakly expressed in the ovine endometrium. However, SLC1A4, SLC1A5, SLC7A8, and SLC43A2 mRNAs were detectable in uterine luminal epithelia (LE), superficial glandular epithelia (sGE), and/or glandular epithelia (GE). SLC1A1 and SLC7A5 mRNAs were most abundant in LE/sGE and GE. SLC1A3 and SLC38A4 mRNAs were most abundant in uterine stroma. SLC38A6 mRNA was detected only in cells with a stromal distribution suggesting immune lineage. SLC1A5 mR...
Gregg D Stanwood - One of the best experts on this subject based on the ideXlab platform.
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ocd candidate gene SLC1A1 eaat3 impacts basal ganglia mediated activity and stereotypic behavior
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Isaac D Zike, Muhammad O Chohan, Jared M Kopelman, Emily N Krasnow, Daniel Flicker, Katherine M Nautiyal, Michael Bubser, Christoph Kellendonk, Carrie K Jones, Gregg D StanwoodAbstract:Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of SLC1A1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, SLC1A1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D1 receptor binding in the dorsal striatum of SLC1A1-STOP mice. SLC1A1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of SLC1A1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in SLC1A1-STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.
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OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior.
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Isaac D Zike, Muhammad O Chohan, Jared M Kopelman, Emily N Krasnow, Daniel Flicker, Katherine M Nautiyal, Michael Bubser, Christoph Kellendonk, Carrie K Jones, Gregg D StanwoodAbstract:Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of SLC1A1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, SLC1A1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D1 receptor binding in the dorsal striatum of SLC1A1-STOP mice. SLC1A1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of SLC1A1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in SLC1A1-STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.
Edwin H. Cook - One of the best experts on this subject based on the ideXlab platform.
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Family-based association testing of glutamate transporter genes in autism.
Psychiatric genetics, 2011Co-Authors: Suma Jacob, Camille W. Brune, Judith A. Badner, Katherine Ernstrom, Eric Courchesne, Catherine Lord, Bennett L. Leventhal, Edwin H. Cook, Soo Jeong KimAbstract:Glutamate transporters are critical for signaling and excitotoxicity because they regulate extracellular glutamate in the synapse. Four glutamate transporter genes, SLC1A1, SLC1A2, SLC1A3, and SLC1A6, are positional and functional candidates for autism. Studies have implicated SLC1A1 in obsessive compulsive disorder (Arnold et al. 2006) and autism spectrum disorder (ASD) (Brune et al. 2008). Up-regulation of SLC1A2 and SLC1A3 has been reported in brains of individuals with autism (Purcell et al. 2001). SLC1A2 is under the highest linkage peak in the Autism Genome Project scan (Szatmari et al. 2007). Both SLC1A3 and SLC1A6 are most abundantly expressed in cerebellum (Bridges and Esslinger 2005) where structural and functional deficits occur in autism. Based on these lines of evidence, we hypothesized that variations in these four glutamate transporter genes confer risk for autism susceptibility. Previously we tested the association between autism and SLC1A1 in a strictly defined sample (N=85) and a found nominally significant association with a SLC1A1 SNP (rs301979) (Brune et al. 2008). Subsequently, we recruited additional families (N= 68) with either “strict autism” (N=39) or “broad ASD” (N=29). “Strict” autism was defined as a proband with Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) autism plus a best estimate diagnosis of autism by a clinical psychologist and/or child psychiatrist. The “broad ASD” probands had a best estimate diagnosis of any ASD (autism, Asperger’s disorder or PDD-NOS) plus combinations of ADI-R/ADOS criteria of Autism/ASD, ASD/Autism, or ASD/ASD. Altogether, 14 SNPs were genotyped in 153 trio families using TaqMan® SNP genotyping assay, including four SLC1A1 SNPs (rs301430, rs301979, rs301434, rs301443), three SLC1A2 SNPs (rs3088168, rs911562, rs1923291), three SLC1A3 SNPs (rs13173144, rs2269271, rs2301066), three SLC1A6 SNPs (rs10414225, rs873599, rs2285980), and one C9ORF68 (gene overlapping SLC1A1) SNP (rs384535). We dropped rs13173144 (SLC1A3, p=0.014) and rs384535 (C9ORF68, p=0.024) due to deviation from Hardy-Weinberg Equilibrium in founders; dropped four trio families because of Mendelian errors in remaining SNPs. Family-Based Association Test (FBAT) was performed on the new sample (N=68), strict combined sample (N=124) and overall combined sample (N=153) for both additive and recessive models. Only p < 0.05 uncorrected for multiple testing are reported. Association between rs301979 (SLC1A1) and autism was observed in the new samples (recessive model, Z=−2.778, p=0.005) as well as in the overall combined samples (additive, Z=−2.137, p=0.033; recessive, Z=−2.424, p=0.015). One SLC1A2 SNP (rs3088168) was nominally significant in the new sample under a recessive model (Z=−2.178, p=0.029), but not in the overall combined sample. Exploratory haplotype analyses revealed nominally significant associations between five SNP pairs including rs301979-rs301434 (p=0.04), rs301979-rs1923291 (p=0.02), rs1923291-rs911562 (p=0.03), rs911562-rs10414225 (p=0.01), rs301443-rs2285980 (p=0.01) under a recessive model. In summary, this study supported the previous association between SLC1A1 and autism, but failed to provide additional evidence for associations with three other glutamate transporter genes. However, given the small sample size and power, these genes require further investigation with denser markers and exploration of copy number variations in a larger sample set.
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Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder.
Archives of general psychiatry, 2006Co-Authors: Diane E. Dickel, Bennett L. Leventhal, Edwin H. Cook, Jeremy Veenstra-vanderweele, Nancy J. Cox, Daniel Fischer, Michelle Van Etten-lee, Joseph A. Himle, Gregory L. HannaAbstract:Context The first 2 independent linkage studies for obsessive-compulsive disorder (OCD) identified a region on 9p24 with suggestive evidence for linkage. The glutamate transporter gene solute carrier family 1, member 1 ( SLC1A1 ) is a promising functional candidate in this region because altered glutamatergic concentrations have been found in the striatum and anterior cingulate in neuroimaging studies of pediatric OCD. Objective To determine whether genotypes at polymorphisms in the SLC1A1 gene region are associated with early-onset OCD. Design Family-based analysis of association using the transmission disequilibrium test, confirmed using the family-based association test. Setting Anxiety disorders program in an academic medical center. Participants Seventy-one probands with DSM-III-R or DSM-IV OCD and their parents. Methods Nine single nucleotide polymorphisms spaced throughout the SLC1A1 gene region were genotyped. Results Significant association was detected at rs3780412 ( P = .04) and rs301430 ( P = .03), 2 common adjacent single nucleotide polymorphisms in the 3′ region of SLC1A1 . Analysis by sex revealed that association at rs3780412 was limited to male probands ( P = .002). Significant association was also detected for the T/C haplotype at rs301430-rs301979 ( P = .03), the only haplotype block identified among the 9 single nucleotide polymorphisms. Analysis by sex also revealed that the haplotype association was limited to male probands ( P = .003). A deletion in the 3′ flanking region of SLC1A1 was also detected that imperfectly segregated with OCD in a large, multigenerational family with multiple affected individuals. Conclusions The 3′ region of SLC1A1 may contain a susceptibility allele for early-onset OCD, with differential effects in males and females. The results also provide further support for the involvement of a glutamatergic dysfunction in the pathogenesis of early-onset OCD.
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association testing of the positional and functional candidate gene SLC1A1 eaac1 in early onset obsessive compulsive disorder
Archives of General Psychiatry, 2006Co-Authors: Diane E. Dickel, Bennett L. Leventhal, Edwin H. Cook, Nancy J. Cox, Daniel Fischer, Joseph A. Himle, Jeremy Veenstravanderweele, Michelle Van Ettenlee, Gregory L. HannaAbstract:Context The first 2 independent linkage studies for obsessive-compulsive disorder (OCD) identified a region on 9p24 with suggestive evidence for linkage. The glutamate transporter gene solute carrier family 1, member 1 ( SLC1A1 ) is a promising functional candidate in this region because altered glutamatergic concentrations have been found in the striatum and anterior cingulate in neuroimaging studies of pediatric OCD. Objective To determine whether genotypes at polymorphisms in the SLC1A1 gene region are associated with early-onset OCD. Design Family-based analysis of association using the transmission disequilibrium test, confirmed using the family-based association test. Setting Anxiety disorders program in an academic medical center. Participants Seventy-one probands with DSM-III-R or DSM-IV OCD and their parents. Methods Nine single nucleotide polymorphisms spaced throughout the SLC1A1 gene region were genotyped. Results Significant association was detected at rs3780412 ( P = .04) and rs301430 ( P = .03), 2 common adjacent single nucleotide polymorphisms in the 3′ region of SLC1A1 . Analysis by sex revealed that association at rs3780412 was limited to male probands ( P = .002). Significant association was also detected for the T/C haplotype at rs301430-rs301979 ( P = .03), the only haplotype block identified among the 9 single nucleotide polymorphisms. Analysis by sex also revealed that the haplotype association was limited to male probands ( P = .003). A deletion in the 3′ flanking region of SLC1A1 was also detected that imperfectly segregated with OCD in a large, multigenerational family with multiple affected individuals. Conclusions The 3′ region of SLC1A1 may contain a susceptibility allele for early-onset OCD, with differential effects in males and females. The results also provide further support for the involvement of a glutamatergic dysfunction in the pathogenesis of early-onset OCD.
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Genomic organization of the SLC1A1/EAAC1 gene and mutation screening in early-onset obsessive-compulsive disorder.
Molecular psychiatry, 2001Co-Authors: Jeremy Veenstra-vanderweele, Gregory L. Hanna, Bennett L. Leventhal, Soo Jeong Kim, D. Gonen, Edwin H. CookAbstract:The first genome scan conducted in early-onset obsessive-compulsive disorder used a non-parametric analysis to identify a peak in a region of chromosome 9 containing the gene SLC1A1, which codes for the neuronal and epithelial glutamate transporter EAAC1. Interaction between the glutamatergic and serotonergic systems within the striatum suggests EAAC1 as a functional candidate in OCD as well. We determined the genomic organization of SLC1A1 primarily by using primers designed from cDNA sequence to amplify from adaptor-ligated genomic DNA restriction fragments. In order to confirm SLC1A1 as a positional candidate in early-onset OCD, common single nucleotide polymorphisms (SNPs) were identified that enabled mapping of SLC1A1 within the region of the lod score peak. Based on the linkage evidence, the coding region was sequenced in the probands of the seven families included in the genome scan. No evidence was found for a functional mutation, but several SNPs were identified. Capillary electrophoresis SSCP typing of a haplotype consisting of two common SNPs within EAAC1 revealed no significant linkage disequilibrium.
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genomic organization of the SLC1A1 eaac1 gene and mutation screening in early onset obsessive compulsive disorder
Molecular Psychiatry, 2001Co-Authors: Jeremy Veenstravanderweele, Gregory L. Hanna, Bennett L. Leventhal, Soo Jeong Kim, D. Gonen, Edwin H. CookAbstract:The first genome scan conducted in early-onset obsessive-compulsive disorder used a non-parametric analysis to identify a peak in a region of chromosome 9 containing the gene SLC1A1, which codes for the neuronal and epithelial glutamate transporter EAAC1. Interaction between the glutamatergic and serotonergic systems within the striatum suggests EAAC1 as a functional candidate in OCD as well. We determined the genomic organization of SLC1A1 primarily by using primers designed from cDNA sequence to amplify from adaptor-ligated genomic DNA restriction fragments. In order to confirm SLC1A1 as a positional candidate in early-onset OCD, common single nucleotide polymorphisms (SNPs) were identified that enabled mapping of SLC1A1 within the region of the lod score peak. Based on the linkage evidence, the coding region was sequenced in the probands of the seven families included in the genome scan. No evidence was found for a functional mutation, but several SNPs were identified. Capillary electrophoresis SSCP typing of a haplotype consisting of two common SNPs within EAAC1 revealed no significant linkage disequilibrium.
Yoshikatsu Kanai - One of the best experts on this subject based on the ideXlab platform.
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the slc1 high affinity glutamate and neutral amino acid transporter family
Molecular Aspects of Medicine, 2013Co-Authors: Yoshikatsu Kanai, Benjamin Clemencon, Alexandre Simonin, Michele Leuenberger, Martin Lochner, Martin Weisstanner, Matthias A HedigerAbstract:Glutamate transporters play important roles in the termination of excitatory neurotransmission and in providing cells throughout the body with glutamate for metabolic purposes. The high-affinity glutamate transporters EAAC1 (SLC1A1), GLT1 (SLC1A2), GLAST (SLC1A3), EAAT4 (SLC1A6), and EAAT5 (SLC1A7) mediate the cellular uptake of glutamate by the co-transport of three sodium ions (Na(+)) and one proton (H(+)), with the counter-transport of one potassium ion (K(+)). Thereby, they protect the CNS from glutamate-induced neurotoxicity. Loss of function of glutamate transporters has been implicated in the pathogenesis of several diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. In addition, glutamate transporters play a role in glutamate excitotoxicity following an ischemic stroke, due to reversed glutamate transport. Besides glutamate transporters, the SLC1 family encompasses two transporters of neutral amino acids, ASCT1 (SLC1A4) and ASCT2 (SLC1A5). Both transporters facilitate electroneutral exchange of amino acids in neurons and/or cells of the peripheral tissues. Some years ago, a high resolution structure of an archaeal homologue of the SLC1 family was determined, followed by the elucidation of its structure in the presence of the substrate aspartate and the inhibitor d,l-threo-benzyloxy aspartate (d,l-TBOA). Historically, the first few known inhibitors of SLC1 transporters were based on constrained glutamate analogs which were active in the high micromolar range but often also showed off-target activity at glutamate receptors. Further development led to the discovery of l-threo-β-hydroxyaspartate derivatives, some of which effectively inhibited SLC1 transporters at nanomolar concentrations. More recently, small molecule inhibitors have been identified whose structures are not based on amino acids. Activators of SLC1 family members have also been discovered but there are only a few examples known.
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The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects
Pflügers Archiv, 2004Co-Authors: Yoshikatsu Kanai, Matthias A HedigerAbstract:The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l -Glu, l -Asp and d -Asp, accompanied by the cotransport of 3 Na^+ and 1 H^+, and the countertransport of 1 K^+, whereas ASC transporters mediate Na^+-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to “reversed glutamate transport”, which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS.
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the glutamate neutral amino acid transporter family slc1 molecular physiological and pharmacological aspects
Pflügers Archiv: European Journal of Physiology, 2004Co-Authors: Yoshikatsu Kanai, Matthias A HedigerAbstract:The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l-Glu, l-Asp and d-Asp, accompanied by the cotransport of 3 Na+ and 1 H+, and the countertransport of 1 K+, whereas ASC transporters mediate Na+-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to “reversed glutamate transport”, which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS.
