title: Isoforms of the neuronal glutamate transporter gene, SLC1A1/EAAC1, negatively modulate glutamate uptake: relevance to obsessive-compulsive disorder.
abstract: The SLC1A1 gene, which encodes the neuronal glutamate transporter, EAAC1, has consistently been implicated in obsessive-compulsive disorder (OCD) in genetic studies. Moreover, neuroimaging, biochemical and clinical studies support a role for glutamatergic dysfunction in OCD. Although SLC1A1 is an excellent candidate gene for OCD, little is known about its regulation at the genomic level. Here, we report the identification and characterization of three alternative SLC1A1/EAAC1 mRNAs: a transcript derived from an internal promoter, termed P2 to distinguish it from the transcript generated by the primary promoter (P1), and two alternatively spliced mRNAs: ex2skip, which is missing exon 2, and ex11skip, which is missing exon 11. All isoforms inhibit glutamate uptake from the full-length EAAC1 transporter. Ex2skip and ex11skip also display partial colocalization and interact with the full-length EAAC1 protein. The three isoforms are evolutionarily conserved between human and mouse, and are expressed in brain, kidney and lymphocytes under nonpathological conditions, suggesting that the isoforms are physiological regulators of EAAC1. Moreover, under specific conditions, all SLC1A1 transcripts were differentially expressed in lymphocytes derived from subjects with OCD compared with controls. These initial results reveal the complexity of SLC1A1 regulation and the potential clinical utility of profiling glutamatergic gene expression in OCD and other psychiatric disorders.
authors.affiliation: Department of Psychiatry and Human Behavior, Brown University, BioMedical Center, Providence, RI 02912, USA.
authors.forename: B
authors.initials: B
authors.lastname: Porton
authors.forename: B D
authors.initials: BD
authors.lastname: Greenberg
authors.forename: K
authors.initials: K
authors.lastname: Askland
authors.forename: L M
authors.initials: LM
authors.lastname: Serra
authors.forename: J
authors.initials: J
authors.lastname: Gesmonde
authors.forename: G
authors.initials: G
authors.lastname: Rudnick
authors.forename: S A
authors.initials: SA
authors.lastname: Rasmussen
authors.forename: H-T
authors.initials: HT
authors.lastname: Kao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics* / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism* / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009771:Obsessive-Compulsive Disorder / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms; D055815:Young Adult
chemical_list: D050580:Excitatory Amino Acid Transporter 3; D020033:Protein Isoforms; C493400:SLC1A1 protein, human; C493399:Slc1a1 protein, mouse; D018698:Glutamic Acid