title: Human dopamine transporter gene: differential regulation of 18-kb haplotypes.
abstract: OBJECTIVE
  Since previous functional studies of short haplotypes and polymorphic sites of SLC6A3 have shown variant-dependent and drug-sensitive promoter activity, this study aimed to understand whether a large SLC6A3 regulatory region, containing these small haplotypes and polymorphic sites, can display haplotype-dependent promoter activity in a drug-sensitive and pathway-related manner.
  
  
  METHODS
  By creating and using a single copy number luciferase-reporter vector, we examined regulation of two different SLC6A3 haplotypes (A and B) of the 5´ 18-kb promoter and two known downstream regulatory variable number tandem repeats by 17 drugs in four different cellular models.
  
  
  RESULTS
  The two regulatory haplotypes displayed up to 3.2-fold difference in promoter activity. The regulations were drug selective (37.5% of the drugs showed effects), and both haplotype and cell type dependent. Pathway analysis revealed at least 13 main signaling hubs targeting SLC6A3, including histone deacetylation, AKT, PKC and CK2 α-chains.
  
  
  CONCLUSIONS
  SLC6A3 may be regulated via either its promoter or the variable number tandem repeats independently by specific signaling pathways and in a haplotype-dependent manner. Furthermore, we have developed the first pathway map for SLC6A3 regulation. These findings provide a framework for understanding complex and variant-dependent regulations of SLC6A3.
authors.affiliation: Department of Psychiatry, Harvard Medical School & Laboratory of Psychiatric Neurogenomics, Division of Alcohol & Drug Abuse, McLean Hospital, Mailstop 318, 115 Mill Street, Belmont, MA 02478, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Nian
authors.initials: N
authors.lastname: Xiong
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Nuomin
authors.initials: N
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Qing
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Lin
mesh_terms: D002460:Cell Line; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005787:Gene Frequency; D006239:Haplotypes / Q000187:drug effects; D006801:Humans; D018598:Minisatellite Repeats / Q000187:drug effects*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human
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