Autoregulation of the human D(1A) dopamine receptor gene by cAMP

Mari T. Minowa, Sang Hyeon Lee, M. Maral Mouradian

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Stimulation of the D(1A) dopamine receptor increases intracellular cAMP concentration and down-regulates the receptor protein. We evaluated the possibility that this second messenger system could affect the expression of the D(1A) gene as a positive autoregulatory mechanism. Treatment of the D(1A)-expressing cells SK-N-MC with 100 μM dopamine resulted in an initial increase in steady-state levels of the D(1A) mRNA beginning at 30 min, followed by decline below the baseline and then recovery by 24 hr. Forskolin/IBMX (100 μM each) treatment also resulted in a decline followed by recovery. To determine if these changes in D(1A) message levels are due to transcriptional control, transient expression assays were done using reporter gene constructs of the human D(1A) gene 5'-flanking region. Forskolin/IBMX treatment for 19 hr resulted in a four- to seven-fold increase in trans- activation of the human D(1A) gene promoter. Two cAMP-responsive regions in exon 1 of this gene with nuclear protein binding sites within both regions were identified. The segment of the D(1A) gene between these two cAMP- responsive regions contained two additional DNA-protein interaction sites, one of which bound to nuclear factors considerably stronger following forskolin/IBMX treatment. Several consensus sequences for classical transcription factors known to mediate the cAMP response, such as CREB, AP2, and AP1, are found in the human D(1A) gene. However, the location of all but one AP2 site in other parts of this gene and lack of AP2 expression in SK-N- MC cells suggest that these factors are unlikely to transduce this response. Thus, dopamine treatment results in delayed cAMP-mediated trans-activation of the D(1A) gene via an indirect mechanism.

Original languageEnglish (US)
Pages (from-to)759-767
Number of pages9
JournalDNA and Cell Biology
Volume15
Issue number9
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cell Biology

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