MOLECULAR REGULATION OF TRANSMITTER RECEPTOR GENES

Project Details

Description

In FY 91, the Genetic Pharmacology Unit focused on the molecular
regulation of striatal dopamine receptor genes and of a model system for
peptide transmitters:
1. Transcriptional regulation of the Dl dopamine receptor gene. This
project which was initiated at the end of FY 90 involves three main
series of experiments. First, the human adenylate cyclase-linked Dl gene
has been cloned including its 5' regulatory elements, the nucleotide
sequence of a 2.4 kb stretch upstream from the known sequence has been
determined and found to lack TATA and CAAT boxes and to be rich in GC
content. In addition, a transcription initiation site has been
identified and cell type-specific enhancer/promoter activity of several
deletion mutants of the 5' flanking region delineated. Second, the
transcriptional regulation of the mouse Dl gene endogenously expressed in
a neural cell line is being studied in response to various pharmacologic
stimuli. Third, mRNA coding for adenylate cyclase-linked Dl receptor was
identified, for the first time, in renal tissue.
2. Promotor analysis of the rat D2 dopamine receptor gene. Also
initiated during the last quarter of FY 90, the gene coding for the rat
D2 receptor is now successfully cloned which encompasses the 5' upstream
elements based on sequence information and determination of transcription
start site. Like the human Dl gene, the rat D2 gene lacks a TATA box and
a CAAT box. Thus, both the Dl and D2 receptor genes belong to the
category of tissue-specific TATA-lacking genes. The promoter/enhancer
activity of various fragments of the D2 5' untranscribed region is
currently being characterized.
3. Regulation of POMC gene transcription. Studies done in FY 91 were
based on earlier findings in this laboratory about two protein-binding
DNA elements in the 5' upstream region of the mouse POMC gene: one
located between -119 and -106 bp relative to transcription start site and
is highly homologous to AP-2 consensus sequence, and the other located
between bases -137 and -131 and has a 70% homology to, but is distinct
from, AP-1 consensus sequence. Because of the physical proximity of
these two protein-binding elements, their potential interaction in
modulating gene transcription is currently being investigated using the
reporter gene CAT.
StatusNot started

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Neuroscience(all)

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