DETERMINANTS OF DOPAMINE RECEPTOR FUNCTION

Project: Research project

Project Details

Description

Regulation of mesocortical and striatonigral pathways by drugs aimed at
inhibiting or enhancing dopaminergic neurotransmission is a commonly used
strategy for treating many psychiatric and neurodegenerative diseases.
These drugs act through dopamine receptors to elicit both short and long
term changes in ion channel activity, protein kinase activities, and gene
expression. The recent discovery of multiple G-protein-linked dopamine
receptor subtypes exhibiting either classical "D1"-like or "D2-like"
ligand binding and signal transduction properties raises several
questions regarding the specific functions served by each receptor.
Currently there are at least two D1-like and at least three D2-like DA
receptors known. My previous immunohistochemical analyses of several D1-
and D2-like subtypes showed that each receptor protein has a unique
cellular and subcellular distribution within mesocortical, mesolimbic,
and nigrastriatal pathways. These results support the notion that each
subtype serves a unique function. However, subtype-specific signal
transduction differences have not yet been identified in vivo. Without
this functional information, it is difficult to understand the
physiologic requirements for multiple D1-like and D2-like receptor
subtypes. The goal of my research is to identify molecular and cellular
processes that differentially regulate DA receptor function and
localization in vivo using the D1-like receptors as a paradigm. One
experimental approach involves use of the yeast two-hybrid system to
identify proteins that potentially specify subtype-specific coupling to
signal transduction systems or subcellular localization. My strategy is
to use unique sequences within the closely related hD1 and hD5 subtypes
as bait for detecting interacting proteins expressed in human brain. In
complementary approaches, I will use subtype-specific monoclonal
antibodies and affinity chromatography to isolate interacting proteins.
Subtype-specific antibodies will also be used to confirm receptor
interaction with proteins identified in the two-hybrid screen through
immunoprecipitation experiments. This research will lead to a better
understanding of the molecular organization of the DA receptor system,
and identify new molecular targets for treating psychiatric and movement
disorders.
StatusFinished
Effective start/end date1/1/9712/31/01

ASJC

  • Medicine(all)