Structure-Function Analysis of the D3 Dopamine Receptor

Project Details


DESCRIPTION(Provided by applicant):
The dopaminergic system and in particular the D3 dopamine receptor have been
implicated in the etiology ofneuropsychiatric disorders such as schizophrenia
and drug addiction. Studies using genetic, molecul biological and
pharmacological techniques suggest that the D3 dopamine receptor plays an
important role locomotor activity and behavioral effects involving
reinforcement and reward. However the role of L receptor in neuronal signaling
and the molecular mechanisms by which it modulates the physiological and
behavioral effects are not well understood. It has been proposed that the D3
receptor exerts its phenotyp effects by modulating ion channel function and
consequently neuronal signaling.

We have recent demonstrated that the human D3 receptor expressed in the AtT-20
neuroendocrine cell line couples endogenous G-protein activated inward
rectifier potassium (GIRK) channels and P/Q-type calcium channel thereby
modulating spontaneous secretory activity. In this project, we plan to
characterize the properties oft] D3 dopamine receptor and identify the
structural features of the receptor that are involved in coupling to o about
channels. Given the limited expression profile of the D3 receptor in vivo, the
lack of selective pharmacologic ligands, and the need to evaluate properties of
mutated D3 receptors, this study will primarily use the AtT-2 heterologous
expression system. In addition, to assess physiological relevance, we will also
study the I receptor-ion channel coupling in primary cultures of rat nucleus
accumbens neurons using a combination electrophysiology and single cell reverse
transcriptase-PCR. To define the properties of the D3 dopamine receptor, we
will employ methods such as single cell electrophysiology, mutagenesis and
expression recombinant and tagged receptors. We will address three specific
aims: (1) Investigate the coupling of I receptor to ion channels in primary
neuronal cultures from rat nucleus accumbens; (2) Identify the G-proteins and
other regulatory proteins that couple the D3 receptor to ion channels and
characterize the domains of t D3 receptor that interact with these proteins;
and (3) Determine the molecular mechanisms underlying I receptor
desensitization. These experiments will provide a better understanding of the
properties of the I dopamine receptor and the molecular mechanisms by which it
modulates neuronal signaling. In doing so, ti study will make significant
contributions toward ongoing efforts to define the role of D3 receptor
neurological disorders such as schizophrenia.
Effective start/end date8/15/017/31/05


  • National Institute of Mental Health: $309,075.00
  • National Institute of Mental Health: $235,500.00
  • National Institute of Mental Health: $235,500.00


  • Physiology


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