Project

Global analysis of the effect of dopamine D4 receptor ubiquitination on receptor signaling

Code
31521613
Duration
01 January 2013 → 31 December 2015
Funding
Research Foundation - Flanders (FWO)
Research disciplines
  • Engineering and technology
    • Catalysis and reacting systems engineering
    • Chemical product design and formulation
    • General chemical and biochemical engineering
    • Process engineering
    • Separation and membrane technologies
    • Transport phenomena
    • Other (bio)chemical engineering
Keywords
dopamine
 
Project description

Receptors are proteins in cells important for signaling; endogenous molecules released by one cell
influence the other cell by activating receptors. Many receptors are located at the outside of the cells
(ie in the cell membrane). The largest group of membrane receptors consists of the G protein-coupled
receptors (GPCRs). They are called GPCRs because upon stimulation, they activate another type of
protein (G protein) to pass the signal into the cell. GPCRs are involved in disease processes where
they can be over- or understimulated, explaining why the pharmaceutical industry develops stimulators
and blockers of GPCRs.
The dopamine D4 receptor (D4R) is a GPCR and has an interesting feature: in one of the three
intracellular loops there is a variable number of repeats; persons with seven repeats (D4.7R) show a
predisposition to develop Attention Deficit Hyperactivity disorder (ADHD). The functional role of this
region is not known and there have been no major functional differences reported.
We have identified a protein, KLHL12, which specifically interacts with this region and which
enhances an important modification, ubiquitination. The increase in ubiquitination by KLHL12 of
D4.7R is much less compared to the other tested D4R variants. Most studies have focused on the role of
GPCR ubiquitination in receptor degradation; however, our profound investigation does not indicate a
role in degradation. Therefore we are now focusing on the role of ubiquitination in receptor
signaling.