Dopamine Signalling

Dopamine is an important chemical messenger in the brain, responsible for a variety of functions, including mood, cognition and motor functions.  Release of dopamine at nerve terminals initiates a signalling cascade that activates a variety of cellular processes, including gene transcription, cell currents and ion flow.  Failure to regulate this process is associated with a range of neuropsychiatric conditions, including schizophrenia, Tourette syndrome, bipolar disorder, Parkinson’s disease, attention deficit hyperactivity disorder (ADHD) and addiction.  Studies outlining the role of dopamine in schizophrenia, led to a Nobel Prize to Carlsson and Greengard in 2000, and dopamine receptors remain the primary targets for antipsychotic drugs.  However, dopamine signalling is poorly understood at the molecular level.  Further understanding of this process, could lead to new drugs with improved efficacy and reduced side-effects.  We have used the yeast two-hybrid method for studying protein-protein interaction to gain detailed insights into this pathway and identified eleven dopamine receptor interacting proteins (DRIPs).

New Targets

All of the proteins we identified appear to be attractive candidates for drug development, based on their genomic localisation and biological properties.  Most of the DRIPs we have identified map to regions of the genome previously implicated in schizophrenia.  One of the eleven DRIPs we identified is of unknown function.  The remaining proteins appear to be involved in diverse biological functions, including neurotransmitter release, receptor trafficking, signalling and neuronal development.  One of the DRIPs binds both D1 and D3 receptors opening the possibility for focussed drug targeting that avoids dopamine receptors which regulate multiple downstream signalling pathways.

Scientific Landmarks

• Eleven dopamine receptor (DR) interacting proteins (DRIPs) identified.


• Evidence for DRIPs being localised to regions of the genome previously implicated in schizophrenia.


• Evidence for DRIPs being involved in cell death, signalling and neuronal   development, processes known to be involved in schizophrenia.


• Evidence for common signalling pathway involving D1 and D3.


• Genetic, biochemical and pharmacological evidence confirming interactions of  DRIPs with DRs.


• Evidence for role of DRIPs in dopamine signalling.


• Evidence showing DRIPs coexpressed in CNS with dopamine receptors.


• Highly expressing D1, D3 and DRIP-4 stable cell lines generated.


• Genetic study showing evidence for association of DRIPs 2,6,11 with schizophrenia.


• Evidence showing DRIP and dopamine receptor expression is coregulated.


• Evidence of DRIPs involved in trafficking and stability of dopamine receptors.