Orphan g protein-coupled receptors of the striatum - targets for schizophrenia

Schizophrenia is a debilitating disease that affects approximately 1% of the world's population. Symptoms of schizophrenia are divided into three main groups: psychosis, negative symptoms and cognitive impairment. Frontline therapies predominantly antagonise dopamine D2 receptor activity, and whilst these reduce psychosis they have minimal efficacy against the negative and cognitive symptoms. Despite new medications, there remains a paucity of effective treatment regimes with approximately 30% of patients remaining symptomatic.

Furthermore, there is a lack of promising novel targets in clinical development for the treatment of schizophrenia, with only a few emerging putative targets. One nascent target is the orphan G protein-coupled receptor, GPR52. Given the novelty of GPR52, there is a lack of biological and pharmacological information available on this receptors, therefore this project looks to explore and characterise GPR52 cell signalling and pharmacology.

Furthermore, there is scope for the investigation of cell signalling within distinct subcellular compartments using specific biosensors. This project aims to focus on second messenger signalling associated with this receptor, such as cyclic nucleotide accumulation, intracellular Ca2+ mobilisation and β-arrestin recruitment. This will be performed in a recombinant cell line, once a framework is established similar experiments will be executed in mouse brain slices, using state-of-the-art biosensors and microscopy.

Techniques will include recombinant cell culture, second messenger assays, brain dissections and microscopy.

The outcomes of this project will provide significant biological insight into a potential key target for the treatment of schizophrenia.