GPR37 and GPR37L1 differently interact with dopamine 2 receptors in live cells

Receptor-receptor interactions are essential to fine tune receptor responses and new techniques enable closer characterization of the interactions between involved proteins directly in the plasma membrane. Fluorescence cross-correlation spectroscopy (FCCS), which analyses concurrent movement of bound molecules with single-molecule detection limit, was here used to, in live N2a cells, study interactions between the Parkinson's disease (PD) associated orphan receptor GPR37, its homologue GPR37L1, and the two splice variants of the dopamine 2 receptor (D2R). An interaction between GPR37 and both splice forms of D2R was detected. 4-phenylbutyrate (4-PBA), a neuroprotective chemical chaperone known to increase GPR37 expression at the cell surface, increased the fraction of interacting molecules. The interaction was also increased by pramipexole, a D2R agonist commonly used in the treatment of PD, indicating a possible clinically relevance. Cross-correlation, indicating interaction between GPR37L1 and the short isoform of D2R, was also detected. However, this interaction was not changed with 4-PBA or pramipexole treatment. Overall, these data provide further evidence that heteromeric GPR37-D2R exist and can be pharmacologically modulated, which is relevant for the treatment of PD. This article is part of the Special Issue entitled 'Receptor heteromers and their allosteric receptor-receptor interactions'.