Prospects of targeting GPR37 for neurotherapeutics

INTRODUCTION: GPR37 has evolved from a proteostasis-linked liability in Parkinson's disease into a biologically diverse GPCR with potential relevance for oligodendrocyte maturation, neuroimmune resolution, and dopaminergic vulnerability. However, its therapeutic potential remains constrained by incomplete pharmacology and uncertainty regarding the receptor forms and cellular contexts most relevant for intervention. AREAS COVERED: This review evaluates the main features shaping GPR37 druggability, including N-terminal processing, receptor organization, constitutive activity, and the current deorphanization landscape. Relevant literature on GPR37 biology, pharmacology, and translational studies was critically assessed, with emphasis on receptor availability, processing, ligand reproducibility, paralog selectivity, and disease-relevant assay systems. We also discuss ecto-GPR37 as a potential Parkinson's disease biomarker linked to receptor processing. EXPERT OPINION: Progress in the field will depend less on assigning a single endogenous ligand than on developing a rigorous pharmacology toolkit that measures receptor availability, processing, and signaling in parallel. In the near term, biomarker-led and chemical-biology approaches appear more realistic than classical agonist/antagonist development.