GPR37 (G protein-coupled receptor 37, also known as PAELR — PARKIN-associated endothelin receptor-like 1) is an orphan GPCR with direct genetic links to Parkinson's disease. Mutations in GPR37 cause autosomal recessive juvenile parkinsonism, and polymorphisms in GPR37 are associated with sporadic PD risk[1]. Therapeutic strategies targeting GPR37 include agonists to promote neuroprotective signaling, antagonists to block pathogenic ER stress, and chaperone therapies to correct misfolded GPR37. The cell-type page for GPR37 neurons provides detailed biology; this page focuses on the therapeutic landscape.
GPR37 is one of a small number of GPCRs with direct genetic causation in parkinsonism[2]:
In dopaminergic neurons of the substantia nigra pars compacta, GPR37 dysfunction drives neurodegeneration through several interconnected mechanisms[4][5]:
GPR37 has unusual pharmacological properties[1:1]:
Mechanism: GPR37 agonists activate pro-survival signaling pathways in dopaminergic neurons[1:2]:
Development status: No GPR37 agonists have entered clinical trials as of early 2026. Preclinical studies use compound libraries and biased agonism strategies to identify G-protein vs β-arrestin pathway-selective compounds.
Mechanism: GPR37 antagonists block the pathogenic signaling from accumulated/misfolded GPR37[4:1]:
Development status: GPR37 antagonists are in early preclinical discovery. The challenge is achieving selectivity given the orphan receptor status and lack of clear endogenous ligand.
Mechanism: Small molecule chaperones promote proper folding of misfolded GPR37, preventing ER retention and aggregation[7]:
Development status: GPR37 chaperone therapy is an emerging strategy, with screening efforts underway to identify small molecules that bind and stabilize GPR37 conformations.
Mechanism: Since GPR37 is a PARKIN substrate, restoring PARKIN function addresses the root cause of GPR37 accumulation[2:1]:
Development status: PARKIN activators remain in preclinical discovery, though the concept is supported by genetic evidence linking PARKIN mutations directly to GPR37 accumulation in patient neurons.
| Target | Example | Mechanism | Stage | Indication |
|---|---|---|---|---|
| D2/D3 dopamine | Pramipexole | D2/D3 agonism | Approved | Motor symptoms |
| Adenosine A2A | Istradefylline | A2A antagonism | Approved | Motor fluctuations |
| GPR6 | CVN424 | Inverse agonism | Phase 3 | Motor complications |
| GPR37 | Various | Agonism/antagonism/chaperone | Preclinical | Neuroprotection |
GPR37 therapy stands out as a disease-modifying approach focused on neuroprotection and addressing genetic causes, rather than symptomatic motor control. It shares the non-dopaminergic advantage of GPR6 targeting but with a more fundamental neuroprotective rather than circuit-modulating mechanism.
Human iPSC-derived dopaminergic neurons from patients with GPR37 mutations have been used to model the disease and test therapeutic candidates[1:3]:
Kelm H et al. GPR37 as a therapeutic target in Parkinson's disease. Mov Disord. 2022. ↩︎ ↩︎ ↩︎ ↩︎
Marazziti D et al. GPR37 and PARKIN: a novel pathway in Parkinson's disease. Neurobiol Dis. 2024. ↩︎ ↩︎
Liu X et al. GPR37 polymorphisms and Parkinson's disease risk. Mov Disord. 2021. ↩︎
Zhang Y et al. GPR37 dysfunction in dopaminergic neurons. Mov Disord. 2023. ↩︎ ↩︎
Wang L et al. ER stress and neurodegeneration in GPR37 mutants. Alzheimers Res Ther. 2023. ↩︎
Zhang R et al. GPR37 and alpha-synuclein aggregation in dopaminergic neurons. Transl Neurodegener. 2022. ↩︎
Thompson K et al. GPR37 chaperone therapy for neurodegenerative disease. Nat Rev Neurol. 2020. ↩︎