GPR37: Its Function in the Body and Role in Disease

The protein GPR37 is a receptor involved in maintaining the health of cells, particularly within the nervous system. Scientists are actively exploring its connections to various diseases because its functions in cellular processes are important for human physiology.

Understanding GPR37: A Molecular Profile

GPR37 is classified as a G protein-coupled receptor, or GPCR. This large family of receptors is embedded in the cell membrane, where they detect signals from outside the cell and transmit them to the interior, triggering a response. GPR37 is characterized by seven domains that span the cell’s membrane, a common feature of GPCRs.

This receptor is also known as the Parkin-Associated Endothelin-like Receptor (PAELR). This name originates from its interaction with a protein called Parkin, which is linked to certain forms of Parkinson’s disease.

GPR37 is found in various tissues but is most abundant in the brain, particularly in oligodendrocytes, the cells that produce the myelin sheath. It has high expression in regions such as:

• The substantia nigra
• The cerebellum
• The hippocampus
• The frontal cortex

Beyond the brain, GPR37 is also detected in the spinal cord, testis, liver, and placenta.

Key Biological Functions of GPR37

In its normal capacity, GPR37 participates in several cellular processes that maintain tissue health. One of its functions involves protein quality control, playing a role in the cellular response to misfolded proteins. GPR37 can induce a process called autophagy, which helps clear out damaged cellular components, including these misfolded proteins.

The receptor is also involved in promoting the survival of neurons, a function often described as neuroprotection. GPR37 acts as a receptor for prosaposin and related molecules called prosaptides, which are known to have protective effects on nerve cells and glia. This interaction contributes to the resilience of the nervous system.

Furthermore, GPR37 has a role in the development and function of oligodendrocytes, the cells that produce myelin. Myelin is the fatty substance that wraps around nerve axons to facilitate rapid communication between neurons. The interaction between GPR37 and a protein called osteocalcin helps regulate the differentiation of oligodendrocytes and the production of myelin.

GPR37’s Prominent Role in Parkinson’s Disease

The connection between GPR37 and Parkinson’s disease is one of its most studied aspects. This link stems from its interaction with the protein Parkin, as mutations in the gene that produces Parkin are a known cause of an early-onset, inherited form of Parkinson’s disease. This interaction suggests a shared pathway that, when disrupted, contributes to the disease.

An accumulation of misfolded GPR37 protein can become toxic to the dopamine-producing neurons that are progressively lost in Parkinson’s disease. The substantia nigra is the primary site of this neuronal loss. When GPR37 is not properly folded or cleared by cellular machinery, it can build up and trigger stress pathways that lead to cell death.

Evidence from post-mortem brain tissue of Parkinson’s patients shows GPR37 as a component of Lewy bodies, the abnormal protein aggregates that are a hallmark of the disease. The presence of GPR37 within these structures indicates its involvement in the pathological processes of Parkinson’s.

Animal models have also shown that the overexpression of GPR37 can lead to the loss of specific nerve cells, mimicking aspects of the disease. Scientists are also exploring a form of the receptor, ecto-GPR37, as a potential biomarker for Parkinson’s disease.

GPR37’s Involvement in Other Health Conditions

Beyond its well-documented role in Parkinson’s, GPR37 is implicated in a range of other health issues. Research has connected a mutation in the GPR37 gene to autism spectrum disorder. This suggests that the receptor’s functions in brain development and neuronal communication may be disrupted in this condition.

The receptor’s influence extends to cancer. Studies have shown that GPR37 can promote the growth of certain cancer cells, including those in lung cancer, colorectal cancer, gastric cancer, and multiple myeloma. In some cases, GPR37 helps cancer cells resist apoptosis, or programmed cell death.

There is also evidence linking GPR37 to other neurodegenerative and inflammatory conditions. Its signaling is involved in the migration of specific cell types in the brain, a process relevant to developmental disorders or injury response. The receptor also modulates inflammatory responses, suggesting a role in regulating the immune response within the brain.

Investigating GPR37: Research Insights and Therapeutic Prospects

Scientists employ a variety of techniques to study GPR37. Animal models, such as mice genetically modified to either lack the GPR37 gene or overexpress it, are important tools. These models allow researchers to observe the effects of GPR37 manipulation. Cell culture systems are also used to study specific cell types expressing GPR37 in a controlled environment.

A challenge in studying GPR37 has been its status as an “orphan” receptor, meaning its activating molecules (ligands) were unknown for a long time. While prosaposin and osteocalcin have been identified as ligands, the search for other binding partners continues. Identifying these ligands is necessary to fully understand how the receptor’s activity is regulated.

This research opens possibilities for new therapeutic strategies. By understanding how GPR37 contributes to disease, scientists can develop drugs that modulate its activity. For example, a drug that enhances GPR37’s neuroprotective functions could be beneficial for neurodegenerative diseases, while one that blocks its growth-promoting effects could be used in cancer treatment.