GPRC5B: A G-Protein-Coupled Receptor Regulates Macrophage Activity

GPRC5B influences the Prostaglandin Receptor and affects the immune response

February 20, 2025

A team of scientists led by Prof. Dr. Nina Wettschureck at the Max Planck Institute for Heart and Lung Research has succeeded in clarifying the function of a so-called orphan G-protein-coupled receptor. Orphan receptors are receptors whose function has not yet been deciphered. The Bad Nauheimer researchers have now found that the orphan receptor GPRC5B plays a crucial role in regulating macrophage activity. This discovery could provide important impulses for the development of new therapies against inflammatory diseases.

Macrophages play a central role in the defence against pathogens, but are also involved in the development of chronic inflammation.

© pic: canva.com

Macrophages play a central role in the defence against pathogens, but are also involved in the development of chronic inflammation.

© pic: canva.com

Macrophages: The Body's Defense Cells
Macrophages are a specific type of white blood cell. In the immune response, they have the task of neutralizing pathogens and foreign substances as so-called phagocytes. Therefore, they play a central role in defending against pathogens. Their function is regulated by a complex interplay of various signaling molecules, known as inflammatory mediators. A dysregulation can lead to a weakened immune response but also to chronic inflammation.

The research group of Prof. Wettschureck has now shown that a receptor with previously unknown function can regulate the potency of Prostaglandin E2: GPRC5B. This receptor binds to a receptor on the surface of macrophages, the Prostaglandin Receptor EP2. This has a significant impact on its function:

"If GPRC5B binds to the Prostaglandin Receptor EP2, it influences the function of the EP2 receptor and thereby inhibits the activation of the macrophages," says Wettschureck. "In a further experiment, we inhibited the interaction between GPRC5B and the Prostaglandin Receptor. As a result, the macrophages were more active and could, for example, better fight invading bacteria,"

explains Wettschureck. Jeonghyeon Kwon, first author of the study, adds:

The receptor GPRC5B interacts with the PGE2 receptor EP2 in macrophages, leading to an increased membrane availability and signal strength of the EP2 receptor. If GPRC5B is absent or if the interaction between the two receptors is inhibited, this reduces anti-inflammatory EP2 signals. As a result, the migration and phagocytosis of macrophages are enhanced. In an ongoing project, we are currently trying to identify low-molecular-weight compounds that interfere with the GPRC5B/EP2 dimerization and can influence chronic inflammatory processes. The image shows the amino acids involved in the interaction between the two receptors.

© MPI for Heart and Lung Research

The receptor GPRC5B interacts with the PGE2 receptor EP2 in macrophages, leading to an increased membrane availability and signal strength of the EP2 receptor. If GPRC5B is absent or if the interaction between the two receptors is inhibited, this reduces anti-inflammatory EP2 signals. As a result, the migration and phagocytosis of macrophages are enhanced. In an ongoing project, we are currently trying to identify low-molecular-weight compounds that interfere with the GPRC5B/EP2 dimerization and can influence chronic inflammatory processes. The image shows the amino acids involved in the interaction between the two receptors.

© MPI for Heart and Lung Research

"We have also found out exactly how the two receptors interact. This is the basis for a therapeutic approach. We want to develop a drug that targets this regulatory interaction."

The hope is to develop a therapy that can more precisely target acute and chronic inflammatory diseases.