When receptors stop working together

Researchers at the Max Planck Institute develop a new pharmacological approach that specifically targets receptor interactions – with implications for immune defense and blood pressure regulation

G protein-coupled receptors (GPCRs) are among the most important signaling molecules in biology and the most frequently targeted class of receptors in pharmacology. Traditionally, drug development has focused on activating or inhibiting individual receptors.

A new study from our research group lead by Nina Wettschureck introduces in collaboration with the group of Peter Kolb, University of Marburg, a fundamentally different strategy: modulating the functional interactions between receptors themselves.

The researchers investigated the orphan GPCRs GPRC5B and GPRC5C, which do not function simply as independent signaling units but regulate the activity of other GPCRs through receptor–receptor interactions.

Using structural modeling, molecular docking and experimental validation, the team identified the small molecule MP20, which specifically disrupts dimerization of GPRC5B/C with other GPCRs. This provides the first evidence that GPCR dimer interfaces can be directly targeted by a pharmacological compound.

The study demonstrates the functional consequences of this new mode of intervention:

• Strengthening the innate immune system: Disruption of GPRC5B/C interactions enhanced macrophage activation and strengthened innate immune defense mechanisms in models of bacterial and viral infection.
• Effect on blood pressure regulation: In vascular smooth muscle cells, inhibition of GPRC5B/C dimerization altered signaling pathways controlling vascular tone, thereby reducing arterial hypertension.

Beyond these specific biological effects, the key advance lies in the concept itself: receptor–receptor interactions represent an additional layer of pharmacological regulation and a previously underexplored class of therapeutic targets.

By moving beyond the classical “one receptor – one drug” paradigm, this work opens new perspectives for understanding and manipulating complex cellular signaling networks.