Many of the drugs used for heart failure, high blood pressure, asthma, and schizophrenia work by latching onto a single type of protein on the surface of cells—but new evidence suggests these proteins often pair up, and that changes everything. For decades, scientists assumed these proteins, called G protein-coupled receptors (GPCRs), acted alone. Recent studies show they frequently form pairs—either identical twins (homodimers) or mismatched couples (heterodimers). This matters because a drug designed for a lone receptor may behave differently when that receptor is holding hands with a partner. The research team aims to map exactly how and where these pairs form, and why some molecules only bind to the paired versions. If successful, this fundamental science could reshape how pharmaceutical companies screen for new drugs. Instead of testing compounds against single receptors, they could design medicines that target specific receptor pairs. That would mean drugs with greater precision—hitting only the diseased cells—and fewer side effects. This is not yet a practical tool; it is a deep dive into the basic architecture of cell signalling. But understanding how receptors actually organise themselves on the cell surface is the kind of foundational knowledge that has historically opened entirely new classes of treatments.
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A substantial fraction of therapeutic medicines that are used to treat conditions as wide ranging as heart failure, elevated blood pressure, asthma, and schizophrenia act by either activating or inhibiting members of a family of proteins known as G protein-coupled receptors. These recognise the presence of extracellular hormones and neuro-transmitters and convert this information into signals that allow cells to respond. As well as the members of the G protein-coupled receptor family that are the molecular targets of current medicines, there are many more that are being actively explored to understand the details of their function and their potential roles in the development or modulation of disease. For many years it was considered that G protein-coupled receptors existed and functioned as monomers. However, a wide range of recent studies have indicated that this is probably incorrect and that as well as interacting with themselves to form homo-dimers, different members of the G protein-coupled receptor family that are present in the same cell may interact to form hetero-dimers. This may have important consequences both for understanding the action of currently used drugs and, more importantly, in the manner in which novel therapeutic medicines are identified and developed. The proposal plans to build on the insights my team and I have developed in this area over the past 5 years to understand the molecular basis of how and where G protein-coupled receptor homo-and hetero-dimers form and may be regulated and to take advantage of the identification of a number of hetero-dimer-selective ligands to understand the basis of this selectivity. This is likely to contribute to the development of novel medicines with greater selectivity and more limited side effects.
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