Allosteric modulation in monomers and oligomers of a G protein-coupled receptor

Proteins called G protein-coupled receptors (GPCRs) are found on the surface of cells throughout the body. Hormones or other signal molecules – collectively known as ligands – from outside the cell can bind to the receptors to activate them. This causes a change in the structure of the receptor, which triggers a signal inside the cell to alter the cell’s behavior. GPCRs are known to form clusters of two or more receptor units, but it is not known if these clusters have unique properties or what role they play in cells. Many drugs can bind to GPCRs and most of them block the activity of the receptors by taking the place of the natural ligand. Another way to alter the activity of a GPCR is with so-called 'allosteric' drugs. These bind to different sites on the receptor than the natural ligands do and can inhibit or enhance binding of the ligands by altering the shape of the receptor. Shivnaraine et al. investigated how a type of GPCR called muscarinic cholinergic receptors interact within clusters. This involved developing a method to track the receptor in mammalian cells using a fluorescent sensor that detects changes in the allosteric site. The experiments show that two or more GPCRs need to interact for the receptors to respond to allosteric drugs in a manner that reflects the normal effect of the drugs on the body. This result is unexpected in light of the assumption that individual receptor molecules act independently. Shivnaraine et al.’s findings indicate that the clusters may play a role in the normal behavior of GPCRs in cells. A future challenge is to understand exactly how the GPCRs interact with each other.