30 – 40% of all the drugs currently in clinical use are thought to target G Protein Coupled Receptors (GPCRs). Just how many GPCRs inhabit our genome isn’t clear. The latest estimate is 850 which is 4.2% of the 20,077 annotated protein genes we have. That being the case, it behooves drug chemists to know everything about them and how they work.
A recent paper [ Cell vol. 166 pp. 907 – 919 ’16 ] shows that a lot of the old thinking about GPCRs is wrong. Binding of a ligand to a GCPR results in a conformational change in its 7 transmembrane segments, so that the parts inside the cell bind to a heterotrimer of proteins which bind (and hydrolyze) GTP — this is the G protein. So far so good. The trimer splits up into its 3 constituents, unimaginatively called alpha, beta and gamma, each of which can act as a messenger that a ligand from outside the cell has landed on a GPCR, binding to other proteins causing all sorts of effects (e.g. can act as a second messenger)
All good things must end, and termination of GPCR signaling was thought to involve phosphorylation of the intracellular segment of the GPCR, binding of another protein (betaArrestin), removal from the cell membrane (so it can no longer bind its extracellular ligand) and then either destruction or recycling back to the cell membrane. So the old paradigm was betaArrestin binding equals the end of signaling.
It was thought that betaArrestin and the G protein competed for binding to the same intracellular amino acids of the GPCR. Not so says this paper. For some GPCRs both can bind, and signaling can continue, even though the complex of GPCR, G protein and betaArrestin is now inside the cell in an endosome. The complex is called the Multiplex. The examples given are GPCRs for parathyroid hormone (PTH) and Thyroid Stimulating Hormone (TSH). Blurry pictures are given of the complex. GPCRs have been divided into several classes and GPCRs for TSH and PTH are class B GPCRs — which contain a long phosphorylatable tail in the cytoplasm. The G protein binds to these GPCRs by its core region, while betaArrestin binds to the tail. Signaling continues apace.