From sight to pumping blood to fighting infections, almost every biological function depends on a diverse array of cell surface receptors called G protein coupled receptors (GPCRs). Nested within the cell membrane, these “gatekeepers” pick up a wide variety of external signals and trigger internal chain reactions that turn on (or off) vital processes such as cell division, metabolism or cell death. Pioneering work on their structure and function led to the Nobel Prize in 2012.
These receptors have a 7-member “loop” embedded in the membrane with a “tail” dangling inside the cell. When foreign particles dock to their outer surface, their shape shifts and they activate molecular messengers bound to the inner tail, primarily G-proteins, which then set off a complex cascade of fundamental molecular events.
At times, GPCR signalling needs to be turned off; to prevent uncontrolled cell division, for example. Enter ß-arrestins (ßarrs). They shut down GPCR signalling by masking G-protein binding sites, while also triggering other, independent signalling pathways. Sometimes, ßarrs force GPCRs to be drawn into the cell for digestion.
Scientists widely believed that for ßarr to do these actions, it needs to bind to both the “tail” and the “loop” of the GPCR. New research shows that ßarr binding to the GPCR tail alone is enough to trigger both ßarr-controlled signalling pathways and GPCR absorption into the cell. The results were published in Nature Communications.
Senior author Arun K. Shukla believes that these findings could change the way drug development for GPCRs is being approached.
GPCRs are highly sought-after targets for drugs aimed at tackling a variety of conditions including cancer, diabetes, congestive heart failure and central nervous system disorders. “About half of the currently prescribed medicines work by targeting these receptors,” says Shukla, an Assistant Professor and Wellcome Trust/DBT Intermediate Fellow at the Department of Biological Sciences and Bioengineering, IIT Kanpur.
“Up to this point, people were designing drugs that will bind to the receptor and change its shape in such a way that it engages with ßarr on both sites,” he says. But now “simpler” drugs can be designed that bring about a much smaller structural change in the receptor, he adds.
Recently, research has also focused on developing more effective drugs that preferentially turn on either ßarr or G-protein pathways (“biased ligands”), to reduce unwanted side effects triggered by the other. A drug called carvedilol, for example, selectively activates ßarr-dependent pathways to relax heart muscles after a heart attack. It was generally believed that even ßarr-biased drugs such as carvedilol need to incite ßarr binding at both sites of the GPCR, says Shukla. “We have shown that this is not true. That is an entirely novel mechanistic detail that was lacking before with respect to how biased ligands work.”
Shukla’s team created synthetic GPCR-ßarr complexes with and without loop binding by genetically removing one of the transmembrane loops. The findings were reported in adrenaline receptors, but Shukla believes that the mechanism could be similar for other GPCR classes as well. His team also plans to delve deeper into uncovering other ßarr functions that may be driven by this single-site interaction.