Beta-arrestins attach themselves to outer cell membranes, waiting for hormones or neurotransmitters to land on receptors – an unexpected and surprising finding recently published in Cell.
Researchers led by Davide Calebiro, MD, professor of Molecular Endocrinology in the Institute of Metabolism and Systems Research at the University of Birmingham and Co-Director of the Centre of Membrane Proteins and Receptors (COMPARE) of the Universities of Birmingham and Nottingham point out that beta-arrestin is involved in controlling the activity of G protein-coupled receptors (GPCRs). GPCRs are major targets for drug development and between 30-40% of all current therapeutics are against these receptors. Once the receptors are activated, beta-arrestins dampen the signal in a process called desensitization but can also mediate signals of their own.
For this study, Calebiro and his team used innovative single-molecule microscopy and computational methods they developed to observe for the first time how individual beta-arrestin molecules work in cells with unprecedented detail. Surprisingly, the interactions between beta-arrestins and active receptors are much more dynamic than previously thought, allowing for a far better control of receptor-mediated signals.
Calebiro likens beta-arrestins to air traffic controllers, sensing when receptors are activated by a hormone or a neurotransmitter to modulate the flow of signals within cells. By doing so, they play a key role in signal desensitization, a fundamental biological process that allows our organism to adapt to prolonged stimulation.
“Altogether, our findings redefine the current model of receptor-β-arrestin interactions by revealing a critical role of β-arrestin binding to the lipid bilayer for efficient β-arrestin interaction with receptors and for accumulation on the plasma membrane,” the authors conclude.
“These results are highly unexpected and could pave the way to novel therapeutic approaches for diseases such as heart failure and diabetes or the development of more effective and better tolerated analgesics,” Calebiro says.