Proteins that act as air traffic controllers, managing the flow of signals in and out of human cells, have been observed for the first time in unprecedented detail using advanced microscopy techniques.
Described in new research published today in Cell, An international team of researchers led by Professor Davide Calebiro from the University of Birmingham has seen how beta-arrestin, a protein involved in managing a common and important group of cellular gateways, known as receptors, works.
Beta-arrestin is involved in controlling the activity of G protein-coupled receptors (GPCRs), which are the largest group of receptors in the human body and mediate the effects of many hormones and neurotransmitters. As a result, GPCRs are important targets for drug development and 30-40% of all current therapies are against these receptors. Once the receptors are activated, beta-arrestins dampen the signal in a process called desensitization, but they can also mediate their own signals.
The new study published in Cell has unexpectedly revealed that beta-arrestins stick to the outer cell membrane waiting for hormones or neurotransmitters to reach the receptors. Surprisingly, the interactions between beta-arrestins and active receptors are much more dynamic than previously thought, allowing much better control of receptor-mediated signals.
Davide Calebiro, Professor of Molecular Endocrinology at the Institute for Metabolism and Systems Research at the University of Birmingham and co-director of the Center for Membrane Proteins and Receptors (COMPARE) at the Universities of Birmingham and Nottingham, said:
“In our study, we used innovative single-molecule microscopy and computational methods developed in our lab to observe for the first time how individual beta-arrestin molecules function in our cells in unprecedented detail.
“We have revealed a new mechanism that explains how beta-arrestins can efficiently interact with receptors on a cell’s plasma membrane. Acting like air traffic controllers, these proteins detect when receptors are activated by a hormone or neurotransmitter. to modulate the flow of signals within our cells, and in doing so they play a key role in signal desensitization, a fundamental biological process that allows our bodies to adapt to prolonged stimulation.
“These results are highly unexpected and could pave the way towards new therapeutic approaches for diseases such as heart failure and diabetes or the development of more effective and better tolerated pain relievers.”
Pioneering research methods could lead to new drug therapies
This success was only made possible by the unique multidisciplinary collaborative environment provided by COMPARE, a world-leading research center for the study of membrane proteins and receptors bringing together 36 research groups with complementary expertise in cell biology, receptor pharmacology, biophysics, advanced microscopy. and computer science.
The novel single-molecule microscopy and computational approaches developed in this study could provide an important new tool for future drug development, allowing researchers to directly observe how therapeutic agents modulate receptor activity in living cells. in unprecedented detail. In the future, the COMPARE researchers led by Professor Calebiro plan to further automate the current pipeline so that it can be used to detect new drugs such as biased opioids that are currently in development for the treatment of pain.
Dr. Zsombor Koszegi, who shares first co-authorship on the study with Dr. Jak Grimes and Dr. Yann Lanoiselée, said:
“Being able to see for the first time how individual receptors and beta-arrestins work in our cells was incredibly exciting.
“Our findings are highly unexpected and take our understanding of how beta-arrestin coordinates receptor signaling to a whole new level, with important implications for cell biology and drug discovery.”
The research was funded by the Wellcome Trust, the Medical Research Council and the DBT/Wellcome Trust India Alliance.
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