For the first time, using cutting-edge imaging techniques, proteins that regulate the flow of messages into and out of human cells have been seen in unparalleled detail.
An international team of researchers led by Professor Davide Calebiro from the University of Birmingham have observed how beta-arrestin, a protein involved in controlling a common and significant group of cellular gateways known as receptors, functions, as described in new research published today in Cell.
The greatest class of receptors in the human body, G protein-coupled receptors (GPCRs), which mediate the effects of numerous hormones and neurotransmitters, are regulated by beta-arrestin.
As a result, 30–40% of all currently used therapies are directed against GPCRs, which are important targets for drug research. Beta-arrestins can mediate their own signals in addition to dampening the signal once the receptors have been engaged, a process known as desensitization.
Unexpectedly, the new study published in Cell has shown that beta-arrestins cling to the outer cell membrane as they wait for hormones or neurotransmitters to bind to receptors.
Surprisingly, beta-arrestins and active receptors interact in a way that is much more dynamic than was previously believed, which improves the ability to modulate receptor-mediated signals.
Our findings are highly unexpected and bring our understanding of the way beta-arrestin coordinates receptor signalling to a whole new level, with major implications for cell biology and drug discovery.
Dr. Zsombor Koszegi
Davide Calebiro, 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 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 work in our cells with unprecedented detail.”
“We have revealed a new mechanism that explains how beta-arrestins can efficiently interact with receptors on the plasma membrane of a cell. Acting like air traffic controllers, these proteins sense when receptors are activated by a hormone or a neurotransmitter to modulate the flow of signals within our cells. By doing so, they play a key role in signal desensitisation, a fundamental biological process that allows our organism to adapt to prolonged stimulation.”
“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.”
Pioneering research methods could lead to novel drug therapies
Only COMPARE’s exceptional multidisciplinary collaborative environment, which brings together 36 research groups with complementary expertise in cell biology, receptor pharmacology, biophysics, advanced microscopy, and computer science, could have made this success possible. COMPARE is a world-renowned research center for the study of membrane proteins and receptors.
With the aid of the cutting-edge single-molecule microscopy and computational methods created in this study, researchers may have access to a powerful new tool for developing drugs in the future. They will be able to see up close and in extreme detail how therapeutic chemicals modify receptor activation in living cells.
The process will eventually be further automated by COMPARE researchers under the direction of Prof. Calebiro so that it may be used to screen for novel medications such biased opioids, which are currently being developed for the treatment of pain.
Dr. Zsombor Koszegi, who shares first co-authorship of 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 bring our understanding of the way beta-arrestin coordinates receptor signalling to a whole new level, with major implications for cell biology and drug discovery.”
The Wellcome Trust, Medical Research Council and the DBT/Wellcome Trust India Alliance funded the research.
