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Cellular traffic controllers caught managing flow of signals from receptors

First time that individual beta-arrestin molecules are directly observed as they control receptor-mediated signals in living cells using advanced microscopy.

4 May 2023
Air traffic controllers sat in control tower at Heathrow Airport in London, UK with airport and planes in the background

Inside Heathrow Air Traffic Control Tower by NATS - UK air traffic control is licensed under CC BY-ND 2.0

Proteins that act like air traffic controllers, managing the flow of signals in and out of human cells, have been observed for the first time with 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 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 desensitisation but can also mediate signals of their own.

The new study published in Cell has unexpectedly revealed that beta-arrestins attach themselves to the outer cell membrane waiting for hormones or neurotransmitters to land on receptors. 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.

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.

Professor Davide Calebiro

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.”

Close up of a selection of medicines including white round pills, white and black capsules

Pioneering research methods could lead to novel drug therapies

This success was only possible thanks to the unique multidisciplinary collaborative environment provided by COMPARE, a world-leading research centre for the study of membrane proteins and receptors that brings 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 a significant new tool for future drug development, allowing researchers to directly observe how therapeutic agents modulate receptor activity in living cells with unprecedented detail. In the future, COMPARE researchers led by Prof Calebiro plan to further automate the current pipeline so that it can be used to screen for novel drugs such as biased opioids currently in development 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 research was funded by the Wellcome Trust, Medical Research Council and the DBT/Wellcome Trust India Alliance.

Notes for editors

  • For media enquiries please contact Tim Mayo, Press Office, University of Birmingham, tel: +44 (0)7920 405040.
  • The University of Birmingham is ranked amongst the world’s top 100 institutions. Its work brings people from across the world to Birmingham, including researchers, teachers and more than 6,500 international students from over 150 countries.
  • The University of Birmingham is a founding member of Birmingham Health Partners (BHP), a strategic alliance which transcends organisational boundaries to rapidly translate healthcare research findings into new diagnostics, drugs and devices for patients. Birmingham Health Partners is a strategic alliance between seven organisations who collaborate to bring healthcare innovations through to clinical application:
    • University of Birmingham
    • University Hospitals Birmingham NHS Foundation Trust
    • Birmingham Women's and Children's Hospitals NHS Foundation Trust
    • Aston University
    • The Royal Orthopaedic Hospital NHS Foundation Trust
    • Sandwell and West Birmingham Hospitals NHS Trust
    • West Midlands Academic Health Science Network
    • Birmingham and Solihull Mental Health NHS Foundation Trust
  • Wellcome supports science to solve the urgent health challenges facing everyone. We support discovery research into life, health and wellbeing, and we’re taking on three worldwide health challenges: mental health, infectious disease and climate and health.

Featured staff

  • Professor Davide Calebiro

    Head of the Department of Metabolism and Systems Science

    Staff Profile for Professor Davide Calebiro, Professor of Molecular Endocrinology and Wellcome Senior Research Fellow at the Department of Metabolism and Systems Science at the University of Birmingham.

    Phone: +44 (0)121 414 3928
    Email: d.calebiro@bham.ac.uk

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