Analyzing the Complex Sequence of Events Involved in Beta-Arrestin Interactions

Proteins that work like air traffic controllers, controlling the flow of signals in and out of human cells, have been examined in unparalleled detail for the first time using modern microscope techniques.

Analyzing the Complex Sequence of Events Involved in Beta-Arrestin Interactions

Image Credit: University of Birmingham

An international group of scientists guided by Professor Davide Calebiro of the University of Birmingham examined how beta-arrestin, a protein involved in controlling a common and essential group of cellular gateways known as receptors, operates in new research published in Cell.

Beta-arrestin regulates the activation of G protein-coupled receptors (GPCRs), which are the most numerous receptors in the human body, and modulate the effects of numerous hormones and neurotransmitters.

As a result, GPCRs are important targets for drug development, with 30–40% of all existing medicines targeting these receptors. When the receptors are activated, beta-arrestins dampen the signal in a process known as desensitization, but they can also mediate their own signals.

Recent research released in Cell has revealed that beta-arrestins adhere to the outer cell membrane and wait for hormones or neurotransmitters to bind to receptors. Interestingly, interactions between beta-arrestins and active receptors are significantly more dynamic than previously anticipated, allowing for much better regulation of receptor-mediated signals.

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.”

Davide Calebiro, Professor, Molecular Endocrinology, Institute of Metabolism and Systems Research, University of Birmingham

Davide Calebiro is also the Co-Director of the Centre of Membrane Proteins and Receptors (COMPARE) of the Universities of Birmingham and Nottingham.

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 desensitization, a fundamental biological process that allows our organism to adapt to prolonged stimulation,” Davide Calebiro adds.

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.”

Davide Calebiro, Professor, Molecular Endocrinology, Institute of Metabolism and Systems Research, University of Birmingham

Pioneering Research Methods Could Lead to Novel Drug Therapies

This breakthrough was only possible because of COMPARE, a world-leading research center for the study of membrane proteins and receptors that merges 36 research groups with complementary skills in cell biology, biophysics, receptor pharmacology, advanced microscopy, and computer science.

This study’s innovative single-molecule imaging and computational methodologies could give a vital new tool for future drug development, enabling scientists to directly examine how therapeutic drugs influence receptor activation in living cells in unprecedented detail.

COMPARE researchers headed by Prof. Calebiro intend to further automate the present pipeline in the future so that it can be used to screen for new drugs, such as biased opioids now under development for pain management.

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 signaling to a whole new level, with major implications for cell biology and drug discovery,” says Dr Zsombor Koszegi, who shares first co-authorship of the study with Dr Jak Grimes and Dr Yann Lanoiselée.

Source:
Journal reference:

Grimes, J., et al. (2023). Plasma membrane preassociation drives β-arrestin coupling to receptors and activation. Cell. doi.org/10.1016/j.cell.2023.04.018.

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