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

Date:
May 4, 2023
Source:
University of Birmingham
Summary:
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. New findings could inform the development of better
drugs for pain relief, diabetes or heart failure.


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FULL STORY ========================================================================== 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.

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 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 Lanoisele'e, 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.

* RELATED_TOPICS
o Health_&_Medicine
# Vitamin_A # Stem_Cells # Immune_System #
Alzheimer's_Research # Pharmacology # Human_Biology #
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* RELATED_TERMS
o Analgesic o Confocal_laser_scanning_microscopy o Artery o
Echocardiography o Psychedelic_drug o Suicide o Chemotherapy
o Chronic_pain

========================================================================== Story Source: Materials provided by University_of_Birmingham. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jak Grimes, Zsombor Koszegi, Yann Lanoisele'e, Tamara Miljus,
Shannon L.

O'Brien, Tomasz M. Stepniewski, Brian Medel-Lacruz, Mithu Baidya,
Maria Makarova, Ravi Mistry, Joe"lle Goulding, Julia Drube,
Carsten Hoffmann, Dylan M. Owen, Arun K. Shukla, Jana Selent,
Stephen J. Hill, Davide Calebiro. Plasma membrane preassociation
drives b-arrestin coupling to receptors and activation. Cell,
2023; DOI: 10.1016/j.cell.2023.04.018 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/05/230504121035.htm

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