MSGID: 1:317/3 645486cd   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
   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   
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   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.   
      
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   Story Source: Materials provided by University_of_Birmingham. Note:   
   Content may be edited for style and length.   
      
      
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   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   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/05/230504121035.htm   
      
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