¹Department of Metabolism and Systems Science (MSS), College of Medicine and Health, University of Birmingham, UK

²Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, UK

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and major drug targets. Whereas structural studies have provided major insights into the activation mechanisms of GPCRs, how these receptors operate in our cells to produce specific biological responses remains insufficiently understood. Davide’s group develops innovative optical methods based on FRET/BRET and single-molecule microscopy that enable studying GPCR signalling in living cells with unprecedented spatiotemporal resolution. Using these approaches, they were among the first to demonstrate that GPCRs are not only active at the plasma membrane but also in the endosomal compartment, which has challenged the classical model of GPCR signalling. Ongoing work in the Calebiro lab is dedicated to further clarifying the physiological and pharmacological implications of GPCR signalling at intracellular sites, with a particular focus on metabolically relevant GPCRs. In parallel, they have further developed their innovative single-molecule approaches, which previously led to the discovery of receptor-G protein signalling nanodomains at the plasma membrane, to study other fundamental aspects of GPCR signalling such as the mechanisms of b-arrestin recruitment and activation. Altogether, Davide’s work has revealed that the molecular events governing GPCR signalling are much more complex and dynamic than previously thought, which has important implications for our understanding of GPCR signalling and the development of ‘intelligent’ drugs targeting this important family of membrane receptors.

1. Grimes J, Koszegi Z, Lanoiselée Y, Miljus T, O'Brien SL, Stepniewski TM, Medel-Lacruz B, Baidya M, Makarova M, Mistry R, Goulding J, Drube J, Hoffmann C, Owen DM, Shukla AK, Selent J, Hill SJ, Calebiro D. Plasma membrane preassociation drives b-arrestin coupling to receptors and activation. Cell 2023, 186:2238-2255.
2. Jobin ML, Siddig S, Koszegi Z, Lanoiselée Y, Khayenko V, Sungkaworn T, Werner C, Seier K, Misigaiski C, Mantovani G, Sauer M, Maric HM, Calebiro D. Filamin A organizes g‑aminobutyric acid type B receptors at the plasma membrane. Nature Communications 2023, 14:34.
3. Siddig S, Aufmkolk S, Doose S, Jobin ML, Werner C, Sauer M, Calebiro D. Super-resolution imaging reveals the nanoscale organization of metabotropic glutamate receptors at presynaptic active zones. Science Advances 2020, 6:eaay7193.
4. Sungkaworn T, Jobin ML, Burnecki K, Weron A, Lohse MJ, Calebiro D. Single-molecule imaging reveals receptor-G protein interactions at cell surface hot spots. Nature 2017, 550:543-547. doi: 10.1038/nature24264
5. Beuschlein F*, Fassnacht M*, Assié G*, Calebiro D*, Stratakis CA*, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A, Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabin M, Zabel U, Szarek E, Salpea P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ, Reincke M, Bertherat J, Strom TM, Allolio B. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N Engl J Med. 2014, 370:1019-28.
6. Calebiro Dº, Nikolaev VO, Gagliani MC, de Filippis T, Dees C, Tacchetti C, Persani L, Lohse MJº. Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. PLoS Biology 2009, 7:e1000172.