Shedding new light on GPCR signalling: why space and time matter

Shedding new light on GPCR signalling: why space and time matter

Professor Davide Calebiro MD PhD DSc FRCPa,b

aDepartment of Metabolism and Systems Science (MSS), College of Medicine and Health, University of Birmingham, UK
bCentre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, UK

Davide studied Medicine in Milan and Stockholm and obtained a clinical specialisation in Endocrinology and Metabolic Diseases and a PhD in Molecular Medicine from the University of Milan. He joined the University of Birmingham in 2017, where he is currently Head of the Department of Metabolism and Systems Science (MSS), and Co-Director of the Centre of Membrane Proteins and Receptors (COMPARE).
Throughout his career, Davide has given major contributions to clarifying several fundamental mechanisms underlying signalling by G protein-coupled receptors (GPCRs), the largest family of cell receptors and major drug targets, above all in the context of endocrine and metabolic physiology and disease. For this purpose, he has pioneered advanced optical approaches, such as FRET and single-molecule microscopy, which he combines with innovative probes and computational methods to monitor GPCR signalling in living cells and tissues with unprecedented detail.
His interdisciplinary efforts have led to seminal discoveries into the mechanisms that allow GPCRs to produce efficient and specific biological responses. Above all, his work has led to the groundbreaking discovery of a whole new paradigm of ‘endosomal’ GPCR signalling, which has changed the previously widely accepted textbook knowledge of GPCRs as cell-surface receptors1,2. Ongoing work in the Calebiro lab is dedicated to further clarifying the physiological and pharmacological implications of endosomal GPCR signalling, with a particular focus on metabolically relevant GPCRs.
Using innovative single-molecule microscopy approaches, his team succeed for the first time in visualising individual receptors and G proteins as they diffuse and interact at the surface of living cells3. This pioneering work revealed the existence of dynamic signalling nanodomains at the plasma membrane (‘hotspots’), which confer efficiency and specificity to GPCR signalling. More recently, his group extended these studies to the key interactions between receptors and arrestins that are implicated in fast signal desensitisation and receptor internalisation, revealing a crucial role for arrestin pre-association with the lipid bilayer4.
In parallel, Davide’s work has clarified the involvement of deranged GPCR/cAMP signalling in endocrine disease. Among other findings, his lab identified new genetic causes and mechanisms at the basis of thyroid disorders and Cushing’s syndrome. This includes the discovery of somatic mutations in the catalytic subunit of protein kinase A (PRKACA) as the main cause of Cushing’s syndrome due to cortisol-secreting adrenal adenomas5.
Altogether, Davide’s work has revealed that the molecular events governing GPCR signalling are much more complex and organised than previously thought, occurring in dynamic nanodomains at both the plasma membrane and intracellular organelles that confine GPCR signals in time and space. These findings hold promise for the development of a new generation of ‘intelligent’ therapies, capable of modulating GPCR signalling at specific subcellular nanodomains and, thus, produce more effective therapeutic responses with fewer side effects6.
1. Calebiro D et al. Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. PLoS Biology 2009, 7:e1000172. doi: 10.1371/journal.pbio.1000172
2. Godbole A et al. TSH receptors en route to the TGN induce local Gs-protein signaling and gene transcription. Nature Communications 2017, 8:443. doi: 10.1038/s41467-017-00357-2
3. Sungkaworn T et al. Single-molecule imaging reveals receptor-G protein interactions at cell surface hot spots. Nature 2017, 550:543-547. doi: 10.1038/nature24264
4. Grimes J et al. Plasma membrane preassociation drives -arrestin coupling to receptors and activation. Cell 2023, 186:2238-2255. doi: 10.1016/j.cell.2023.04.018
5. Beuschlein F et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome. N Engl J Med. 2014, 370:1019-28. doi: 10.1056/NEJMoa1310359
6. Calebiro D et al. Endomembrane GPCR signaling: 15 years on, the quest continues. Trends Biochem Sci. 2025, 50:46-60. doi: 10.1016/j.tibs.2024.10.006

Professor Davide Calebiro, MD PhD DSc FRCP

Davide Calebiro is Chair of Molecular Endocrinology, Wellcome Trust Senior Research Fellow and Head of the Department of Metabolism and Systems Science (MSS) at the University of Birmingham. He is also Co-Director of the Centre of Membrane Proteins and Receptors (COMPARE), a joint interdisciplinary research centre of Universities of Birmingham and Nottingham.
Davide studied Medicine in Milan and Stockholm, and obtained a PhD in Molecular Medicine and a Clinical Specialisation in Endocrinology and Metabolic Disease from the University of Milan. Between 2009 and 2017, he was a Group Leader at the Institute of Pharmacology and Toxicology and Rudolf Virchow Center of the University of Würzburg, Germany.
He leads an interdisciplinary research team comprising biologists, chemists, physicists, engineers and computer scientists focusing on the basic mechanisms of G protein-coupled receptor (GPCR) signalling and their involvement in endocrine, metabolic and cardiovascular diseases. To study GPCR signalling, they develop and use innovative optical methods based on FRET, BRET and single-molecule microscopy, which allow them to directly observe signalling events in living cells and tissues with unprecedented spatiotemporal resolution.
Using single-molecule microscopy and other innovative approaches, Davide’s team have revealed several important mechanisms that allow GPCRs to produce efficient and specific biological responses. Above all, his work has uncovered a whole new paradigm of ‘endosomal’ GPCR signalling, which has changed the previously widely accepted textbook knowledge of GPCRs as cell-surface receptors and holds promise for the development of novel pharmacological therapies (e.g. biased GPCR agonists for the therapy of diabetes).
Davide’s work has been published in prestigious scientific journals such as Nature, Cell, New England Journal of Medicine, Journal of Clinical Investigation, PLoS Biology, PNAS, Nature Communications and Science Advances, attracting several prizes and awards. He has served on multiple panels and committees, including the ENDO Annual Meeting Steering Committee and the MRC Molecular & Cellular Medicine Board.