The Calebiro group investigates the basic mechanisms of G protein-coupled receptor (GPCR) signalling and their alterations in metabolic and endocrine disease.
A key focus is the development of innovative microscopy methods (such as FRET and single-molecule microscopy), in combination with new biosensors, to monitor receptor signalling directly in living cells and tissues with unprecedented spatiotemporal resolution. This is combined with novel mathematical and computational approaches to extract quantitative information from complex imaging data and model receptor signalling at both molecular and cellular level.
Using this multi-disciplinary approach, the Calebiro group has redefined fundamental mechanisms of GPCR signalling, including the important discovery that GPCRs are not only active at the plasma membrane, as previously thought, but also at intracellular sites such as endosomes and the Golgi complex. These findings challenge the classical model of GPCR signalling and could lead to novel drugs with improved efficacy and less side effects.
Moreover, the Calebiro group has a long-standing experience in the investigation of genetic alterations in GPCR signalling. This has led to the identification of genetic causes of disease, including the discovery that activating mutations in the catalytic α subunit of protein kinase A (PRKACA) are responsible for cortisol-secreting adrenocortical adenomas leading to Cushing’s syndrome.
The ultimate goal of the Calebiro group is to advance our understanding of the molecular and cellular mechanisms of GPCR signalling in order to devise innovative pharmacological therapies for endocrine and metabolic diseases.
This video shows single-molecule imaging of individual receptors and G proteins at the surface of a living cell.
Receptors (green) and G proteins (magenta) were labelled with small organic fluorophores, imaged by TIRF microscopy and tracked as they diffuse and interact on the plasma membrane.
Figure 1: Actin filaments provide barriers to receptor diffusion on the plasma membrane. Shown are trajectories of individual receptors (green) overlaid on a superresolved (PALM) image of the actin cytoskeleton (orange). Modified from Sungkaworn et al. Nature 2017.
Figure 2: Hot spots for GPCR signalling on the surface of living cells as revealed by single-molecule microscopy. Each dot corresponds to an interaction between a receptor and a G protein. Modified from Sungkaworn et al. Nature 2017.
Figure 3: GPCRs signalling in the trans-Golgi network captured by a nanobody recognizing the active Gs protein (Nb37; orange). Modified from Godbole et al. Nat. Commun. 2017
Current group members:
Zsombor Koszegi
Shannon O’Brien
Yann Lanoiselée
Tama Miljus
Jak Grimes
Emma Tripp
Ravi Mistry
Research Groups and Centres
Follow Davide Calebiro on Twitter @DavideCalebiro
Our Centre of Membrane Proteins and Receptors (COMPARE)