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Endocrine Abstracts (2018) 59 APW1.3 | DOI: 10.1530/endoabs.59.APW1.3

SFEBES2018 APPLIED PHYSIOLOGY WORKSHOP GPCRS: hotspots and complexes (3 abstracts)

The nanodomain organization of GPCR signalling: lessons from TSH receptors and beyond

Davide Calebiro


University of Birmingham, Bimrningham, UK.


My group investigates the basic mechanisms of G protein-coupled receptor (GPCR) signalling and their alterations in endocrine disease, which we study using innovative microscopy methods such as fluorescence resonance energy transfer (FRET) and single-molecule microscopy. Using these methods, we have demonstrated that GPCRs do not only signal via cyclic AMP at the cell surface but also at intracellular sites (Calebiro et al., PLoS Biology 2009). We have shown that this is required for the biological effects of hormones like TSH and LH. Moreover, we have demonstrated for the first time that this occurs via retrograde trafficking of the internalized receptors to the trans-Golgi network (TGN), where they induce local cAMP signalling (Godbole et al., Nat Commun 2017). In parallel, we have developed an innovative single-molecule microscopy approach to investigate receptor interactions on the plasma membrane with unprecedented spatiotemporal resolution. Using this approach, we could demonstrate that GPCRs from transient complexes that differ considerably in size and location among receptors (Calebiro et al., PNAS 2013) Very recently, we were the first to directly visualize individual receptors and G proteins as they interact and signal in living cells (Sungkaworn et al., Nature 2017). This has revealed ‘hot spots’ for G protein signalling on the plasma membrane, which we hypothesize confer speed and specificity to GPCR signalling. Altogether, the most recent findings by our and other groups suggest that GPCR signalling is highly organized in time and space, which likely plays a key role in determining signal specificity downstream of this important family of membrane receptors. These findings also have major implications for drug discovery, as they might provide a new basis to precisely modulate GPCR activity, and, thus, develop innovative drugs with improved efficacy and tolerability for diseases such as diabetes or heart failure.

Volume 59

Society for Endocrinology BES 2018

Glasgow, UK
19 Nov 2018 - 21 Nov 2018

Society for Endocrinology 

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