New paradigm of GPCR signalling at intracellular sites in metabolic diseases

Aim of this project is to use innovative optical methods developed in our labs to investigate a new emerging paradigm in G protein-coupled receptor (GPCR) signalling and its implications for the pharmacological therapy of metabolic diseases.

G protein coupled receptors mediate the effects of several hormones and neurotransmitters and are major pharmacological targets. Whereas these receptors were long believed to signal exclusively at the plasma membrane, recent studies by our and other groups have revealed that several GPCRs signal also at intracellular sites, such as early endosomes or the Golgi/trans-Golgi network (Calebiro et al., 2009; Godbole et al., 2017). This new concept is revolutionizing our understanding of GPCR biology and might provide new strategies to treat diabetes, obesity and other complex diseases (Calebiro et al., 2010).

The successful applicant will investigate the contribution of intracellular vs. cell-surface signalling in the regulation of adipocyte metabolism by two GPCRs (GPR120 and HCA2), which are emerging pharmacological targets for metabolic diseases. Advanced live cell imaging methods, such as FRET, BRET, FCS, superresolution and single-molecule microscopy, will be used to directly visualize signalling events in living cells with unprecedented spatiotemporal resolution (Calebiro et al., 2014; Briddon & Hill, 2018; Wagner et al., 2015; Sungkaworn et al., 2017). This will be combined with advanced methods such as high-resolution mitochondrial respiration, targeted lipidomics and metabolic tracing to assess adipocyte metabolism (Morgan et al., 2014; Zeng et al., 2016).

We expect this project to lead to a deeper understanding of the mechanisms involved in the regulation of adipocyte metabolism by GPCRs and to the identification of new potential molecular targets for the therapy of metabolic diseases.

The successful applicant will join a vibrant, dynamic and internationally-recognised interdisciplinary team at the Institute of Metabolism and Systems Research (University of Birmingham) and at the Centre of Membrane Proteins and Receptors (COMPARE), a new joint research centre of the Universities of Nottingham and Birmingham aimed at investigating the organization of membrane receptors using advanced optical methods.

Person Specification

Applicants should have a strong background in Cell Biology, Biochemistry or Pharmacology, and ideally knowledge of basic imaging methods. They should have a commitment to research in Receptor Pharmacology and Metabolism and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

Funding Notes

Due to the nature of funding attached to this studentship we are not able to accept applications from overseas applicants

References

• Briddon SJ, Hill SJ (2018) Studying GCPR pharmacology in membrane microdomains: Fluorescence Correlation Spectroscopy comes of age. Trends Pharmacol. Sci. (in press)
• Calebiro D, Nikolaev VO, Gagliani MC, de Filippis T, Dees C, Tacchetti C, Persani L, Lohse MJ (2009) Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. PLoS Biol 7, e1000172
• Calebiro D, Nikolaev VO, Persani L, Lohse MJ (2010) Signaling by internalized G-protein-coupled receptors. Trends Pharmacol Sci 31, 221-228
• Calebiro D, Maiellaro I (2014) cAMP signaling microdomains and their observation by optical methods. Frontiers in cellular neuroscience 8, 350
• Godbole A, Lyga S, Lohse MJ, Calebiro D (2017) Internalized TSH receptors en route to the TGN induce local Gs-protein signaling and gene transcription. Nature communications 8, 443
• Morgan SA, McCabe EL, Gathercole LL, Hassan-Smith ZK, Larner DP, Bujalska IJ, Stewart PM, Tomlinson JW, Lavery GG (2014) 11beta-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. Proc Natl Acad Sci U S A 111, E2482-2491
• Sungkaworn T, Jobin ML, Burnecki K, Weron A, Lohse MJ, Calebiro D (2017) Single-molecule imaging reveals receptor-G protein interactions at cell surface hot spots. Nature 550, 543-547
• Wagner J, Sungkaworn T, Heinze KG, Lohse MJ, Calebiro D (2015) Single-Molecule Fluorescence Microscopy for the Analysis of Fast Receptor Dynamics. Methods Mol Biol 1335, 53-66
• Zeng X, Jedrychowski MP, Chen Y, Serag S, Lavery GG, Gygi SP, Spiegelman BM (2016) Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation. Genes & development 30, 1822-1836