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Department of Pharmacology

 

 

Graham Ladds PhD - Group Leader

Reader in Receptor Pharmacology
 
 
Tel:  +44 (0)1223 334020 (office)
+44 (0)1223 334028 (lab)

 

 

Keywords:

G proteins, GPCRs, Signal Bias, cell signalling, RAMPs, computational modelling, RGS proteins, mathematical simulations.

Investigator Biography

Graham studied Biochemistry at the University of Birmingham before completing a PhD in yeast pheromone signalling at Warwick. He continued to work at Warwick as a post-doc studying pro-hormone convertases before securing a 5-year independent fellowship funded through the NHS. This project enabled him to return to his interest of GPCRs. He progressed through the ranks at Warwick become an Associate Professor before leaving in 2015 to join the Department of Pharmacology at Cambridge, where he is also a Fellow of St John’s College. In 2020, he was promoted to a Readership in Receptor Pharmacology and was elected a Fellow of the British Pharmacological Society. His research group use a combination of pharmacological investigations and mathematical modelling to study factors that control agonist bias at GPCRs. These investigations have enabled him to foster strong collaborations with the pharmaceutical industry (GSK, Takeda and Firmenich) which have recently been enhanced though him being awarded a Royal Society Industry Fellowship to collaborate with AstraZeneca.

Lab members

Dr Matthew Harris - Dr Dawi Safitri - Ms Abigail Pearce - Ms Anna Suchankova - Mr Matthew Rosa - Mr Theo Redfern-Nichols - Mr Edward Willis - Ms Rosalind Xuang

Research Summary

Our research uses a multi-disciplinary approach to investigate the molecular basis of G protein signalling. We combine computational modelling with in vivo experimentation using model organisms to probe the dynamics of G protein action.

Our current focus is on the molecular mechanisms that family B G protein-coupled receptors (GPCRs) utilise to engender signalling bias. Specifically we are establishing the extent and consequences of receptor modifying activity proteins (RAMPs) association with the human family B GPCRs. Many physiologically important hormones and neurotransmitters act via family B GPCRs. These include substances such as GLP-1 and glucagon, relevant to diabetes and other metabolic disorders especially common in the elderly. RAMPs are found throughout the body. However, until recently, the consequences of RAMP-receptor interactions remained unknown. A recent study of two receptors has shown that RAMPs have important consequences for the way they function and we are now extending these studies to all 15 family B GPCRs.

Our initial studies use yeast cells but we aim to extend them to mammalian systems and eventually we aim to explore the physiological consequences of these interactions using sophisticated in-vivo models. Furthermore, it is likely that the association of the RAMP with a receptor will create a unique architecture of the resulting complex that can be selectively targeted by drugs.

Key references

Clark, A.J., Mullooly, N., Safitri, D., Harris, M., de Vries, T., MassenVanDenBrink, A., Poyner, D.R., Gianni, D., Wigglesworth, M. & Ladds. G. (2021) CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR agonist bias in primary human cardiovascular cells. Commun. Biol. 4:776.

Deganutti, G., Barkan, K., Preti, B., Leuenberger, M., Wall, M., Frenguelli, B.G., Lochner, M., Ladds, G.* & Reynolds C. A.* (2021) Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor. ACS Pharmacol. Transl. Sci. DOI: acsptsci.0c00195.

Marti-Solano, M., Crilly, S.E., Malinverni, D., …Ladds, G. …. Babu, M.M. (2020) Combinatorial expression of functionally distinct GPCR isoforms can diversify receptor signalling response. Nature 588(7838):E24. doi: 10.1038/s41586-020-2999-9.

MacKie, D.I., Nielsen, N.R., Harris, M., Singh. S., Davis, R.B., Dy, D., Ladds, G., and Caron, K.M. (2019) RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis. Proc. Natl. Acad. Sci. 116:24093-24099.

Shaw, W.M., Yamauchi, H., Mead, J., Gowers, G.F., Oling, D., Larsson, N., Wigglesworth, M.*, Ladds, G.* and Ellis, T.* (2019) Engineering a model cell for rational tuning of GPCR signalling Cell. 177: 782-796. (F1000Prime recommended).