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Multi-disciplinary approach to investigate the molecular basis of G protein signalling

 

Graham Ladds PhD - Group Leader

 
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 with John Davey 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 was appointed a lecture at Warwick in 2006. He is a full member of the British Pharmacology Society and regularly attends meetings both in the UK and Australia. He has a long-standing collaboration with Dr Simon Dowell at GlaxoSmithKline. His group is interested in RAMP-mediated signalling bias of family B GPCRs.

Lab members

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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

1. Weston, C., Winfield, I., Harris, M., Hodgson, R., Shah, A., Dowell, S.J., Moarec, J-C, Woodlock, D.A., Reynolds, C.A., Poyner, D.R., Watkins, H.A. and Ladds, G. (2016) RAMP-directed G protein signaling specificity for the calcitonin gene-related peptide family of receptors. J. Biol. Chem. pii: jbc.M116.751362.

2. Knight, A., Hemmings, J.L., Frenguelli, B.G., Dowell, S.J., Lochner, M. and Ladds, G. (2016) Discovery of Novel Adenosine Receptor Agonists that Exhibit Subtype Selectivity. J. Med Chem. 59: 947.

3. Shigeto, M., Ramracheya, R., Cha, C-Y., Chibalina, M., Tarasov, A., Philippaert, K., Reinbothe, T., Rorsman, N., Salehi. A., Sones, W., Vergari, E., Weston, C., Gorelik, J., Katsura, M., Nikolaev, O., Vennekens, R., Zaccolo, M., Gallione, A., Johnson, P.R.V., Kaku, K., Ladds, G. and Rorsman, P. (2015) Physiological concentrations of GLP-1 increases insulin secretion in mouse and human pancreatic b-cells by PKC-dependent activation of TRPM4 channels. J Clin Invest. 125: 4714.

4. Weston, C., Li, J., Li, N., Barkan, G., Richards, G.O., Roberts, D., Skerry, T.M., Poyner, D., Pardamwar, M., Reynolds, C.A., Dowell, S., Willars, G. and Ladds, G. (2015) Modulation of glucagon receptor pharmacology by RAMP2. J. Biol. Chem. 290: 23009.

5. Prokic, E., Weston, C., Yamawaki, N., Hall, S., Stanford, I., Ladds, G. and Woodhall, G. (2015) Benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons alters cortical oscillatory dynamics. Neuropharmacology. 95: 192.