Project Outline

G protein-coupled receptors (GPCRs) represent a very wide array of cell-surface receptors for a multitude of neurotransmitters and inter-cellular signalling molecules. In contrast to inotropic receptors, which signal via the movement of ions through their associated ion channels, GPCRs influence cells via biochemical cascades linked to their associated G-proteins, of which there are also many types. Our lab has been interested in GPCRs associated with one particular signalling molecule – adenosine. Adenosine has four GPCRs, one of which, the A1R, plays very important role in inhibiting the action of neurones, and indeed the heart. This dual action on the nervous and cardiovascular systems has hampered the development of A1R agonists that might be otherwise be useful in the treatment of a variety of neurological conditions, such as stroke and epilepsy. However, we have recently discovered a molecule, BnOCPA, that has strong effects on some aspects of neuronal function, but none on the heart. So much so that BnOCPA is a powerful pain killer without causing the side effects of the decrease in heart rate, blood pressure and respiration commonly seen with A1R agonists.

This project will investigate this peculiar molecule and its derivatives. In particular we will ask fundamental questions as to how this molecule can do what it does, where it does this in the nervous system, and if it is equally effective in a variety of other models of pain. The project will be a collaboration with colleagues at the Universities of Coventry, Cambridge and Bern who are experts in molecular simulations, GPCR cell signalling and organic synthetic chemistry, respectively.

References

Wall MJ, Hill E, Huckstepp R, Barkan K, Deganutti G, Leuenberger M, Preti B, Winfield I, Carvalho S, Suchankova A, Wei H, Safitri D, Huang X, Imlach W, La Mache C, Dean E, Hume C, Hayward S, Oliver J, Zhao FY, Spanswick D, Reynolds CA, Lochner M, Ladds G, Frenguelli BG. (2022) Selective activation of Gαob by an adenosine A₁ receptor agonist elicits analgesia without cardiorespiratory depression. Nat Commun. 13:4150. https://www.nature.com/articles/s41467-022-31652-2.

Techniques

• In vitro tissue preparation
• In vivo models of pain
• Electrophysiology (patch clamp & extracellular recordings)
• Neuropharmacology
• GPCR signalling assays (eg BRET)