Furness Group - Research projects

Mechanisms for differential GPCR:effector coupling

G protein coupled receptors can be activated to a varied extent by different ligands. This is the basis for partial efficacy, which has been exploited for a subset of medicines. We have previously shown part of the mechanism for this differential receptor-transducer at the calcitonin receptor and this project seeks to extend this work using single molecule studies. Part of this project is in collaboration with Dr Chris Ritchie (School of Chemistry, Monash University).

The complexity of receptor signaling in the control of appetite

The Ghrelin receptor is a relatively recently discovered GPCR involved in increasing appetite. Its involvement in feeding and feeding-reward pathways rely on the ability of the Ghrelin receptor to signal in the absence of ligand and for it to interact with dopamine D2 and oxytocin receptors. We believe the Ghrelin receptor acts in specific neurons to alter the pathway to which dopamine and oxytocin receptors couple.

The project involves the investigation of the biophysical basis of Dopamine D2 and Oxytocin receptor coupling in the presence of the Ghrelin receptor.  This project is part of a new collaboration with Professor J.B. Furness. at the Florey Institute of Neuroscience (Melbourne).

The Conformational Basis of MC4R Regulation and Function

The melanocortin 4 receptor (MC4R) is critically involved in regulation of appetite. Mutations in this receptor are the most common cause of monogenic obesity, accounting for up to 6% of early onset obesity. Like the ghrlin receptor, MC4R is able to signal in the absence of a ligand. Interestingly it has a natural ligand that switches it off (stimulating appetite) and another that switches it on (supressing appetite). Signalling at this is further complicated by the fact that it interacts with a poorly characterised co-receptor that modulates its function. This project seeks to understand tha biophysical basis for this receptor to be able to be tuned both up and down by endogenous hormones.

Available student projects

Project 1:  Single-molecule fluorescence to study dynamic conformational changes in G proteins.

Project 2:  Molecular pharmacology and G protein selectivity for the Melanocortin 4 receptor.

Project 3:  The influence of the Ghrelin Receptor on the molecular pharmacology and G protein selectivity of the Dopamine D2 receptor.

Project 4:  Single molecule molecular dynamics at Dopamine D2 receptor.