MIPS research discovers new activation process for G protein coupled-receptors

In a paper published today in Science Signaling, researchers from the Monash Institute of Pharmaceutical Sciences (MIPS) have discovered that G protein coupled receptors (GPCRs) can be activated by ultra-low concentrations of ligand - more than one billion times lower than currently presumed.

GPCRs, which respond to multiple stimuli including neurotransmitters, hormones, odours and light are the targets of over 50 per cent of current pharmaceuticals. GPCRs are the largest superfamily of all receptors. An understanding of their functionality has assisted commercial pharmaceutical development and contributed to drug discovery for chronic pain and cardiovascular disease.

The new MIPS research has shed light on the activation process of GPCR function. The activation by ultra-low concentrations of ligand occurs by only one receptor per cell, and causes signalling responses that are distinct in both space and time compared to responses from higher concentrations. As a consequence, these ultra-low concentrations of drug also cause a distinct cellular response.

Lead researcher, NHMRC RD Wright Career Development Fellow and Group Leader of the Signalosome and Compartmentalisation Laboratory, Doctor Michelle Halls said that the findings have been made possible through unique signal measuring processes.

“We have been able to demonstrate these cellular responses through signal measurement in different areas of a cell in real time. Our findings have implications for drug discovery and how we develop and utilise medications that are targeting GPCRs,” said Doctor Halls.

This study is an international and interdisciplinary collaboration led by Doctor Halls, MIPS researchers Doctor Srgjan Civciristov and Doctor Bronwyn Evans and researchers from the Monash University Biomedicine Discovery Institute, Los Alamos National Laboratories, University of Nottingham and the Technion-Israel Institute of Technology.

Doctor Halls’ laboratory studies how GPCR signalling is controlled by the organisation of receptors into protein complexes, and into discrete compartments of the cell membrane. These findings contribute to ongoing research in the area of drug discovery biology.

“Our findings not only present novel information on GPCR signalling but challenge the accepted paradigms of drug action as we know it.”

Contact: Divya Krishnan

Phone: 0466 910 111

Email: divya.krishnan@monash.edu