The research focused on G protein-coupled receptors (GPCRs), a family of transmembrane receptors on the surface of cells that activate internal signal transduction pathways in response to external stimuli. In the human body, G-protein signalling mediates reactions from tastes and smells to stimulants such as adrenaline or caffeine.

Crucially, GPCRs are also the target for an estimated 40-50 per cent of modern medicines, including antihistamines, antihypertensives, asthma therapies and antidepressants.

Describing their work in the journal Current Biology, Michael Lee and Henrik Dohlman from, respectively, the University of North Carolina at Chapel Hill's Department of Pharmacology and its Department of Biochemistry and Biophysics, noted that GPCRs generally function as guanine-nucleotide exchange factors (GEFs).

Once activated through agonist binding, the receptor induces a conformational change in the G protein a subunit, which results in the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) and initiates G-protein signalling. This process is terminated when GTP is hydrolysed to GDP.

What distinguishes the University of North Carolina research is that Lee and Dohlman identified a new protein, Arr4, which is not a receptor yet binds directly to and activates the G-protein signalling pathway from within the cell.

"No drug is 100 per cent effective, 100 per cent free of side-effects and 100 per cent safe," Dohlman pointed out. "The more options we have biochemically, the more selective we can be in designing new drugs. If we can find another way of modulating G-proteins, we could expand the drug targets that are available to pharmacology."

Lee used a mutant form of G-protein to search in yeast cells for any messengers that were not receptors but did display an affinity for G-proteins. He identified seven such proteins, including Arr4. This soluble intracellular protein was then further investigated to determine its function.

Like receptors, Arr4 accelerates guanine-nucleotide exchange and stabilises the nucleotide-free state of the G protein a subunit, the researchers found. Arr4 also promotes G protein-dependent cellular responses, including mitogen-activated protein kinase (MAPK) phosphorylation, new gene transcription, and mating.

"Our data suggest that intracellular proteins function in co-operation with mating pheromones to amplify G protein signalling, thereby leading to full pathway activation," the authors wrote.

As Lee explained, Arr4 may allow the cell to go through several additional cycles of signal activation without further recourse to the G protein-coupled receptor.

"Our current thinking is, it's not so much that this is the ignition for signalling, it's more like an overdrive," he commented. "Once the pathway is activated by the hormone outside, Arr4 sustains the activity inside."