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Antipodean molecular pharmacology of G protein-coupled receptors

Published: 23 May 2018
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It’s OK. I get it. My enthusiasm is a little over-the-top. But ‘c’mon!’ (to borrow a phrase from fellow enthusiastic-type, Australian tennis player Lleyton Hewitt), G protein-coupled receptors (GPCRs) are awesome!

With more than 800 members, GPCRs are the largest membrane protein family in the human genome. They follow a universal template of an extracellular N-terminus, seven transmembrane-spanning helices and an intracellular C-terminus, but beyond this they all have their own little personalities. Some have crazy hairdos, some need a friend to get to their destination, some are more like swingers, coupling with different partners depending on their mood. Through their various binding sites, GPCRs can be turned on, turned off or very precisely tuned to achieve a biological outcome. The ones I am most interested in are a little lost – these orphan GPCRs are yet to be paired with their endogenous ligand. This means that they are tough nuts to crack… let me tell you that a pharmacologist without a ligand is a sad sight indeed.

Australia has an established international presence in GPCR pharmacology and I was lucky enough to be an undergraduate at the University of Melbourne when Arthur Christopoulos and Patrick Sexton were first starting to build their formidable partnership. In a strong pharmacology department run by Jim Angus, former colleague of Sir James Black, I was put through my analytical pharmacology paces by Michael Lew , who taught me to love GPCRs and the things they could do. I undertook an Honours year in the fledgling Christopoulos laboratory alongside Lauren May, well known to the British Pharmacological Society’s members from her time in Nottingham with Steve Hill, and there was no turning back – I was hooked on GPCRs.

Coming from a family riddled with cardiovascular disease, I combined both of my passions by joining the laboratory of Wally Thomas at the Baker Heart Research Institute for my PhD. Wally is a wonderful man and he taught me many things in the laboratory, but his greatest gift was encouragement to believe in myself, flee the nest and aim for the biggest GPCR labs in the world. And with that, I found myself on a four year overseas research fellowship in wonderful Glasgow (I mean this genuinely – I love the city and miss all the ‘Weegies’ I left behind) in the laboratory of Graeme Milligan, GPCR guru. I blame Graeme for my journey into the difficult world of orphan GPCRs (although he did warn me!) as he introduced me to the free fatty acid receptor family of GPCRs. They were deorphanised in 2003 and beasts to work with, at that time lacking any ligands with decent potency (or even solubility). I liked the idea that we had to push these metabolite receptors and our assay systems to their very limits in order to squeeze out any clues that might help us understand them more . This is even more so the case with orphan GPCRs and I am often overheard to use stronger words than ‘beasts’ to describe them.

In early 2011, I returned to Australia with the desire to learn in vivo pharmacology so that I could take orphan GPCR targets from in silico models all the way to animals . And thus I find myself still at the Victor Chang Cardiac Research Institute today, running a lab with two postdocs, a research assistant, two PhD students and three interns.

Science in Australia is wonderful but different to what I experienced in the UK. You have to be more organised, for starters, as reagents aren’t kept in stock nearby and are often shipped from Europe or the USA. We also operate on a yearly grant cycle so our summers are lost to grant and fellowship submissions while the rest of our countrymen sun themselves on beaches or attend Test matches and tennis tournaments. Funding here is as bad as the rest of the world so it is very competitive to get a break, although there is a strong emphasis on supporting early career researchers and there are plenty of opportunities for talented young pharmacologists from overseas. So, on a parting note, I encourage fellow GPCR fans to visit us all in Australia – we have our annual ASCEPT pharmacology meeting this year in Adelaide (27 to 30 November 2018) followed by the highcalibre 10th Molecular Pharmacology of GPCRs meeting in Melbourne (2 - 4 December 2018). I hope to see you there!

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About the author

Nicola Smith

Victor Chang Cardiac Research Institute, Australia

Dr Nicola J Smith is a National Heart Foundation Future Leader Fellow and head of the Molecular Pharmacology Laboratory at the Victor Chang Cardiac Research Institute. She is a conjoint Senior Lecturer at the University of New South Wales. Nicola graduated from the University of Melbourne with a BA, BSc (Hons) and PhD and received a National Heart Foundation/NHMRC CJ Martin Fellowship to undertake post-doctoral training first with Professor Graeme Milligan at the University of Glasgow and then Professor Bob Graham at the Victor Chang. Her passion is the study of orphan G protein-coupled receptors in health and disease.