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Personal profile

Biography

NHMRC RD Wright Career Development Fellow (2014-2019)
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences

NHMRC CJ Martin Overseas Biomedical Fellow (2008-2013)
Department of Pharmacology, University of Cambridge, UK
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences

Research interests

It is important to understand signal organisation in cells because all physiological and pathological processes depend on cell signalling.

Cells contain the ‘machinery’ to receive an astoundingly diverse range of stimuli (light, odours, hormones, lipids) and relay this information to perform distinct and diverse functions (including sight, smell, cell migration and metabolism). Cells achieve this through large numbers of receptors expressed on the cell surface but interestingly, these receptors interact with a limited number of cell signalling pathways. This is well illustrated by the largest class of receptor proteins, the G protein-coupled receptors (GPCRs). In response to these stimuli, ~800 different GPCRs activate the same 4-5 canonical signalling pathways but initiate a variety of cell responses such as migration, contraction, gene transcription and metabolism. With >100 different types of GPCRs expressed on average on each cell, it has been difficult to rationalise how signalling can simultaneously coordinate a variety of cellular responses.

By measuring localised signals in live cells my team has shown that signals from GPCRs are highly localised and organised in both space and time. That is, the types of signals activated by the GPCR are dependent on receptor location and are often restricted to tightly regulated subcellular compartments. This is facilitated by their physical incorporation into extensive protein scaffolding networks. With our inter-disciplinary collaborators, this knowledge has driven cutting-edge drug development to target GPCRs in specific subcellular locations. This new generation of targeted therapeutics has much greater efficacy than current drugs which are designed to bind all receptors at the cell surface.

Supervision interests

Our research is focussed on understanding how receptors control localised signalling, how this can be hijacked by disease, and how we can target these signals to gain greater therapeutic efficacy.

We do this by combining high resolution microscopy and cell biology with advanced mass spectrometry and drug delivery approaches. Current projects include characterising novel properties of GPCRs when incorporated into protein complexes, defining how GPCR signalling is altered in highly metastatic cancer cells to drive invasion, and understanding how intracellular binding proteins can affect activation of nuclear hormone receptors.

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Projects

Research Output

Endosomal Signaling of Delta Opioid Receptors Is an Endogenous Mechanism and Therapeutic Target for Relief From Inflammatory Pain

Jiménez-Vargas, N. N., Gong, J., Wisdom, M. J., Jensen, D. D., Latorre, R., Hegron, A., Teng, S. L., Di Cello, J., Rajasekhar, P., Veldhuis, N. A., Carbone, S., Yu, Y., Lopez, C. L., Polanco, J. J., Canals, M., Reed, D., Lomax, A. E., Schmidt, B. L., Leong, K. W., Vanner, S. & 3 others, Halls, M. L., Bunnett, N. & Poole, D. P., Jun 2020, (Accepted/In press) In : Proceedings of the National Academy of Sciences of the United States of America. 12 p.

Research output: Contribution to journalArticleResearchpeer-review

Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists

Gillis, A., Gondin, A. B., Kliewer, A., Sanchez, J., Lim, H. D., Alamein, C., Manandhar, P., Santiago, M., Fritzwanker, S., Schmiedel, F., Katte, T. A., Reekie, T. A., Grimsey, N. L., Kassiou, M., Kellam, B., Krasel, C., Halls, M. L., Connor, M., Lane, J. R., Schulz, S. & 2 others, Christie, M. J. & Canals, M., 31 Mar 2020, In : Science Signaling. 13, 625, 18 p., eaaz3140.

Research output: Contribution to journalArticleResearchpeer-review

A ligand-induced structural change in fatty acid-binding protein 1 is associated with potentiation of peroxisome proliferator-activated receptor α agonists

Patil, R., Mohanty, B., Liu, B., Chandrashekaran, I. R., Headey, S. J., Williams, M. L., Clements, C. S., Ilyichova, O., Doak, B. C., Genissel, P., Weaver, R., Vuillard, L., Halls, M. L., Porter, C. J. H. & Scanlon, M. J., 8 Mar 2019, In : The Journal of Biological Chemistry. 294, 10, p. 3720-3734 15 p.

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via β 2 -adrenoceptors without causing classical receptor desensitization

Mukaida, S., Sato, M., Öberg, A. I., Dehvari, N., Olsen, J. M., Kocan, M., Halls, M. L., Merlin, J., Sandström, A. L., Csikasz, R. I., Evans, B. A., Summers, R. J., Hutchinson, D. S. & Bengtsson, T., 1 May 2019, In : American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 316, 5, p. R666-R677 12 p.

Research output: Contribution to journalArticleResearchpeer-review

Open Access
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2 Citations (Scopus)

GRK mediates µ-opioid receptor plasma membrane reorganization

Gondin, A. B., Halls, M. L., Canals, M. & Briddon, S. J., 1 May 2019, In : Frontiers in Molecular Neuroscience. 12, 14 p., 104.

Research output: Contribution to journalArticleResearchpeer-review

Open Access
File
3 Citations (Scopus)