Investigating the roles that G protein coupled receptors play in hypertension

About the Project

G protein-coupled receptors (GPCRs) constitute a very large family of heptahelical, integral membrane proteins that mediate a wide variety of physiological processes ranging from the transmission of light and odorant signals to the mediation of neurotransmission and hormonal actions. GPCR signalling plays a vital role in the regulation of smooth muscle excitability to control a wide range of physiological processes including blood pressure and uterine quiescence during pregnancy. Dis-regulation of these GPCR signalling pathways leads to pathophysiological changes associated with conditions such as hypertension and pre-term labour. Our work is focused on identifying and comparing the molecular mechanisms underlying GPCR regulation of smooth muscle excitability in arterial and uterine smooth muscle both in normal and diseased tissue. Present emphasis centres around G protein-coupled receptor kinases and arrestin proteins which were originally identified as mediators of GPCR desensitization, but now are increasingly identified as complex signalling molecules that regulate diverse process such as cell proliferation, migration, metastasis, transcription regulation and apoptosis.

PhDs are available in the following areas of research:

• GPCR regulation of hypertension/ vascular smooth muscle growth and migration
• GPCR regulation in pre-term labour
• The role of endocannabinoid receptor signalling in reproduction

Work is primarily concerned with the roles that G-protein coupled receptor kinases (GRKs) and arrestin proteins play in the regulation of endogenously expressed GPCRs. GPCRs are a large family of cell surface proteins that decode a plethora of external signals to enable cellular communication. Research focuses on regulation of endogenous GPCR signalling in smooth muscle excitability, with relevance to vascular disease. Here, we are interested in two families of proteins, GRK and non-visual arrestins, which are known not only to negatively regulate GPCR signalling but control signalling pathways involved in increasingly diverse cellular processes e.g. migration, growth, metastasis and hypertension.

We combine fluorescent bioprobes/confocal imaging to examine GPCR regulation in ‘real-time’ in primary cell cultures, within days of isolation. We routinely utilise molecular manipulations of protein levels or function to determine their involvement in multiple GPCR signalling cascades and physiological outputs. Combining these powerful techniques enables unique identification of specific interactions of individual endogenous GRKs/arrestins (or other proteins) and endogenously expressed receptors, often only days after isolation. Recently research has examined the role that GRK and arrestins play in the regulation of MAPK signalling pathways in vascular diseases.

Apply at: https://le.ac.uk/study/research-degrees/research-subjects/molecular-and-cell-biology

PhD entry requirements: https://le.ac.uk/study/research-degrees/entry-reqs

Supervisor contact details:
Dr Jonathon Willets - jmw23@le.ac.uk

References

Alonazi, A. S. A., & Willets, J. M. (2021). G protein-coupled receptor kinase 2 is essential to enable vasoconstrictor-mediated arterial smooth muscle proliferation. Cell Signal, 88, 110152. doi:10.1016/j.cellsig.2021.110152
Nash, C. A., Nelson, C. P., Mistry, R., Moeller-Olsen, C., Christofidou, E., Challiss, R. A. J., & Willets, J. M. (2018). Differential regulation of beta2-adrenoceptor and adenosine A2B receptor signalling by GRK and arrestin proteins in arterial smooth muscle. Cell Signal, 51, 86-98. doi:10.1016/j.cellsig.2018.07.013
Rainbow, R. D., Brennan, S., Jackson, R., Beech, A. J., Bengreed, A., Waldschmidt, H. V., … Willets, J. M. (2018). Small-Molecule G Protein-Coupled Receptor Kinase Inhibitors Attenuate G Protein-Coupled Receptor Kinase 2-Mediated Desensitization of Vasoconstrictor-Induced Arterial Contractions. Mol Pharmacol, 94(3), 1079-1091. doi:10.1124/mol.118.112524