PhD Studentship: Investigating the Lipid Regulation of GPCR Signalling

G-protein coupled receptors (GPCRs) are the largest group of membrane receptors and major drug targets. Whereas GPCRs were traditionally thought to be simple on-off switches, new emerging evidence indicates that these receptors are complex machines capable of sending different signals depending on how they are activated and the local context in which they operate. For instance, GPCRs have been shown to be located in multiple organelles inside our cells, which leads to distinct biological responses. Importantly, understanding this complexity promises to deliver innovative drugs for diseases such as heart failure or diabetes, capable of manipulating GPCR signalling far beyond what is achievable with the simple agonists or antagonists currently used for therapeutic purposes.

In this context, the lipid composition of the biological membranes where receptors are embedded and signal is emerging as a key determinant of the cell responses that they elicit. In fact, the membrane lipidome is diverse and cells utilise considerable energy to maintain specific bilayer compositions. Moreover, lipidomes vary across organelles and many receptors maintain a specific proximal lipid profile (the peri-lipidome). As a result, altered lipidomes, such as occur in chronic diseases like diabetes, are known change the biophysical properties of membranes, ultimately affecting receptor organisation, dynamics and signalling.

Here, we propose to investigate the specific role of membrane lipids in controlling GPCR distribution and dynamics and the knock-on effect on GPCR signalling as well as to explore the possibility of exploiting receptor-lipid interactions to modulate GPCR signalling for therapeutic purposes. To do this we will use 1) in vitro models consisting of purified GPCRs and their interactors such as G proteins and b-arrestins reconstituted in artificial membrane systems, 2) cell-based systems, including the mating yeast where pheromone receptors belonging to the GPCR superfamily control mating, 3) analytical chemistry methods including SMALPs and GC-MS lipidomics, and 4) advanced fluorescence microscopy including single-molecule tracking and super-resolution imaging via single-molecule localisation microscopy (SMLM).

We will make alterations to the membrane lipidome and point/domain mutations to the proteins. Environmentally sensitive membrane dyes will allow us to map membrane biophysical properties, such as viscosity, in these systems. On the functional level, we will study lipid-protein interactions using the mating yeast as a model. Yeast is not only easy to manipulate but also lets us directly and precisely measure the functional outcome of specific manipulations, for example by recording the frequency or efficiency of mating events.

The successful applicant will join a vibrant, dynamic and internationally-recognised interdisciplinary team at the Centre of Membrane Proteins and Receptors (COMPARE), a joint research centre of the Universities of Birmingham and Nottingham aimed at clarifying the organization of membrane receptors to develop innovative pharmacological therapies.

Applicants should have a strong background in Cell Biology, Biochemistry, Biophysics or Pharmacology, and ideally knowledge of basic imaging methods. They should have a commitment to research in Receptor Pharmacology and Biophysics and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

Funding

Funding availability: Funding covers student stipend at standard UKRI rates and UK home fees. Funding is for 3 years with a possibility of 1 year extension.

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