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Single molecule imaging of RAMP-GPCR complexes; towards a new paradigm in pharmacology?

  • Full or part time
  • Application Deadline
    Sunday, January 12, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

We are seeking a highly motivated PhD candidate to join our interdisciplinary team at the Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham (UK), to work on a collaborative project with the groups of Professor David Poyner (Aston University) and Dr Graham Ladds (University of Cambridge). The PhD scholarship is funded by the Midlands Integrative Biosciences Training Partnership (MIBTP). Applications should be sent by 12th January 2020, indicating your preference for this project and Prof. Calebiro as supervisor, following the instructions provided via this link: https://www.birmingham.ac.uk/research/activity/mibtp/index.aspx

For informal enquiries, please contact Prof. Davide Calebiro ()

Project Details
G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and major pharmacological targets. Receptor activity modifying proteins (RAMPs) are single-pass transmembrane proteins that associate with a number of GPCRs, most especially a sub-group known as family B GPCRs. These are receptors for peptides such as the calcitonin gene-related peptide (CGRP), adrenomedullin (AM), amylin and glucagon. Although these are all therapeutically important peptides involved in conditions such as migraine, cardiovascular disease and diabetes mellitus, it has been difficult to find drugs to target their receptors.
There are three RAMPs in humans and they all associate in the endoplasmic reticulum with the same GPCR, known as CLR. This interaction is essential for both the RAMPs and CLR to reach the cell surface. Once there, they can interact with their target peptides; the complex between CLR and RAMP1 gives the CGRP receptor whereas that between CLR and either RAMP2 or RAMP3 generates two AM receptors, known as the AM1 and AM2 receptors(1). In addition to modulating receptor pharmacology, RAMPs can also alter receptor trafficking and signal transduction(2).
It has always been assumed that GPCR-RAMP complexes, once formed, are stable dimers. However, it is now possible to study the behaviour of individual proteins through single molecule imaging and this is revolutionising our understanding of how proteins such as GPCRs work(3). Very recently, we have studied CGRP and AM2 receptors by this method. Unexpectedly, this has shown that CLR and the RAMPs diffuse independently on the plasma membrane, forming transient complexes when they collide and that the number of these complexes is increased after treatment with CGRP. This raises many questions as to how RAMPs operate to change receptor properties and how individual receptors are formed when cells express more than one RAMP.
In this project, we will use single molecule imaging to track the movement of individual molecules, allowing a precise quantification of their diffusion and the kinetics of complex formation; the results will be used to build a dynamic mathematical model of the interactions between CLR and RAMPs on the plasma membrane. The project will give new insights into how RAMPs work, potentially opening up new avenues of drug discovery.

Funding Notes

The PhD scholarship is funded by the Midlands Integrative Biosciences Training Partnership (MIBTP). Applications should be sent by 12th January 2020, indicating your preference for this project and Prof. Calebiro as supervisor, following the instructions provided via this link: View Website

References

1) Hay DL, Garelja ML, Poyner DR, Walker CS. Br J Pharmacol. 2018;175(1):3-17.Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25.
2) Routledge SJ, Ladds G, Poyner DR. The effects of RAMPs upon cell signalling. Mol Cell Endocrinol. 2017 Jul 5;449:12-20.
3) Sungkaworn T, Jobin ML, Burnecki K, Weron A, Lohse MJ, Calebiro D. Single-molecule imaging reveals receptor-G protein interactions at cell surface hot spots. Nature. 2017 Oct 26;550(7677):543-547

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