| Title | Novel GPCR interactions as a target for developing new analgesics to treat chronic pain |
|---|---|
| Supervisors | Charles Kennedy Margaret Cunningham |
| Research Area | Neuroscience, Pharmacology, Cell Biology |
| Description | The therapeutic options for treating chronic inflammatory and neuropathic pain are limited (see Burnstock &Kennedy, 2011), but new targets have recently been identified, including P2Y receptors, which are G protein-coupled receptors (GPCR) that are activated by nucleotides, such as ADP (Kennedy et al., 2013; Alexander et al., 2019). P2Y receptors are expressed in pain-sensing C and A sensory nerve fibres, so could be targeted to control pain. We showed recently that human P2Y1 and P2Y12 receptors interact to form heterodimers, with novel pharmacological and signalling properties that are different from the individual subtypes (Shakya Shrestha et al., 2010). This is important because it is now recognised that GPCR dimers are common and maybe even crucial for GPCR membrane expression and functional activity (Milligan, 2013). Furthermore, there are clear indications that ADP can act via the P2Y1- P2Y12 heterodimer to modify the activity of pain-sensing nerve fibres. Thus this heterodimer is a novel potential target for the clinical control of pain. Aim of project: The aim of this project is first to characterise the physical interaction between P2Y1 and P2Y12 receptors and then to determine how the P2Y1- P2Y12 heterodimer modulates the activity of nerves that sense pain. |
| Techniques Used | During this project you will learn a range of appropriate techniques, including tissue culture, expression of recombinant P2Y receptors, immunoprecipitation, immunohistochemistry, western blotting, confocal microscopy, FRET & BRET imaging analysis and spectrofluorimetric monitoring of intracellular [Ca2+]. These cutting-edge techniques will advance our understanding of how the P2Y1and P2Y12 interact and will help in the search for new, effective analgesics for the treatment of pain disorders. |
| References | Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators (2019). THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors. Br. J. Pharmacol., 176 Suppl 1, S21-S141. Burnstock, G. and Kennedy, C. (2011). P2X receptors in health and disease. Adv. Pharmacol., 61, 333-372. Kennedy, C., Chootip, K., Mitchell, C., Syed, N.H. and Tengah, A. (2013). P2X and P2Y nucleotide receptors as targets in cardiovascular disease. Future Med. Chem., 5, 431-439. Milligan G (2013). The prevalence, maintenance, and relevance of G protein-coupled receptor oligomerization. Mol. Pharmacol., 84, 158-169. Shakya Shrestha, S., Parmar, M., Kennedy, C. and Bushell, T. (2010). Two-pore potassium ion channels are inhibited by both Gq/11- and Gi-coupled P2Y receptors. Mol. Cell. Neurosci., 43, 363-369. |
| Conditions | Applicants should possess or be about to obtain a 1st class or 2:1 Honours degree or equivalent in a relevant discipline in addition to receipt of satisfactory references and an IELTS score of 6.5 where appropriate. |
| Bench Fee | Running costs of £10000 p.a. will be associated with this project in addition to University tuition fees. |
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