Our research focuses on novel modes of signal transduction by G protein-coupled receptors and their potential role in neuronal plasticity associated with psychiatric disorders or antipsychotic treatment, as well as pain and analgesia.
We are interested in receptor-mediated signal transduction, new concepts in molecular pharmacology and novel signalling pathways from G protein-coupled receptors (GPCRs), particularly small G protein-dependent signalling.
We also research protein : protein interactions responsible for the formation and function of novel signalling complexes, together with their role in states of physiological and pathological plasticity in the nervous system.
GPCRs play crucial roles in all physiological systems and act as prime targets for therapeutic intervention in pathological states. They classically signal through heterotrimeric G proteins but particular GPCRs can interact with other proteins to alter receptor trafficking or signalling.
We showed for the first time that certain GPCRs can interact directly with the monomeric G proteins, ARF and Rho, to activate phospholipase D (Nature 392: 411-4). This triggers downstream signalling cascades that can influence trafficking of key mediators of neuronal excitability as well as induce cell proliferation / growth.
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A further theme of our work is the investigation of how key antipsychotics influence the signalling choices made by target GPCRs such as the 5-HT2A receptor.
This work focuses on pathway-specific actions of drugs (biased agonism), the role of receptor polymorphisms in differential drug responses at a molecular level and the influence of psychiatric disorder-related genes on GPCR signalling.
In collaborative studies with Sue Fleetwood-Walker we are addressing the role in chronic pain states of intracellular signalling pathways,related to selected ionotropic and metabotropic receptors and their multi-protein signallingcomplexes, with a view to finding new targets for therapeutic intervention.
Jointly with Sue Fleetwood-Walker, we are further validating the therapeutic potential of TRPM8 channel agonists as analgesics by collaborating with Marie Fallon and Lesley Colvin on open-label and placebo-controlled clinical trials in chronic pain states and are developing a major programme on the synthesis and optimisation of new chemical entities to target this channel.
Sun L, Gooding HL, Brunton PJ, Russell JA, Mitchell R, Fleetwood-Walker S (2013) Phospholipase D-mediated hypersensitivity at central synapses is associated with abnormal behaviours and pain sensitivity in rats exposed to prenatal stress. Int J Biochem Cell Biol. (Epub ahead of print).
Fleetwood-Walker S, Mitchell R (2013) Novel Analgesic Therapy. Patent; UK filing priority date 8th Aug 2013.
Barclay Z, Dickson L, Robertson D, Johnson M, Holland P, Rosie R, Sun L, Jerina H, Lutz E, Fleetwood-Walker S, Mitchell R (2013) Attenuated PLD1 association and signalling at the H452Y polymorphic form of the 5-HT2A receptor. Cell Signal. 25:814-21.
Barclay Z, Dickson L, Robertson DN, Johnson MS, Holland PJ, Rosie R, Sun L, Fleetwood-Walker S, Lutz EM, Mitchell R. (2011) 5-HT2A receptor signalling through phospholipase D associated with its C-terminal tail. Biochem J. 436:651-60.
Arbuckle MI, Komiyama NH, Delaney A, Coba M, Garry EM, Rosie R, Allchorne AJ, Forsyth LH, Bence M, Carlisle HJ, O'Dell TJ, Mitchell R, Fleetwood-Walker SM, Grant SG. (2010) The SH3 domain of postsynaptic density-95 mediates inflammatory pain through phosphatidylinositol 3-kinase recruitment. EMBO Rep. 11:473-8.
Fleetwood-Walker SM, Mitchell R, Proudfoot CWJ, Garry EM (2008) Induction of analgesia in neuropathic pain. International Patent Publication Number WO 2008/015403.
Fleetwood-Walker SM, Proudfoot CWJ. Garry EM, Allchorne A, Vinuela-Fernandez, Mitchell R (2007) Cold Comfort Pharm. Trends in Pharmacological Sciences 28:621-8.
Proudfoot CWJ, Garry EM, Cottrell DF, Rosie R, Anderson H, Robertson DC, Fleetwood-Walker SM and Mitchell R (2006) Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Current Biology 16:1591-1605. Cited in: Science STKE, Nature, Nature Clinical Practice, Lancet Neurology, American Chemical Society News, BBC, Scientific American.
Mitchell R, McCulloch D, Lutz EM, Johnson MS, MacKenzie, CJ, Fennell M, Fink G, Zhou W, Sealfon SC. (1998) Rhodopsin family receptors associate with small G proteins to activate phospholipase D. Nature 392:411-414.
This article was published on Sep 9, 2013