My research focused on novel modes of signal transduction by G protein-coupled receptors.
I am interested in receptor-mediated signal transduction, molecular pharmacology, novel signalling pathways from G protein-coupled receptors (including those involving small G proteins).
I also research protein interactions responsible for formation of signalling complexes and their regulation, and cellular and physiological roles of novel signalling pathways.
G protein-coupled receptors (GPCRs) play crucial roles in all physiological systems and act as prime targets for therapeutic intervention in pathological states.
GPCRs classically signal through heterotrimeric G proteins but particular GPCRs can engage in a variety of other interactions with marked influences on their trafficking, association with other proteins or signalling.
We contributed importantly to this theme by the first demonstration that certain GPCRs can interact directly with the monomeric G proteins, ARF and Rho, to activate phospholipase D (Nature 392: 411-4).
This allows access to an array of additional influences over cellular signalling, protein:protein interactions and vesicular trafficking in exocytosis and endocytosis.
Ongoing work is defining that the critical molecular determinants of GPCR linkage to the ARF/phospholipase D pathway are distinct from those necessary for heterotrimeric G protein coupling and investigating the assembly and regulation of the novel multiprotein signalling complexes shown to incorporate GPCR, ARF and phospholipase D.
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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 (agonist-directed trafficking of receptor signalling), the role of receptor polymorphisms in differential drug responses at a molecular level and the influence of psychiatric disorder-related genes on GPCR signalling.
Identification of pathway-selective influences of antipsychotic agents and allele-related differences in these responses could point the way to improved agents and individually tailored therapeutics.
In collaborative studies with Sue Fleetwood-Walker (Centre for Neuroscience Research) we are addressing the role in chronic pain states of intracellular signalling pathways, selected ionotropic and metabotropic receptors and ion channels (especially thermo-TRP channels, such as TRPM8), within dorsal root ganglia and spinal cord.
We further investigate assembly of multiprotein signalling complexes, in particular those centred on the NMDA and AMPA glutamate receptor subtypes and the regulation of both assembly and function by kinases and other signalling pathways.
Chronic sensitised pain states, such as neuropathic and cancer-induced bone pain represent an unmet therapeutic need, so our aim is to identify novel molecular targets for analgesic intervention.
Several aspects of this work, with funding from industry and charitable sources, contribute to our programme in Translational Pain Research, with dynamically interactive parallel streams in pre-clinical and clinical research (collaboration with Marie Fallon, Cancer Research Centre and Lesley Colvin, Anaesthesia, Critical Care and Pain Medicine).
A further major new initiative on the synthesis and development of novel analgesics for chronic pain has recently gained support through a Scottish Enterprise Proof of Concept Award 2008-2010 (collaboration with Mike Greaney, Chemistry).
Fleetwood-Walker SM, Proudfoot CWJ. Garry EM, Allchorne A, Vinuela-Fernandez and 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.
Johnson MS, Robertson DN, Holland PJ, Lutz EM, and Mitchell R (2006) Role of the conserved NPxxY motif of the 5-HT2A receptor in determining selective interaction with isoforms of ARF. Cellular Signalling 18: 1793-800.
Lutz EM, Ronaldson E, Shaw P, Johnson MS, Holland PJ, and Mitchell R (2006) Characterization of novel splice variants of the PAC1 receptor. Molecular and Cellular Neuroscience 31: 193-209.
This article was published on Mar 5, 2013