Dr Andrew Irving

Regulation of cannabinoid type 1 receptor expression and sub-cellular targeting

Recently there has been much interest in the role of the endogenous cannabinoid system in regulating CNS activity and in the therapeutic potential of cannabinoids. Current research in our laboratory is addressing the cellular actions of the major neuronal cannabinoid receptor (CB1) in the CNS and the regulation of CB1 receptor function. In particular, we are using the latest molecular imaging techniques to investigate the regulation of receptor surface expression and sub-cellular targeting in neurons. Dual labelling immunohistochemical techniques and confocal microscopy are also used to visualise receptor distribution and to investigate conditions that modulate the cell surface expression of these receptors, including agonist-induced internalisation.

The physiological role and therapeutic potential of novel lipid-sensing receptors

There is considerable interest in the physiological and pathophysiological roles of lipid receptors, where the recent identification of ligands for these receptors is opening up an opportunity to develop novel therapeutic targets. A number of newly-deorphanised GPCRs have been identified as lipid receptors, including GPR92, GPR55 and GPR18. The pharmacology of these targets is complex, both in terms of ligand redundancy and contextual effects. Our current research efforts are focussed on GPR55, which can be activated by certain cannabinoid ligands and the endogenous lysophospholipid, lysophosphatidyl inositol. Specifically, we have developed a unique, cell-based assay for GPR55, which allows us to evaluate GPR55 ligands and downstream signalling. Future work in this area will be directed at investigating the expression, function and pharmacology of GPR55 and related lipid receptors in native tissues.

The function of GPCR interacting proteins

Proteins that interact with GPCR’s play an important role in regulating receptor signalling, sub-cellular targeting expression and pharmacology. We are interested in identifying novel GPCR interacting partners for cannabinoid / lipid receptors and evaluating their effects on receptor function.

Modulation of Glutamate receptor trafficking

Changes in the localisation and surface expression of glutamate receptors contributes to synaptic plasticity, a well-established, cellular model of learning and memory. This process can be regulated by a variety of different neuromodulators including the ob gene product and cytokine, leptin. In collaboration with Dr Jenni Harvey (Dundee), we are interested in understanding the cellular mechanisms that underlie this effect and whether other modulatory systems act in a similar manner. Glutamate receptor trafficking is studied using unique antibodies that we have developed to glutamate receptor subunits and new molecular tools (pHluorin-tagged constructs) for visualising dynamic changes in receptor expression in neurons.

Krzywkowski, K., Davies, P.A., Irving A.J., Bräuner-Osborne, H. & Jensen, A.A. (2008) Characterization of the effects of four HTR3B polymorphisms on human 5-HT3AB receptor expression and signalling. Pharmacogenet. Genomics 18:1027-1040.

Henstridge, C.M., Balenga, N.A.B, Ford L.A., Ross R.A., Waldhoer M. & Irving, A.J. (2009) The GPR55 ligand L-alpha-lysophosphatidylinositol promotes nRhoA-dependent Ca2+ signaling and NFAT activation. FASEB J. 2009 23:183-93.

Etherington, L-A., Patterson, G.E., Meechan, L., Boison, D., Irving, A.J., Dale N. & Frenguelli, B.G. (2009) Astrocytic adenosine kinase regulates basal synaptic adenosine levels and seizure activity but not activity-dependent adenosine release in the hippocampus. Neuropharmacology 56:429-37.

O'Malley, D., MacDonald, N., Mizielinska, S., Connolly, C.N., Irving, A.J. & Harvey, J. (2007) Leptin promotes rapid dynamic changes in hippocampal dendritic morphology. Mol. Cel.l Neurosci. 35, 559-572.

Cheng, A., Bollan, K.A., Greenwood, S.M., Irving, A.J. & Connolly, C.N. (2007) Differential subcellular localization of RIC-3 isoforms and their role in determining 5-HT3 receptor composition. J. Biol. Chem. 282, 6158-26166.

McDonald, N.A., Henstridge, C.M., Connolly, C.N. & Irving, A.J. (2007) Generation and functional characterisation of fluorescent, N-terminally tagged CB1 receptor chimeras for live-cell imaging. Mol. Cell Neurosc.i 35, 237-248.