Medway school of pharmacy

My PhD research at the University of Leicester (1981-1984) supervised by Asa Blakeley and Stewart Petersen, used intracellular electrophysiological recording techniques to study the electrical responses of sympathetically innervated smooth muscles, following neurotransmitter release at the neuroeffector junction. In particular, in work published in J Physiol and BJP, I investigated the role of presynaptic adrenoceptors and showed that these receptors have a physiological role as autoreceptors at the level of individual transmitter release sites.

Following my PhD, I spent five years in the laboratories of David Colquhoun and Stuart Cull-Candy at University College London (UCL) studying the biophysical properties of ligand- and voltage-gated ion channels in single, isolated mammalian neurons using patch-clamp and whole-cell electrophysiological recording techniques. For the majority of my time at UCL, I studied the detailed properties of neuronal nicotinic acetylcholine receptors in rat sympathetic ganglion cells and cultured bovine chromaffin cells. I was lead author of a number of key papers published in J Physiol and Proc Roy Soc B showing that these receptors display significant differences in their functional and pharmacological properties when compared with muscle type nicotinic receptors.

At the University of Washington in Seattle (1989-1991), in the laboratory of Bertil Hille, the major focus of my research was to apply my experience in electrophysiology to study the intracellular mechanisms activated by neurotransmitters which couple to G-proteins and how these can modulate the activity of voltage-gated ion channels over time scales ranging from milliseconds to hours. I was able to learn a great deal about these biochemical pathways and how to best study them. Together with two other postdoctoral scientists (David Beech and Laurent Bernheim), I published a series of important papers in PNAS and Neuron characterising the intracellular pathways that neurotransmitters such as acetylcholine and noradrenaline activate to modulate calcium and potassium channel activity in mammalian neurons.

I established my own laboratory in 1991, first at the Royal Free Hospital School of Medicine then, following merger, at UCL. In 1999, I moved my laboratory to Imperial College London when I took up a position there as Reader in Molecular Neuroscience. In 2007, my laboratory relocated again when I became Professor of Pharmacology, Head of Biological Sciences and Director of Research at the Medway School of Pharmacy, University of Kent. I am currently a Royal Society Industry Fellow.

back to top

My laboratory’s research has concentrated in the areas of molecular and cellular neuroscience. We have published extensively in top neuroscience, physiological and pharmacological journals and received regular grant support from the MRC, BBSRC and the Wellcome Trust. The main research focus of my laboratory is the study of neuronal excitability. Our major ongoing research theme is the determination of the roles of different ion channels in controlling the excitability and firing of mammalian neurons. Such neuronal ion channels are important in a variety of clinical conditions, such as epilepsy, stroke, neuropathic pain and depression and represent major potential therapeutic targets for future research. We use a variety of state-of-the-art methodologies to study the properties of these ion channels, including whole-cell and single-channel patch clamp electrophysiology, two-electrode voltage clamp from oocytes, molecular biology (such as site-directed mutagenesis), fluorescent imaging of intracellular ions and fluorescently labelled proteins, tissue culture and computer modelling of ion channel structure and functional behaviour. Much of our work is done in collaboration with other laboratories and, currently, we have collaborative ventures with the pharmaceutical industry, academic laboratories elsewhere in the UK, and groups in Germany, Spain, Finland and Australia.

At present, we are studying the properties of potassium (K) channels in mammalian neurons and their modulation by various pharmacological agents, physiological mediators and neurotransmitter substances. We are also comparing the functional properties of certain native neuronal K channels with recombinant two pore domain K (K2P) channels such as TASK1, TASK3, TREK1 and THIK1. In a seminal PNAS paper published in 2000, my laboratory identified a native leak K current in cerebellar granule neurons (which we called IKSO) which is critical in regulating the excitability of these neurons and correlated the properties of this current with those of the TASK family of K2P channels. Our work since then has contributed greatly to the detailed understanding of the properties and regulation of K2P channels in mammalian neurons, exemplified by our many publications over the last five years in high quality journals such as J Physiol, J Neurosci, BJP, Mol Pharmacol and J Biol Chem. As well as studying the structural, functional and expression properties of these K2P channels, we are investigating their role in a range of diverse physiological and pathophysiological conditions including depression, the detection and transmission of painful stimuli, programmed cell death and the development and maintenance of circadian rhythms.

back to top

• Veale EL, Rees KA, Mathie A*, Trapp S (2010). Dominant negative effects of a non-functional TREK1 splice variant expressed in brain. J Biol Chem  285: 29295-29304. *joint corresponding author

• Mathie A, Al Moubarak E, Veale EL (2010). Gating of two pore domain potassium channels. J Physiol 588: 3149-3156.

• Mathie A (2010). Ion channels as novel therapeutic targets in the treatment of pain. J Pharm Pharmacol 62: 1089-1095.

• Mathie A, Rees KA, El Hachmane MF, Veale EL (2010).  Trafficking of neuronal two pore domain potassium channels. Curr Neuropharmacol 8: 276-286.

• Alexander SPH, Mathie A, Peters JA (2009). Guide to Receptors and Channels (GRAC), 4th edn. Br J Pharmacol 158 (Suppl. 1): S1-S254

• Clarke CE, Veale EL, Wyse K, Vandenberg JI, Mathie A (2008). The M1P1 loop of TASK3 K2P channels apposes the selectivity filter and influences channel function. J Biol Chem 283: 16985-16992.

• Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd Edition. Br J Pharmacol 153 (Suppl. 2): S1-S209.

• Mathie A, Veale EL (2008). Neuronal Potassium Channels. In Encyclopedia of Neuroscience: 2792-2797. eds. Binder M, Hirokawa N, Windhorst U, Hirsch MC, Springer-Verlag (Berlin).

• Veale EL, Buswell R, Clarke CE, Mathie A (2007). Identification of a region in the TASK3 two pore domain potassium channel that is critical for its blockade by methanandamide. Br J Pharmacol 152: 778-786.

• Brickley SG, Aller MI, Sandu C, Veale EL, Alder FG, Sambi H, Mathie A, Wisden W (2007). TASK-3 two-pore domain potassium channels enable sustained high-frequency firing in cerebellar granule neurons. J Neurosci 27: 9329-9340.

• Mathie A, Veale EL (2007). Therapeutic potential of neuronal two pore domain potassium channel modulators. Curr Opin Invest Drugs 8: 555-562.

• Veale EL, Kennard LE, Sutton GL, MacKenzie G, Sandu C, Mathie A (2007). Gaq mediated regulation of TASK3 two pore domain potassium channels: the role of protein kinase C. Mol Pharmacol71: 1666-1675.

• Mathie A (2007). Mammalian K2P channels and their regulation by G protein coupled receptors. J Physiol  578: 377-385.

back to top