profile image for Prof Alistair Mathie

Prof Alistair Mathie

Professor of Pharmacology and Cell Biology

Medway School of Pharmacy

 

Alistair carried out his PhD research at the University of Leicester (1981-1984) supervised by Professor Asa Blakeley and Dr Stewart Petersen, and used intracellular electrophysiological recording techniques to study the electrical responses of sympathetically innervated smooth muscles, following neurotransmitter release at the neuroeffector junction.

Following his PhD, he spent five years as a postdoctoral research associate in the laboratories of Professors 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. Then, from 1989-1991 he held a Fogarty International Research Fellowship at the University of Washington in Seattle, based in the laboratory of Professor Bertil Hille where the major focus of his research was to apply his experience in electrophysiology to study the intracellular mechanisms activated by neurotransmitters which couple to G-proteins and how these can regulate the activity of voltage-gated ion channels.

In 1991, Alistair was appointed Lecturer in Pharmacology at the Royal Free Hospital School of Medicine then, following merger, a Senior Lecturer in Pharmacology at UCL. In 1999, he moved to Imperial College London where he took up a position there as Reader in Molecular Neuroscience. In 2007, he was appointed Professor of Pharmacology and Cell Biology, Head of Biological Sciences and Director of Research at the Medway School of Pharmacy.

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The main research focus of Alistair’s laboratory is the study of mammalian cell excitability and how this is regulated. In particular, his major ongoing research theme is the determination of the roles of different ion channels in controlling the excitability and firing of mammalian cells, particularly neurons. Such 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. His laboratory uses 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 this work is done in collaboration with other laboratories and, currently, he has collaborative ventures with the pharmaceutical industry, academic laboratories elsewhere in the UK, and groups in Germany, USA 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, TRESK and THIK1. In a PNAS paper published in 2000, my laboratory identified a native leak K current in cerebellar granule neurons (which we named 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 few years in high quality journals (see publication list for more details). 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. Our current work is supported by research grants from the BBSRC and the pharmaceutical industry.

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Selected publications
  • Veale EL, Al Moubarak E, Bajaria N, Omoto K, Cao L, Tucker SJ, Stevens EB, Mathie A (2014). Influence of the N-terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels. Mol Pharmacol doi:10.1124/mol.113.091199.
  • Veale EL, Hassan M, Walsh Y, Al Moubarak E, Mathie A (2014). Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. Mol Pharmacol 85: 397-407.
  • El Hachmane MF, Rees KA, Veale EL, Sumbayev VV, Mathie A (2014). Enhancement of TWIK-related acid sensitive potassium channel 3 (TASK3) two pore domain potassium channel activity by TNFa. J Biol Chem 289: 1388-1401.
  • Alexander SPH, Mathie A*, Peters JA (2011). Guide to Receptors and Channels (GRAC), 5th edn. Br J Pharmacol 164 (Suppl. 1): S1-S324. *joint corresponding author
  • 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.

Full publication list

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  • Veale EL, Al Moubarak E, Bajaria N, Omoto K, Cao L, Tucker SJ, Stevens EB, Mathie A (2014). Influence of the N-terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels. Mol Pharmacol doi:10.1124/mol.113.091199.
  • Veale EL, Hassan M, Walsh Y, Al Moubarak E, Mathie A (2014). Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. Mol Pharmacol 85: 397-407.
  • El Hachmane MF, Rees KA, Veale EL, Sumbayev VV, Mathie A (2014). Enhancement of TWIK-related acid sensitive potassium channel 3 (TASK3) two pore domain potassium channel activity by TNFa. J Biol Chem 289: 1388-1401.
  • Alexander SPH, Benson HE, Davenport A, Mathie A, McGrath JC, Pawson AJ, Peters JA, Sharman JL, Spedding M, Harmar AJ (2012). GuideToPharmacology.org – an update. Br J  Pharmacol 167: 697-698
  • Alexander SPH, Mathie A*, Peters JA (2011). Guide to Receptors and Channels (GRAC), 5th edn. Br J Pharmacol 164 (Suppl. 1): S1-S324. *joint corresponding author
  • 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.
  • Mathie A, Veale EL (2009). Neuronal Potassium Channels. In Encyclopedia of Neuroscience: 2792-2797. eds. Binder M, Hirokawa N, Windhorst U, Hirsch MC, Springer-Verlag (Berlin).
  • Mathie A (2009). Physiology and Systems Biology: Clear voices rise above the noise in Beijing. Physiology News 74: 9-12.
  • Alexander SPH, Mathie A*, Peters JA (2009). Guide to Receptors and Channels (GRAC), 4th edn. Br J Pharmacol 158 (Suppl. 1): S1-S254. *joint corresponding author
  • 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. *joint corresponding author
  • 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.
  • Alexander SPH, Mathie A*, Peters JA (2007). British Journal of Pharmacology & Nature Reviews Drug Discovery - Guide to Receptors and Channels. 2nd edition (revised). Brit J Pharmacol 150 (Suppl 1): S1 - S168. *joint corresponding author
  • Mathie A (2007). Mammalian K2P channels and their regulation by G protein coupled receptors. J Physiol 578: 377-385.
  • Mathie A, Sutton GL, Clarke CE, Veale EL (2006). Zinc and copper:  Pharmacological probes and endogenous modulators of neuronal excitability. Pharmacol Ther 111: 567-583.
  • Linden A-M, Aller MI, Leppa E, Vekovischeva O, Aitta-aho T, Veale EL, Mathie A, Rosenberg P, Wisden W, Korpi ER (2006). The in vivo contributions of TASK-1-containing channels to the actions of inhalation anesthetics, the a2 adrenergic sedative dexmedetomidine and cannabinoid agonists. J Pharmacol Exp Ther 317: 615-626.
  • Alexander SPH, Mathie A*, Peters JA (2006). British Journal of Pharmacology & Nature Reviews Drug Discovery - Guide to Receptors and Channels. 2nd Edition. Brit J Pharmacol 147 (Suppl 3): S1-S180. *joint corresponding author
  • Kennard LE, Chumbley JR, Ranatunga KM, Armstrong SJ, Veale EL, Mathie A (2005). Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine. Br J Pharmacol 144: 821-829.
  • Aller MI, Veale EL, Linden A-M, Sandu C, Schwaninger M, Evans L, Korpi E, Mathie A, Wisden W, Brickley SG (2005). Modifying the subunit composition of TASK channels alters the modulation of a leak conductance in cerebellar granule neurons. J Neurosci 25: 11455-11467.
  • Alexander SPH, Mathie A*, Peters JA (2005). British Journal of Pharmacology & Nature Reviews Drug Discovery - Guide to Receptors and Channels. 1st Edition (revised). Brit J Pharmacol 144: S1-S128. *joint corresponding author
  • Clarke CE, Veale EL, Green PJ, Meadows HJ, Mathie A (2004). Selective block of the human 2-P domain potassium channel, TASK-3, and the native leak potassium current, IKSO, by zinc. J Physiol 560: 51-62.
  • Gruss M, Mathie A, Lieb WR, Franks NP (2004). The two-pore-domain K+ channels TREK-1 and TASK-3 are differentially modulated by copper and zinc. Mol Pharmacol 66: 530-537.
  • Gruss M, Bushell TJ, Bright DP, Lieb WR, Mathie A, Franks NP (2004). Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide and cyclopropane. Mol Pharmacol 65: 443-452.
  • Alexander SPH, Mathie A*, Peters JA (2004). British Journal of Pharmacology & Nature Reviews Drug Discovery - Guide to Receptors and Channels. 1st Edition. Brit J Pharmacol 141: S1-S126. *joint corresponding author
  • Mathie A, Clarke CE, Ranatunga KM, Veale EL (2003). What are the roles of the many different types of potassium channel expressed in cerebellar granule cells? Cerebellum2: 11-25.
  • Mathie A, Kennard LE, Veale EL (2003). Neuronal ion channels and their sensitivity to ELF weak electric field effects. Radiat Prot Dosim 106: 311-315.
  • Mathie A, Clarke CE (2002). Background potassium channels move into focus. J Physiol 542: 334.
  • Bushell T, Clarke C, Mathie A, Robertson B (2002). Pharmacological characterisation of a non-inactivating outward current observed in mouse cerebellar Purkinje neurones. Br J Pharmacol 135: 705-712.
  • Boyd DF, Mathie A (2002). Inhibition of the potassium current IKSO, in cerebellar granule cells, by the inhibitors of MEK1 activation, PD 98059 and U 0126. Neuropharmacol 42: 221-228.
  • Alexander SPH, Mathie A*, Peters JA, MacKenzie G, Smith A (2001). TiPs Nomenclature Supplement 2001. Trends in Pharmacol Sci 22 (suppl 1): 1-146. *joint corresponding author
  • Mathie A, Robertson B (2001). Mammalian two-pore domain potassium channels. Physiology News 43: 5-8.
  • Boyd DF, Millar JA, Watkins CS, Mathie A (2000). The role of Ca2+ stores in the muscarinic inhibition of the K+ current,IKSO, in neonatal rat cerebellar granule cells. J Physiol 529: 321-331.
  • Millar JA, Barratt L, Southan AP, Page KM, Fyffe REW, Robertson B, Mathie A (2000). A functional role for the two-pore domain potassium channel, TASK-1, in cerebellar granule neurons. Proc Natl Acad Sci 97: 3614-3618.
  • Jones G, Boyd DF, Yeung SY, Mathie A (2000). Inhibition of delayed rectifier K+ conductance in cultured rat cerebellar granule neurons by activation of calcium-permeable AMPA receptors. Eur J Neurosci 12: 935-944.
  • Prothero LS, Mathie A, Richards CD (2000). Purinergic and muscarinic receptor activation activates a common calcium entry pathway in rat neocortical neurons and glial cells. Neuropharmacol 39: 1768-1778.
  • Richards CD, Mathie A, Emptage NJ (2000). Optical methods for resolving anaesthetic action on CNS synaptic transmission. Progress in Anesthetic Mechanism 6: 48-52.
  • Yeung SY, Millar JA, Mathie A (1999). Inhibition of neuronal KV potassium currents by the antidepressant drug, fluoxetine. Br J Pharmacol 128: 1609-1615.
  • Amos BJ, Mathie A, Richards CD (1998). Activation of group I metabotropic glutamate receptors elicits pH changes in cultured rat cortical glia and neurones. Neurosci 86: 1109-1120.
  • Mathie A, Wooltorton JRA, Watkins CS (1998). Voltage-activated potassium channels in mammalian neurons and their block by novel pharmacological agents. Gen Pharmacol 30: 13-24.
  • Clark S, Jordt S-E, Jentsch T, Mathie A (1998). Characterisation of the hyperpolarisation activated chloride current in dissociated rat sympathetic neurons. J Physiol 506: 665-678.
  • Prothero LS, Richards CD, Mathie A (1998). Inhibition by inorganic ions of a sustained calcium signal evoked by activation of mGlu5 receptors in rat cortical neurons and glia. Br J Pharmacol 125: 1551-1561.
  • Mathie A, Watkins CS (1997). Is EAG the answer to the M current? Trends in Neurosci 20: 14.
  • Watkins CS, Mathie A (1996). A non-inactivating K+ current sensitive to muscarinic receptor activation in rat cultured cerebellar granule neurons. J Physiol 491: 401-412.
  • Watkins CS, Mathie A (1996). Effect on K+ currents in rat cerebellar granule neurones of a membrane-permeable analogue of the calcium chelator BAPTA. Br J Pharmacol 118: 1772-1778.
  • Wooltorton JRA, Mathie A (1995). Potent block of potassium currents in rat isolated sympathetic neurones by the uncharged forms of amitriptyline and related tricyclic compounds. Br J Pharmacol 116: 2191-2200.
  • Hille B, Beech DJ, Bernheim L, Mathie A, Shapiro MS, Wollmuth LP (1995). Multiple G-protein-coupled pathways inhibit N-type Ca channels of neurons. Life Sci 56: 989-992.
  • Watkins CS, Mathie A (1994). Modulation of the gating of the transient outward potassium current of rat isolated cerebellar granule neurons by lanthanum. Pflügers Archiv - Eur J Physiol 428: 209-216.
  • Hille B, Almers W, Beech DJ, Bernheim L, Mathie A, Shapiro MS, Tse A, Tse FW (1994). G protein-coupled receptors modulate the mind. In Molecular Neurobiology: Proceedings of the Second NIMH Conference: 1-8. eds. Zalczman, S., Scheller, R. & Tsien, R. NIH publication (Washington).
  • Wooltorton JRA, Mathie A (1993). Block of potassium currents in rat isolated sympathetic neurones by tricyclic antidepressants and structurally related compounds. Br J Pharmacol 110: 1126-1132.
  • Stansfeld CE, Mathie A (1993). Recording membrane currents of peripheral neurones in short term culture. In Electrophysiology: A Practical Approach: 3-28. ed. Wallis D.I. IRL Press (Oxford).
  • Bernheim L, Mathie A, Hille B (1992). Characterization of muscarinic receptor subtypes inhibiting Ca current and M current in rat sympathetic neurons. Proc Natl Acad Sci 89: 9544-9548.
  • Mathie A, Bernheim L, Hille B (1992). Inhibition of both N- & L- type Ca channels by muscarinic receptor activation in rat sympathetic neurons. Neuron 8: 907-914.
  • Yang J, Mathie A, Hille B (1992). 5-HT3-receptor channels in dissociated rat superior cervical ganglion neurons. J Physiol 448: 237-256.
  • Beech DJ, Bernheim L, Mathie A, Hille B (1991). Intracellular Ca buffers disrupt muscarinic suppression of Ca-current and M-current in rat sympathetic neurons. Proc Natl Acad Sci 88: 652-656.
  • Mathie A, Cull-Candy SG, Colquhoun D (1991). Conductance & kinetic properties of single nicotinic acetylcholine receptor-channels in rat sympathetic neurones. J Physiol 439: 717-750.
  • Wyllie DJA, Mathie A, Symonds CJ, Cull-Candy SG (1991). Activation of glutamate receptors and glutamate uptake in identified macroglial cells in rat cerebellar cultures. J Physiol 432: 235-258.
  • Mathie A, Colquhoun D, Cull-Candy SG (1990). Rectification of currents activated by nicotinic acetylcholine receptors in rat sympathetic ganglion neurones. J Physiol 427: 625-655.
  • Colquhoun D, Cachelin AB, Marshall CG, Mathie A, Ogden DC (1990). Function of nicotinic synapses. Prog Brain Res 84: 43-50.
  • Colquhoun D, Mathie A, Mulrine NK, Ogden, DC (1989). Studies on single acetylcholine receptor channels in muscle end-plate and sympathetic neurones. Fernstrom Foundation Series  13: 217-234.
  • Cull-Candy SG, Mathie A*, Powis DA (1988). Nicotinic acetylcholine receptor-channels and their block by clonidine in cultured bovine chromaffin cells. ^J Physiol 402: 255-278. *corresponding author; ^journal listed authors in alphabetical order at this time
  • Mathie A, Cull-Candy SG, Colquhoun D (1988). The mammalian neuronal nicotinic receptor and its block by drugs. In Neurotox '88: Molecular Basis of Drug and Pesticide Action: 393-403. ed. Lunt, G. Elsevier (Amsterdam).
  • Colquhoun D, Ogden DC, Mathie A (1987). Nicotinic acetylcholine receptors of nerve and muscle. Trends in Pharmacol Sci 8: 465-472.
  • Mathie A, Cull-Candy SG, Colquhoun D (1987). Single-channel and whole-cell currents evoked by acetylcholine in dissociated sympathetic neurones of the rat. Proc Roy Soc B 232: 239-248.
  • Cull-Candy SG, Mathie A (1986). Ion channels activated by acetylcholine and γ-aminobutyric acid in freshly dissociated sympathetic neurones of the rat. Neurosci Letts 66: 275-280.
  • Blakeley AGH, Mathie A, Petersen SA (1986). Interactions between the effects of yohimbine, clonidine and [Ca]O on the electrical response of the mouse vas deferens. ^Br J Pharmacol 88: 807-814.^journal listed authors in alphabetical order at this time
  • Blakeley AGH, Cunnane TC, Maskell T, Mathie A, Petersen SA (1984). α-adrenoceptors and facilitation at a sympathetic neuroeffector junction. J Auton Pharmacol 4: 53-58.
  • Blakeley AGH, Mathie A, Petersen SA (1984). Facilitation at single release sites of a sympathetic neuroeffector junction in the mouse. ^J Physiol 349: 57-71. ^journal listed authors in alphabetical order at this time
  • Blakeley AGH, Mathie A, Petersen SA (1984). Is the vesicle the unit of transmission at the sympathetic neuroeffector junction? -electrophysiological evidence. In Catecholamines, Part A., Basic and Peripheral Mechanisms: 65-78. eds. Usdin, E., Carlsson, A., Dahlstrom, A. & Engel, J. Alan R Liss inc. (New York).

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