Regulation of ion channels that control neural excitability

DAB1

Professor David A. Brown FIBiol, FRS joined the department in April 1987 and served as Head of Department from October 1987 to April 2002. He graduated from University College with a BSc degree in Chemistry, Zoology and Physiology, followed by Special Physiology, and from St Bartholomew's Hospital Medical College with a PhD in Pharmacology. Prior to coming to UCL he was Wellcome Professor of Pharmacology at the School of Pharmacy. He has also held visiting professorships in the Universities of Chicago, Iowa and Texas, and the University of Kanazawa (Japan), and has been a Fogarty Scholar-in-Residence at the National Institutes of Health in the United States. He was elected FRS in 1990 and was awarded the Feldberg Prize in 1992. He is past editor-in-chief of the British Journal of Pharmacology, and has served on the editorial boards of many other journals, including the Journal of Physiology, Neuron, Trends in Neuroscience and Proceedings of the Royal Society.

Lab Members:

· Dr. Steve Marsh
· Dr. Alexander K. Filippov (Honorary Research Associate)
· Dr. Vselovod Telezhkin (Visiting Research Associate)
· Dr. James Halliwell (deceased). James was a much-valued member of our laboratories from 1968 to 1971 and from 1978 to 1990, and continued to share labs with us from 2003 until his death on March 7th 2012. His obituary, with recollections by some of his colleagues, may be seen on the Physiological Society’s website (search 2012 when following this link).
· Dr. Alexander Selyanko (deceased). Alex was another highly-respected and long-standing member of our laboratory from 1983-4 and from1991until his death on September 23rd, 2001. His obituary on pages 33-34 in the Spring 2002 issue of Physiology News is available following this link

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DAB2

Nerve cells communicate through electrical signals termed action potentials. These are generated through the transient opening of voltage-gated sodium channels in the outer membrane. Each action potential is very brief and constitutes the individual `bit' for information processing in the nervous system. However, nerve cell membranes are also equipped with a variety of other voltage-gated and calcium-gated ion channels, operating over slower time-scales. These set up membrane ionic currents whose function is to regulate the frequency and pattern of the action potential discharges. The size and duration of these controlling currents vary from one type of nerve cell to another, giving rise to a wide variety of individual `behaviour patterns' in different nerve cells. Some of these currents are under the control of chemical neurotransmitters (see `Pharmacology of Synaptic Transmission'), which can therefore change the sensitivity and firing behaviour pattern of the receptive neurone. This form of selective tuning is important in such mental functions as arousal and memory retrieval.

We study the effects of transmitters and drugs on these controlling currents. We work mainly (but not exclusively) on a class of potassium-conducting ion channels dubbed ‘M-channels’ that are composed of subunits of the Kv7 potassium channel family. Spontaneous mutations of the genes coding for these channels cause human diseases such as epilepsy, and drugs that enhance their activity have anti-epileptic, anti-nociceptive and other properties. The activity of the ion channels is measured by electrophysiological recording techniques in single neurones in isolated preparations of the mammalian peripheral and central nervous system and in isolated nerve cells and cell lines in tissue culture. Molecular biological and biochemical techniques (eg. DNA transfection, antibody injection) are used to reconstitute and modify receptors, ion channels and transducing proteins, and to study the pathways linking individual receptors.


link to M-Channel kinetic modeling


Symposium. In July 2013 a Symposium on Ion Channel Regulation and Neuronal Physiology, organized by Dr. Mala M. Shah (UCL SoP) and Professor Trevor Smart (UCL,NPP), and sponsored by the Physiological and British Pharmacological Societies, was held at the Royal Society to celebrate David Brown’s research career.

A report of this meeting in Physiology News (Winter 2013, page 17) can be viewed   here.

Selected publications:

  • Robbins J, Passmore GM, Abogadie FC, Reilly JM, Brown DA (2013) Effects of KCNQ2 gene truncation on M-type Kv7 potassium currents. PLoS One. 8(8):e71809. doi: 10.1371[Get PDF]
  • Reilly JM, Telezhkin V, Passmore GM, Marsh SJ, Brown DA (2013) Kv7/M-type potassium channels in rat skin keratinocytes. Pflugers Arch. 465:1371-1381. [Get PDF]
  • Telezhkin V, Thomas AM, Harmer SC, Tinker A, Brown DA (2013) A basic residue in the proximal C-terminus is necessary for efficient activation of the M-channel subunit Kv7.2 by PI(4,5)P(2). Pflugers Arch. 465:945-953. [Get PDF]
  • Filippov AK, Brown DA (2012) A mechanism for nerve cell excitation by norepinephrine via alpha-1 adrenoceptors: inhibition of potassium M-current. Cell Mol Neurobiol         [Get PDF]
  • Telezhkin V, Brown DA, Gibb AJ (2012) Distinct subunit contributions to the activation of M-type potassium channels by PI(4,5)P2 J Gen Physiol 140:41-53  [Get PDF]
  • Telezhkin V, Reilly JM, Thomas AM, Tinker A, Brown DA (2012) Structural requirements of membrane phospholipids for M-type potassium channel activation and binding. J Bio Chem 287(13):10001-12 [Get PDF]
  • Passmore GM, Reilly JM, Thakur M, Keasberry VN, Marsh SJ, Dickenson AH, Brown DA (2012) Functional significance of M-type potassium channels in nociceptive cutaneous sensory endings. Front Mol Neurosci 5:63 [Get PDF]
  • Shah MM, Migliore M, Brown DA (2011) Differential effects of Kv7 (M-) channels on synaptic integration in distinct subcellular compartments of rat hippocampal pyramidal neurons. J Physiol 589:6029-6038 [Get PDF]
  • Brown DA (2011) G proteins. Pp. 199-224 in Textbook of Receptor Pharmacology, 3rd edition, ed. JC Foreman, T Johansen & AJ Gibb (London:CRC Press)
  • Nicholls JG, Martin AR, Fuchs P, Brown DA,Diamond ME, Weisblat DA (2011) From Neuron to Brain 5th edition. (Sunderland, MA, USA: Sinauer Associates Inc.)
  • Filippov AK, Simon J, Barnard EA, Brown DA. (2010) The scaffold protein NHERF2 determines the coupling of P2Y1 nucleotide and mGluR5 glutamate receptor to different ion channels in neurons. J Neurosci. 30:11068-11072. [GetPDF]
  • Brown DA (2010) Muscarinic acetylcholine receptors (mAChRs) in the nervous system: some functions and mechanisms.. J. Molec. Neurosci. 41:340–346. [Get PDF]
  • Brown DA, Passmore, GM. (2010). Some new insights into the molecular mechanisms of pain perception. J. Clin. Invest.120: 1380-1383.[Get PDF]
  • Brown DA & Passmore, GM. (2009). Neural KCNQ (Kv7) channels. Br. J. Pharmacol. 156: 1185–1195.[Get PDF]
  • Shah MM, Migliore M, Valencia I, Cooper EC, Brown DA. (2008) Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons. Proc Natl Acad Sci USA, 105:7869-7874. [Get PDF]
  • Lang PM, Fleckenstein J, Passmore GM, Brown DA, Grafe P. (2008) Retigabine reduces the excitability of unmyelinated peripheral human axons. Neuropharmacology. 54:1271-1278.[Get PDF]
  • Hughes S, Marsh SJ, Tinker A, Brown DA. (2007) PIP(2)-dependent inhibition of M-type (Kv7.2/7.3) potassium channels: direct on-line assessment of PIP(2) depletion by Gq-coupled receptors in single living neurons. Pflugers Arch. 455:115-124. [Get PDF]
  • Robbins J, Marsh SJ, Brown DA. (2006) Probing the regulation of M (Kv7) potassium channels in intact neurons with membrane-targeted peptides. J Neurosci. 26, 7950-7961. [Get PDF]
  • Filippov AK,Choi RC, Simon J, Barnard EA, Brown DA. (2006) Activation of P2Y1 nucleotide receptors induces inhibition of the M-type K+ current in rat hippocampal pyramidal neurons. J Neurosci. 26, 9340-93488. [Get PDF]
  • Allen TG, Abogadie FC, Brown DA. (2006). Simultaneous release of glutamate and acetylcholine from single magnocellular "cholinergic" basal forebrain neurons. J Neurosci. 26,1588-1595 [Get PDF]
  • Delmas, P & Brown, D.A. (2005). Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat Rev Neurosci. 6, 850-862. [Get PDF]
  • Winks, J.S., Hughes, S., Filippov, A.K., Tatulian, L., Abogadie, F.C., Brown, D.A. & Marsh, S.J. (2005). Relationship between membrane phosphatidylinositol-4,5-bisphosphate and receptor-mediated inhibition of native neuronal M channels. J. Neurosci. 25, 3400-3413 [Get PDF]
  • Filippov, A.K., Fernandez-Fernandez, J.M., Marsh, S.J., Simon, J., Barnard, E.A. & Brown, D.A. (2004). Activation and inhibition of neuronal G protein-gated inwardly rectifying K+ channels by P2Y nucleotide receptors. Mol. Pharmacol., 66, 468-477. [Get PDF]
  • Delmas, P., Crest, M. & Brown, D.A. (2004). The functional organization of phospholipase-C signalling microdomains in neurons. Trends in Neurosci., 27, 41-47. [Get PDF]
  • Allen, T.G.J. & Brown D.A. (2004). Modulation of the excitability of cholinergic basal forebrain neurons by KATP channels. J. Physiol. 554, 353-370
    [Get PDF]
  • Passmore, G.M., Selyanko, A.A., Mistry, M., Al-Qatari, M., Marsh, S.J., Matthews, E.A., Dickenson, A.H., Brown, T.A., Burbidge, S.A., Main, M. & Brown, D.A. (2003). KCNQ/M currentsin sensory neurons: significance for pain therapy. J. Neurosci., 23, 7227-7236.
    [Get PDF]
  • Commentary on Passmore et al. (2003)
    [Get PDF]
  • N. Wanaverbecq, S. J. Marsh, M. Al-Qatari & D. A. Brown (2003) The plasma membrane calcium-ATPase as a major mechanism for intracellular calcium regulation in neurones from the rat superior cervical ganglion. J. Physiol. 550, 83-101
    [Get PDF]
  • Filippov AK, Simon J, Barnard EA, Brown DA. (2003). Coupling of the nucleotide P2Y(4) receptor to neuronal ion channels. Br J Pharmacol. 138, 400-6.
    [Get PDF]
  • Hadley, J.K., Passmore, G.M., Tatulian, L., Al-Qatari, M., Ye, F., Wickenden, A.D. & Brown, D.A. (2003). Stoichiometry of expressed KCNQ2/KCNQ3 channels and subunit composition of native ganglionic M-channels deduced from block by tetraethylammonium (TEA). J. Neurosci., 23, 5012-5019
    [Get PDF]
  • Hoshi, N., Zhang, J-S., Omaki, M., Takeuchi, T., Yokoyama, S., Wanaverbecq, N., Langeberg, L.K., Yoneda, Y., Scott, J.D., Brown, D.A. & Higashida, H. (2003). AKAP150 signaling promotes suppression of the M-current by muscarinic agonists. Nat. Neurosci. 6, 564-571
    [Get PDF]
  • Tatulian, L. & Brown, D.A. (2003). Effect of the KCNQ potassium channel opener, retigabine, on single KCNQ2/3 channels expressed in CHO cells. J.Physiol. , 549, 57-63
    [Get PDF]
  • Selyanko, A.A., Delmas, P., Hadley, J.K., Tatulian, L., Wood, I.C., Mistry, M., London, B. & Brown, D.A. (2002). Dominant-negative subunits reveal potassium channel families that contribute to M-like potassium current. J. Neurosci., 22, RC212(1-5)
    [Get PDF]
  • Commentary on Dalmas et al. by Johenning & Erhlich (2002). Neuron, 34, 173-178 [Get PDF]
  • Delmas, P., Nomura, H., Li, X., Lakkis, M., Luo, Y., Segal, Y., Fernandez-Fernandez, J.M., Harris, P., Frischauf, A-M., Brown, D.A. & Zhou, J. (2002a). Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2. J. Biol. Chem., 277, 11276-11283.
    [Get PDF]
  • Abogadie, F.C., Bron, R., Marsh, S.J., Drew, L.J., Haley, J.E., Buckley, N.J., Brown, D.A. & Delmas, P. (2002). Adenovirus-mediated Gq-protein antisense transfer in neurons replicates Gq gene knockout strategies. Neuropharmacology, 42, 950-957. [Get PDF]
  • Delmas, P., Wanaverbecq, N., Abogadie, F.C., Mistry, M. & Brown, D.A. (2002). Signalling microdomains define the specificity of receptor-mediated InsP3 pathways in neurons. Neuron, 34, 209-220.
    [Get PDF]
  • Shah, M.M., Mistry, M., Marsh, S.J., Brown, D.A. & Delmas, P. (2002). Molecular correlates of the M-current in cultured rat hippocampal neurons. J.Physiol., 544, 29-37
    [Get PDF]
  • Pan, Z., Selyanko, A.A., Hadley, J.K., Brown, D.A., Dixon, J.E. & McKinnon, D. (2001). Alternative splicing of KCNQ2 potassium channel transcripts contributes to the functional diversity of M-currents. J. Physiol., 531, 347-358.
    [Get PDF]
  • Selyanko, A.A., Hadley, J.K. & Brown, D.A. (2001). Properties of single M-type KCNQ2/KCNQ3 potassium channels expressed in mammalian cells. J. Physiol. 534, 15-24
    [Get PDF]
  • Fernandez-Fernandez, J.M., Abogadie, F.C., Milligan, G., Delmas, P. & Brown, D.A. (2001). Multiple pertussis toxin-sensitive G proteins can couple receptors to GIRK channels in rat sympathetic neurones when heterologously-expressed, but only native Gi proteins do so in situ. Eur. J. Neurosci. 14, 283-292.
    [Get PDF]
  • Tatulian, L., Delmas, P., Abogadie, F.C. & Brown, D.A. (2001). Activation of expressed KCNQ potassium currents and native neuronal M-type currents by the anti-convulsant drug retigabine. J. Neurosci. 21, 5535-5545.
    [Get PDF]
  • Delmas, P., Abogadie, F.C., Buckley, N.J. & Brown, D.A. (2000). Calcium channel gating and modulation by neurotransmitters depend on cellular compartmentation. Nature Neurosci., 3, 670-678.
    [Get PDF]
  • Filippov, A.K., Couve, A., Pangalos, M.N., Walsh, F.S., Brown, D.A. & Moss, S.J. (2000). Heteromeric assembly of GABABR1 and GABABR2 receptor subunits inhibits Ca2+ current in sympathetic neurons. J.Biol.Chem., 20, 2867-2874.
    [Get PDF]
  • Selyanko, A.A., Hadley, J.K., Wood, I.C., Abogadie, F.C., Jentsch, T.J. & Brown, D.A. (2000). Inhibition of KCNQ1-4 channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors. J.Physiol., 522, 349-355.
    [Get PDF]
  • Selyanko, A.A. & Brown, D.A. (1999). M-channel gating and simulation. Biophys. J., 77, 701-713.
    [Get PDF]
  • Selyanko, A.A., Hadley, J.K., Wood, I.C., Abogadie, F.C., Delmas, P., Buckley, N.J., London, B. & Brown, D.A. (1999). Two types of K+ channel subunit, Erg1 and KCNQ2/3, contribute to the M-like current in a mammalian neuronal cell. J.Neurosci., 19, 7742-7756.
    [Get PDF]
  • Haley, J.E., Abogadie, F.C., Delmas, P., Dayrell, M., Vallis, Y., Milligan, G., Caulfield, M.P., Brown, D.A. & Buckley, N.J. (1998). The alpha subunit of Gq contributes to muscarinic inhibition of the M-type potassium current in sympathetic neurons. J.Neurosci., 18, 4521-4531
    [Get PDF]
  • Allen, T.G.J. & Brown, D.A. (1996). Detection and modulation of acetylcholine release from neurites of rat cultured basal forebrain cells. J.Physiol., 492, 453-466.
    [Get PDF]