Prof Lucia Sivilotti

Photo

Personal Profile

Name: Lucia Sivilotti Email: l.sivilotti@ucl.ac.uk
Title: Prof Tel:
Department: Neuro, Physiology & Pharmacology Fax:
Position: Professor of Pharmacology Address: Medical Sciences Building, Gower St, London, WC1E 6BT
Research Domain: Basic Life Sciences, Neuroscience Web Page: Personal Web Page

Profile

Research Description

We work at understanding the functioning of receptors that mediate fast synaptic transmission, and focus on two classes of ion channels in the nicotinic superfamily, nicotinic and glycine receptors. Different types of nicotinic receptors (which are all excitatory and activated by the transmitter acetylcholine) mediate the initiation of muscle contraction by the peripheral terminals of motor neurones in the spinal cord and the regulation of involuntary bodily functions, such as blood pressure at the level of autonomic ganglia. Yet other forms of nicotinic receptors are present in the brain and are affected by the nicotine in tobacco smoke. Glycine receptors are activated by the simplest amino acid, glycine, and are inhibitory, acting to dampen excessive neuronal activity, particularly in the lower levels of the central nervous system, such as the spinal cord. For instance, without glycine transmission there would be no coordination between muscles that have opposite effects on the movement of a limb. In man, inherited mutations in nicotinic or glycine receptors are known to produce neurological disease. Our general aim is to understand in quantitative terms how a receptor functions as a one-molecule machine. This is only possible because, thanks to the techniques of patch clamp and single channel recording, the activity of a single receptor molecule can be seen in real time. This type of work is important not just for neuroscience (i.e. for understanding synaptic transmission), but also for pharmacology. Indeed, to this day concepts that are central to pharmacology and receptor theory, such as partial agonism and efficacy, are well understood (i.e. can be quantitatively formulated) only for receptors that belong to the ligand-gated ion channel class (largely because of past research in this department). Some of the questions being investigated include: * How do differences in the properties of the several types of receptors derive from differences in the sort of protein subunits that make them up (each of which is produced by a different gene)? * How does the binding of the transmitter to the receptor result in channel opening and what portions of the subunits are important in this process? * How many molecules of transmitter need to bind for the channel to open efficiently? * How do disease mutations in the amino acid sequence of subunits impair the working of the receptor? A combination of electrophysiological recording and molecular biology techniques are used in the laboratory in order to obtain in cell cultures or in Xenopus oocytes receptors that are similar to those in the brain of humans and animals. We then record the electrical currents they produce both in their normal form and in forms that have been mutated. While a range of electrophysiological recording techniques are in everyday use in the laboratory, a strong focus is on single channel recording and its interpretation.


Research Activities

Molecular function of channels in the nicotinic superfamily

Education Description

I contribute to several Pharmacology courses for science students in years 1-3
PHAR1001 (tutorials)
PHAR2002/5 General and Systematic Pharmacology (lectures, tutorials, coursework)
PHAR2003 Experimental Pharmacology (seminars, tutorials); I am in charge of the "Unknown Drug" Project practicals in the second half of this course, where teams of students identify an adrenergic drug by designing and carrying out wet lab experiments (lecture, tutorials, practicals, coursework)
PHAR3011 Synaptic Pharmacology (lectures, coursework)
PHAR3001/2 Neuropharmacology (lecture, coursework)

In the Medical School I am the deputy organiser of the Basic Pharmacology part of the Use of Medicines/Pharmacology Module (lectures and tutorials to Medical Students).

I offer research projects in my lab to undergraduates (PHAR3010) and postgraduates (MSc Neuroscience, rotation PhD students)

I also participate to the teaching of postgraduates, in particular to the MRes of the CoMPLEX Doctoral Training Centre (practical) and the BBSRC Doctoral Training Programme (lectures)

I am one of the two graduate tutors for CoMPLEX and the personal tutor of 14 undergraduates (PHOL1001 scheme)

Together with David Colquhoun, I organise a summer course. This is a week-long intensive workshop on the principles of Understanding ion channels in terms of mechanisms, aimed at postgraduates and postdoctoral researchers in this research area.

UCL Collaborators

External Collaborators

Publications

    2014

    • Yu R, Hurdiss E, Greiner T, Lape R, Sivilotti L, Biggin PC (2014). Agonist and Antagonist Binding in Human Glycine Receptors.. Biochemistry, , - . doi:10.1021/bi500815f

    2013

    • Calderhead B, Epstein M, Sivilotti L, Girolami M (2013). Bayesian approaches for mechanistic ion channel modeling.. Methods Mol Biol, 1021, 247 - 272. doi:10.1007/978-1-62703-450-0_13
    • Marabelli A, Moroni M, Lape R, Sivilotti LG (2013). The kinetic properties of the α3 rat glycine receptor make it suitable for mediating fast synaptic inhibition.. J Physiol, 591(Pt 13), 3289 - 3308. doi:10.1113/jphysiol.2013.252189

    2012

    • Zimmermann I, Marabelli A, Bertozzi C, Sivilotti LG, Dutzler R (2012). Inhibition of the prokaryotic pentameric ligand-gated ion channel ELIC by divalent cations.. PLoS Biol, 10(11), e1001429 - . doi:10.1371/journal.pbio.1001429
    • Lape R, Plested AJ, Moroni M, Colquhoun D, Sivilotti LG (2012). The α1K276E startle disease mutation reveals multiple intermediate states in the gating of glycine receptors.. J Neurosci, 32(4), 1336 - 1352. doi:10.1523/JNEUROSCI.4346-11.2012

    2011

    • Moroni M, Meyer JO, Lahmann C, Sivilotti LG (2011). In glycine and GABA(A) channels, different subunits contribute asymmetrically to channel conductance via residues in the extracellular domain.. J Biol Chem, 286(15), 13414 - 13422. doi:10.1074/jbc.M110.204610
    • Krashia P, Lape R, Lodesani F, Colquhoun D, Sivilotti LG (2011). The long activations of α2 glycine channels can be described by a mechanism with reaction intermediates ("flip").. J Gen Physiol, 137(2), 197 - 216. doi:10.1085/jgp.201010521
    • Moroni M, Biro I, Giugliano M, Vijayan R, Biggin PC, Beato M, Sivilotti LG (2011). Chloride ions in the pore of glycine and GABA channels shape the time course and voltage dependence of agonist currents.. J Neurosci, 31(40), 14095 - 14106. doi:10.1523/JNEUROSCI.1985-11.2011

    2010

    • Krashia P, Moroni M, Broadbent S, Hofmann G, Kracun S, Beato M, Groot-Kormelink PJ, Sivilotti LG (2010). Human α3β4 neuronal nicotinic receptors show different stoichiometry if they are expressed in Xenopus oocytes or mammalian HEK293 cells. PLoS One, 5(10), - . doi:10.1371/journal.pone.0013611
    • Sivilotti LG (2010). What single channel analysis tells us of the activation mechanism of ligand-gated channels: the case of the glycine receptor. The Journal of Physiology, 588, 45 - 58. doi:10.1113/jphysiol.2009.178525

    2009

    • Colquhoun D, Lape R, Sivilotti L (2009). Single ion channels. In Knight A (Ed.), Single Molecule Biology (pp. 223 - 251). : Academic Press.
    • Lape R, Krashia P, Colquhoun D, Sivilotti LG (2009). Agonist and blocking actions of choline and tetramethylammonium on human muscle acetylcholine receptors. The Journal of Physiology, 587, 5045 - 5072. doi:10.1113/jphysiol.2009.176305
    • Houston CM, Bright DP, Sivilotti LG, Beato M, Smart TG (2009). Intracellular chloride ions regulate the time course of GABA-mediated inhibitory synaptic transmission. J Neurosci, 29(33), 10416 - 10423. doi:10.1523/​JNEUROSCI.1670-09

    2008

    • Lape R, Colquhoun D, Sivilotti LG (2008). On the nature of partial agonism in the nicotinic superfamily. Nature, 454(7205), 722 - 727. doi:10.1038/nature07139
    • Pitt SJ, Sivilotti LG, Beato M (2008). High intracellular chloride slows the decay of glycinergic currents. Journal of Neuroscience, 28, 11454 - 11467. doi:10.1523/​JNEUROSCI.3890-08.2008

    2007

    • Plested AJR, Groot-Kormelink PJ, Colquhoun D, Sivilotti LG (2007). Single channel study of the spasmodic mutation α1A52S in recombinant rat glycine receptors. The Journal of Physiology, 581(1), 51 - 73. doi:10.1113/jphysiol.2006.126920
    • Beato M, Sivilotti LG (2007). Single-channel properties of glycine receptors of juvenile rat spinal motoneurones in vitro.. J Physiol, 580(Pt. 2), 497 - 506. doi:10.1113/jphysiol.2006.125740
    • Beato M, Burzomato V, Sivilotti LG (2007). The kinetics of inhibition of rat recombinant heteromeric alpha1beta glycine receptors by the low-affinity antagonist SR-95531.. J Physiol, 580(Pt 1), 171 - 179. doi:10.1113/jphysiol.2006.126888

    2006

    • Groot-Kormelink PJ, Broadbent S, Beato M, Sivilotti LG (2006). Constraining the expression of nicotinic acetylcholine receptors by using pentameric constructs.. Mol Pharmacol, 69(2), 558 - 563. doi:10.1124/mol.105.019356
    • Broadbent S, Groot-Kormelink PJ, Krashia PA, Harkness PC, Millar NS, Beato M, Sivilotti LG (2006). Incorporation of the beta3 subunit has a dominant-negative effect on the function of recombinant central-type neuronal nicotinic receptors.. Mol Pharmacol, 70(4), 1350 - 1357. doi:10.1124/mol.106.026682

    2004

    • Burzomato V, Beato M, Groot-Kormelink PJ, Colquhoun D, Sivilotti LG (2004). Single-channel behavior of heteromeric alpha1beta glycine receptors: an attempt to detect a conformational change before the channel opens.. J Neurosci, 24(48), 10924 - 10940. doi:10.1523/JNEUROSCI.3424-04.2004
    • Beato M, Groot-Kormelink PJ, Colquhoun D, Sivilotti LG (2004). The activation mechanism of α1 homomeric glycine receptors. Journal of Neuroscience, 24, 895 - 906. doi:10.1523/JNEUROSCI.4420-03.2004
    • Colquhoun D, Sivilotti LG (2004). Function and structure in glycine receptors and some of their relatives.. Trends Neurosci, 27(6), 337 - 344. doi:10.1016/j.tins.2004.04.010
    • Groot-Kormelink PJ, Broadbent SD, Boorman JP, Sivilotti LG (2004). Incomplete incorporation of tandem subunits in recombinant neuronal nicotinic receptors.. J Gen Physiol, 123(6), 697 - 708. doi:10.1085/jgp.200409042

    2003

    • Colquhoun D, Unwin N, Shelley C, Hatton CJ, Sivilotti L (2003). Nicotinic acetylcholine receptors. In Abraham D (Ed.), Burger's Medicinal Chemistry (pp. 357 - 405). : J. Wiley.
    • Burzomato V, Groot-Kormelink PJ, Sivilotti LG, Beato M (2003). Stoichiometry of recombinant heteromeric glycine receptors revealed by a pore-lining region point mutation. Receptors Channels, 9(6), 353 - 361.
    • Boorman JP, Beato M, Groot-Kormelink PJ, Broadbent SD, Sivilotti LG (2003). The effects of ß3 subunit incorporation on the pharmacology and single channel properties of oocyte-expressed human alpha3ß4 neuronal nicotinic receptors. Journal of Biological Chemistry, 278(45), 44033 - 44040.

    2002

    • Colquhoun D, Sivilotti L (2002). Acetylcholine receptor-nicotinic. In Creighton TE (Ed.), The Encyclopedia of Molecular Medicine (pp. 9 - 14). : John Wiley & Sons Inc..
    • Beato M, Groot-Kormelink P, Colquhoun D, Sivilotti LG (2002). Openings of the recombinant rat α1 homomeric glycine receptor as a function of the number of agonist molecules bound. Journal of General Physiology, 119, 443 - 466. doi:10.1085/jgp.20028530
    • Groot-Kormelink PJ, Beato M, Finite C, Harvey RJ, Sivilotti LG (2002). Achieving optimal expression for single channel recording: a plasmid ratio approach to the expression of alpha1 glycine receptors in HEK293 cells. Journal of Neuroscience Methods, 113, 207 - 214. doi:10.1016/S0165-0270(01)00500-3

    2001

    • Groot-Kormelink PJ, Boorman JP, Sivilotti LG (2001). Formation of functional alpha3beta4alpha5 human neuronal nicotinic receptors in Xenopus oocytes: a reporter mutation approach.. Br J Pharmacol, 134(4), 789 - 796. doi:10.1038/sj.bjp.0704313
    • Sivilotti L (2001). Nicotinic receptors: Molecular issues - Target article on nicotine-addiction. PSYCOLOQUY, 12(4), 1 - 8.

    2000

    • Boorman JPB, Groot-Kormelink PJ, Sivilotti LG (2000). Stoichiometry of human recombinant neuronal nicotinic receptors containing the β3 subunit expressed in Xenopus oocytes.. The Journal of Physiology, 529, 565 - 577.
    • Sivilotti LG, Colquhoun D, Millar N (2000). Comparison of native and recombinant neuronal nicotinic receptors: Problems of measurement and expression. In Clementi F, Fornasari D, Gotti C (Ed.), Neuronal Nicotinic Receptors, Handbook of Experimental Pharmacology (pp. 379 - 416). : Springer Verlag.

    1998

    • Lewis TM, Sivilotti LG, Colquhoun D, Gardiner RM, Schoepfer R, Rees M (1998). Properties of human glycine receptors containing the hyperekplexia mutation α1 (K276E) expressed in Xenopus oocytes. The Journal of Physiology, 507, 25 - 40.
    • Groot-Kormelink PJ, Luyten WHML, Colquhoun D, Sivilotti LG (1998). A receptor mutation approach shows incorporation of the "orphan" subunit β3 into a functional nicotinic receptor. Journal of Biological Chemistry, 273, 15317 - 15320.

    1997

    • Lewis TM, Harkness PC, Sivilotti LG, Colquhoun D, Millar NS (1997). The ion channel properties of a rat recombinant neuronal nicotinic receptor are dependent on the host cell type. The Journal of Physiology, 505, 299 - 306.
    • Sivilotti L, Okuse K, Akopian AN, Moss S, Wood JN (1997). A single serine residue confers tetrodotoxin insensitivity on the rat sensory-neuron-specific sodium channnel SNS. Federation of European Biochemical Societies Letters, 409(1), 49 - 52.
    • Okuse K, Akopian AN, Souslova V, Sivilotti L, Dolphin AC, Wood JN (1997). Sensory neuron voltage-gated sodium channels and nociception. In Borsook D (Ed.), Molecular Neurobiology of Pain (pp. 239 - 257). : IASP Press.
    • Akopian AN, Souslova V, Sivilotti L, Wood JN (1997). Structure and distribution of a broadly-expressed atypical sodium channel. Federation of European Biochemical Societies Letters, 400, 183 - 187.
    • Sivilotti LG, McNeil DK, Lewis TM, Nassar MA, Schoepfer R, Colquhoun D (1997). Recombinant nicotinic receptors, expressed in Xenopus oocyte, do not resemble rat sympathetic ganglion receptors in single channel behaviour. The Journal of Physiology, 500, 123 - 138.

    1996

    • Akopian AN, Sivilotti L, Wood JN (1996). A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 379, 257 - 262.

    1995

    • Chen CC, Akopian AN, Sivilotti LG, Colquhoun D, Burnstock G, Wood JN (1995). A P2X purinoceptor expressed by a subset of sensory neurons. Nature, 377, 428 - 428. doi:10.1038/377428a0
    • Sivilotti L, Colquhoun D (1995). Acetylcholine receptors: too many channels, too few functions. Science, 269, 1681 - 1682. doi:10.1126/science.7569892
    • Sivilotti LG, Gerber G, Rawat B, Woolf CJ (1995). Morphine selectively depresses the slowest, NMDA-independent component of C-fibre-evoked synaptic activity in the rat spinal cord in vitro.. Eur J Neurosci, 7(1), 12 - 18.

    1994

    • Covernton PJO, Kojima H, Sivilotti LG, Gibb AJ, Colquhoun D (1994). Comparison of neuronal nicotinic receptors in rat sympathetic neurones with subunit pairs expressed in Xenopus oocytes. The Journal of Physiology, 481, 27 - 34.
    • Sivilotti L, Woolf CJ (1994). The contribution of GABAA and glycine receptors to central sensitization: disinhibition and touch-evoked allodynia in the spinal cord.. Journal of Neurophysiology, 72, 169 - 179.
    • Woolf CJ, Shortland P, Sivilotti LG (1994). Sensitization of high mechanothreshold superficial dorsal horn neurons following chemosensitive primary afferent activation. Pain, 58, 141 - 155.

    1993

    • SIVILOTTI LG, THOMPSON SWN, WOOLF CJ (1993). RATE OF RISE OF THE CUMULATIVE DEPOLARIZATION EVOKED BY REPETITIVE STIMULATION OF SMALL-CALIBER AFFERENTS IS A PREDICTOR OF ACTION-POTENTIAL WINDUP IN RAT SPINAL NEURONS INVITRO. J NEUROPHYSIOL, 69(5), 1621 - 1631.
    • Thompson SWN, Woolf CJ, Sivilotti LG (1993). Small caliber afferents produce a heterosynaptic facilitation of the synaptic responses evoked by primary afferent A-fibers in the neonatal rat spinal cord in vitro. Journal of Neurophysiology, 69, 2116 - 2128.

    1992

    • Thompson SWN, Gerber G, Sivilotti LG, Woolf CJ (1992). Long duration ventral root potentials in the neonatal rat spinal cord in vitro; the effects of ionotropic and metabotropic excitatory amino acid receptor antagonists. Brain Research, 595, 87 - 97.

    1991

    • Sivilotti L, Nistri A (1991). GABA receptor mechanisms in the central nervous system.. Progress in Neurobiology, 36, 35 - 92.

    1990

    • Mazda GY, Nistri A, Sivilotti L (1990). The effect of GABA on the frog optic tectum is sensitive to ammonium and to penicillin. European Journal of Pharmacology, 179, 111 - 118.
    • NISTRI A, SIVILOTTI L, WELSH DM (1990). AN ELECTROPHYSIOLOGICAL STUDY OF THE ACTION OF N-METHYL-D-ASPARTATE ON EXCITATORY SYNAPTIC TRANSMISSION IN THE OPTIC TECTUM OF THE FROG INVITRO. NEUROPHARMACOLOGY, 29(7), 681 - 687.

    1989

    • Sivilotti L, Nistri A (1989). Pharmacology of a novel effect of γ-aminobutyric acid on the frog optic tectum in vitro. European Journal of Pharmacology, 164, 205 - 212.
    • Sivilotti L, Nistri A (1989). Antagonism of the actions of glutamate by pentobarbitone or midazolam in the frog optic tectum in vitro.. Neuropharmacology, 28(10), 1107 - 1112.

    1988

    • Sivilotti L, Nistri A (1988). Complex effects of baclofen on synaptic transmission of the frog optic tectum in vitro. Neuroscience Letters, 85, 249 - 254.
    • Sivilotti L (1988). Nipecotic acid enhances synaptic transmission in the frog optic tectum by an action independent from GABA uptake inhibition.. Neuroscience Letters, 88, 107 - 112.

    1986

    • Sivilotti L, Nistri A (1986). Biphasic effects of glycine on synaptic responses of the frog optic tectum in vitro. Neuroscience Letters, 66, 25 - 30.
    • Sivilotti L (1986). Field potentials from the frog optic tectum in vitro. Brain Research Bulletin, 16, 553 - 556.

    1985

    • Beani L, Bianchi C, Nilsson L, Nordberg A, Romanelli L, Sivilotti L (1985). The effects of nicotine and cytisine on 3H-acetylcholine release from cortical slices of guinea-pig brain. Naunyn-Schmiedeberg's Archives of Pharmacology, 331, 293 - 296.
    • Corradetti R, King AE, Nistri A, Rovira C, Sivilotti L (1985). Pharmacological characterization of D-aminophosphonovaleric acid antagonism of amino acid and synaptically evoked excitations on frog motoneurones in vitro: an intracellular study. British Journal of Pharmacology, 86, 19 - 26.
    • Nistri A, Sivilotti L (1985). An unusual effect of γ-aminobutyric acid on synaptic transmission of frog tectal neurones in vitro. British Journal of Pharmacology, 85, 917 - 922.

    1984

    • Beani L, Bianchi C, Siniscalchi A, Sivilotti L, Tanganelli S, Veratti E (1984). Different approaches to study acetylcholine release: endogenous acetylcholine versus tritium efflux. Naunyn-Schmiedeberg's Archives of Pharmacology, 328, 119 - 126.