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Research InterestsDr Trevor Lewis | | (Position Details) | | Phone 02 9385 1102 | | Email | | Qualifications BSc (Hons), PhD Adel |
| | | School/Unit |
| School of Medical Sciences | | http://medicalsciences.med.unsw.edu.au/
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| | Broad Research Areas | |
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Physiology
Neuroscience
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| | | | Specific Research Keywords | |
| Structure & Function of Ion Channels
Ion Channels
Ligand gated ion channels
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| | | | Research Interests | |
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Ligand-gated ion channels are one of the fundamental building blocks for a functioning nervous system. They are responsible for the fast transmission of signals between nerve cells at specialised junctions called synapses. Research is undertaken on the human glycine receptor as a model system of ligand-gated channels in general. The overall aim is to relate the functional characteristics of the glycine receptor to what is know about its protein structure. Two strands are currently being investigated. The first is the conformational changes that follow ligand binding to allow the ion channel pore to open. This is concentrating particularly on the interface between the transmembrane domain and the extracellular domain of the receptor. The second strand is the relationship between the structure of the ion channel pore and what characteristics determine the ability to select for anions in preference to cations.
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| | | | ILP Research Interests (Will supervise ILP students) |
| Electrophysiology
Molecular Biology
Physiology
Synapses
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| | | | Project Topics for current Honours Students |
| Membrane Biophysics Laboratory
Ligand-gated ion channels are one of the fundamental building blocks for a functioning nervous system mediating fast synaptic transmission between nerve cells. The current focus of research in the Membrane Biophysics Laboratory is the relationship between the structure and the function of the inhibitory GABA and glycine activated ligand-gated ion channels. These channels are investigated by using a combination of patch clamp recordings from recombinant receptors expressed in cultured cells and molecular biology techniques to introduce specific amino acid mutations. The following honours projects are currently available, although students interested in related projects are encouraged to discuss their ideas with us.
Project 1: Investigating the relative movement of loop structures in the extracellular domain of the glycine receptor. These structures have been implicated in the mechanism that leads to opening of the channel pore following ligand binding.
Project 2: Identification and functional characterization of amino acid residues within the cytoplasmic M3-M4 loop of the glycine receptor. We hypothesise that this region is important in determining both the ion permeation properties and desensitization kinetics of the receptor-channel.
Skills learnt: mammalian cell culture techniques, transient transfection of mammalian cells, whole-cell and single-channel patch clamp electrophysiology, biophysical analysis of ion channel properties, immuno-histochemistry of transfected cells. | |
| | | | Society Memberships & Professional Activities | |
| Australian Physiological Society (AuPS)
Australian Society for Medical Research (ASMR)
Australian Society for Biophysics (ASB)
Society for Neuroscience (SfN) | |
| | | | Funding Sources | |
| NHMRC project grant 455310 (Schofield, Lewis, Barry, Clements). | |
| | | | Key works/Publications | |
| Cederholm J.M.E., Schofield P.R. and Lewis T.M. (2009) Gating mechanisms in Cys-loop receptors. European Biophysics Journal DOI: 10.1007/s00249-009-0452-y
Absalom N.L., Schofield P.R. and Lewis T.M. (2009)Pore Structure of the Cys-loop Ligand-gated Ion Channels. Neurochemical Research DOI: 10.1007/s11064-009-9971-2
Carland J.E., Cooper M.A., Sugiharto S., Jeong H-J., Lewis T.M., Barry P.H., Peters J.A., Lambert J.J. and Moorhouse A.J. (2008). Characterization of the effects of charged residues in the intracellular loop on ion permeation in alpha 1 glycine receptor-channels. Journal of Biological Chemistry 284(4), 2023-2030.
Sugiharto S., Lewis T.M., Moorhouse A.J., Schofield P.R. and Barry P.H. (2008). Anion-cation permeability correlates with hydrated counter-ion size in glycine receptor channels. Biophysical Journal 95(10), 4698-4715.
Qu, W., Moorhouse, A.J., Chandra, M., Pierce, K.D., Lewis, T.M., Barry, P.H. (2006). A single P-loop glutamate point mutation to either lysine or arginine switches the cation-anion selectivity of the CNGA2 channel. Journal of General Physiology 127(4), 375-389.
Qu W., Moorhouse, A.J., Lewis, T.M., Pierce, K.D. and Barry, P.H. (2005). Mutation of the pore glutamate affects both cytoplasmic and external dequalinium block in the rat olfactory CNGA2 channel. European Biophysics Journal with Biophysics Letters 34, 442-453.
Absalom, N.L., Lewis, T.M. and Schofield, P.R. (2004). Mechanisms of channel gating of the ligand-gated ion channel superfamily inferred from protein structure. Experimental Physiology 89, 145-153.
Absalom, N.L., Lewis, T.M., Kaplan, W., Pierce, K.D. and Schofield, P.R. (2003). Role of charged residues in coupling ligand binding and channel activation in the extracellular domain of the glycine receptor. Journal of Biological Chemistry 278 (50), 50151–50157.
Lewis, T.M., Schofield, P.R. and McClellan, A.M.L. (2003). Kinetic determinants of agonist action at the recombinant human glycine receptor. Journal of Physiology 549, 361–374.
Rees, M.I., Lewis, T.M., Kwok, J.B.J., Mortier, G.R., Govaert, P., Snell, R.G., Schofield, P.R. and Owen, M.J. (2002). Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB). Human Molecular Genetics 11, 853-860.
Rees, M.I., Lewis, T.M., Vafa, B., Corry, P., Jungbluth, H., Muntoni, F., Stephenson, J.B.P., Kerr, M., Ferry, C., Snell, R., Schofield, P.R. and Owen, M.J. (2001). Compound heterozygosity and nonsense mutations in the alpha1-subunit of the inhibitory glycine receptor in hyperekplexia. Human Genetics 109, 267-270.
Lewis, T.M. and Schofield, P.R. (1999). Structure-function relationships of the human glycine receptor: insights from hyperekplexia mutations. Annals New York Academy of Sciences 868, 681-684.
Vafa, B., Lewis, T.M., Cunningham, A.M., Jacques, P., Lynch, J.W. and Schofield, P.R. (1999). Identification of a new ligand binding domain in the alpha1 subunit of the inhibitory glycine receptor. Journal of Neurochemistry 73, 2158-2166.
Lewis, T.M., Sivilotti, L.G., Colquhoun, D., Gardiner, R.M., Schoepfer, R. and Rees, M. (1998). Properties of human glycine receptors containing the hyperekplexia mutation alpha1(K276E), expressed in Xenopus oocytes. Journal of Physiology 507, 25-40.
Lewis, T.M., Harkness, P.C., Sivilotti, L.G., Colquhoun, D. and Millar, N.S. (1997). The ion channel properties of a rat recombinant neuronal nicotinic receptor are dependent on the host cell type. Journal of Physiology 505, 299-306. | |
| | | | Further Information | |
| http://medicalsciences.med.unsw.edu.au/SOMSWeb.nsf/page/Membrane+Biophysics+Lab | |
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