研究领域

Receptors and Membrane Biology

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 investigating changes that occur at the interface between the transmembrane domain and the extracellular domain of the receptor, and at the inter-subunit interfaces. The second strand is the relationship between the structure of the ion channel pore and what characteristics determine ion selectivity. Collaborative projects are also being undertaken with Prof Mary Collins and Dr Nathan Absalom (Pharmacy, University of Sydney) to characterise the binding site and actions of novel ligands at neuronal nicotinic acetylcholine receptors.

近期论文

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Carland JE; Yamamoto I; Hanrahan JR; Abdel-Halim H; Lewis TM; Absalom N; Chebib M, 2015, 'A hydrophobic area of the GABA ρ₁ receptor containing phenylalanine 124 influences both receptor activation and deactivation.', Journal of Molecular Neuroscience, vol. 55, no. 2, pp. 305 - 313 Absalom NL; Quek G; Lewis TM; Qudah T; Von Arenstorff I; Ambrus JI; Harpsøe K; Karim N; Balle T; McLeod MD; Chebib M, 2013, 'Covalent trapping of methyllycaconitine at the α4-α4 interface of the α4α2 nicotinic acetylcholine receptor: Antagonist binding site and mode of receptor inhibition revealed', Journal of Biological Chemistry, vol. 288, no. 37, pp. 26521 - 26532, http://dx.doi.org/10.1074/jbc.M113.475053 Barry PH; Lewis TM; Moorhouse AJ, 2013, 'An optimised 3 M KCl salt-bridge technique used to measure and validate theoretical liquid junction potential values in patch-clamping and electrophysiology', European Biophysics Journal, vol. 42, no. 8, pp. 631 - 646, http://dx.doi.org/10.1007/s00249-013-0911-3 Huang SH; Lewis TM; Lummis SC; Thompson AJ; Chebib M; Johnston GA; Duke RK, 2012, 'Mixed antagonistic effects of the ginkgolides at recombinant human ρ1 GABAC receptors.', Neuropharmacology, vol. 63, no. 6, pp. 1127 - 1139 Cederholm JME; Absalom NL; Sugiharto S; Griffith R; Schofield PR; Lewis TM, 2010, 'Conformational changes in extracellular loop 2 associated with signal transduction in the glycine receptor', Journal of Neurochemistry, vol. 115, no. 5, pp. 1245 - 1255, http://dx.doi.org/10.1111/j.1471-4159.2010.07021.x Barry PH; Sugiharto S; Lewis TM; Moorhouse AJ, 2010, 'Further analysis of counterion permeation through anion-selective glycine receptor channels.', Channels, vol. 4, no. 3, pp. 142 - 149 Sugiharto S; Carland JE; Lewis TM; Moorhouse AJ; Barry PH, 2010, 'External divalent cations increase anion-cation permeability ratio in glycine receptor channels', Pfluegers Archiv: European journal of physiology, vol. 460, no. 1, pp. 131 - 152, http://dx.doi.org/10.1007/s00424-010-0792-6 Carland JE; Cooper MA; Sugiharto S; Jeong HJ; Lewis TM; Barry PH; Peters JA; Lambert JJ; Moorhouse AJ, 2009, 'Characterization of the effects of charged residues in the intracellular loop on ion permeation in α1 glycine receptor channels', Journal of Biological Chemistry, vol. 284, no. 4, pp. 2023 - 2030, http://dx.doi.org/10.1074/jbc.M806618200 Cederholm JME; Schofield PR; Lewis TM, 2009, 'Gating mechanisms in Cys-loop receptors', European Biophysics Journal, vol. 39, no. 1, pp. 37 - 49, http://dx.doi.org/10.1007/s00249-009-0452-y Absalom NL; Schofield PR; Lewis TM, 2009, 'Pore structure of the Cys-loop ligand-gated ion channels', Neurochemical Research, vol. 34, no. 10, pp. 1805 - 1815, http://dx.doi.org/10.1007/s11064-009-9971-2 Sugiharto S; Lewis TM; Moorhouse AJ; Schofield PR; Barry PH, 2008, 'Anion-cation permeability correlates with hydrated counterion size in glycine receptor channels', Biophysical Journal, vol. 95, no. 10, pp. 4698 - 4715, http://dx.doi.org/10.1529/biophysj.107.125690 Qu W; Moorhouse AJ; Chandra M; Pierce KD; Lewis TM; Barry PH, 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, vol. 127, no. 4, pp. 375 - 389, http://dx.doi.org/10.1085/jgp.200509378 Qu W; Moorhouse AJ; Lewis TM; Pierce KD; Barry PH, 2005, 'Mutation of the pore glutamate affects both cytoplasmic and external dequalinium block in the rat olfactory CNGA2 channel', European Biophysics Journal, vol. 34, no. 5, pp. 442 - 453, http://dx.doi.org/10.1007/s00249-005-0479-7 Absalom NL; Lewis TM; Schofield PR, 2004, 'Mechanisms of channel gating of the ligand-gated ion channel superfamily inferred from protein structure', Experimental Physiology, vol. 89, no. 2, pp. 145 - 153, http://dx.doi.org/10.1113/expphysiol.2003.026815 Morris R; Morgan BS; Lewis TM; Pierce KD; Pisano A; Schofield PR, 2004, 'In vivo somatic delivery of plasmid DNA and retrograde transport to obtain cell-specific gene expression in the central nervous system', Journal of Neurochemistry, vol. 90, no. 6, pp. 1445 - 1452, http://dx.doi.org/10.1111/j.1471-4159.2004.02612.x Lewis TM; Schofield PR; McClellan AML, 2003, 'Kinetic determinants of agonist action at the recombinant human glycine receptor', The Journal of Physiology, vol. 549, no. 2, pp. 361 - 374 Absalom NL; Lewis TM; Kaplan W; Pierce KD; Schofield PR, 2003, 'Role of Charged Residues in Coupling Ligand Binding and Channel Activation in the Extracellular Domain of the Glycine Receptor', Journal of Biological Chemistry, vol. 278, no. 50, pp. 50151 - 50157, http://dx.doi.org/10.1074/jbc.M305357200 Rees MI; Lewis TM; Kwok JBJ; Mortier GR; Govaert P; Snell RG; Schofield PR; Owen MJ, 2002, 'Hyperekplexia associated with compound heterozygote mutations in the β-subunit of the human inhibitory glycine receptor (GLRB)', Human Molecular Genetics, vol. 11, no. 7, pp. 853 - 860 Rees MI; Lewis TM; Vafa B; Ferrie C; Corry P; Muntoni F; Jungbluth H; Stephenson JB; Kerr M; Snell RG; Schofield PR; Owen MJ, 2001, 'Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia.', Human Genetics, vol. 109, no. 3, pp. 267 - 270 Vafa B; Lewis TM; Cunningham AM; Jacques P; Lynch JW; Schofield PR, 1999, 'Identification of a new ligand binding domain in the subunit of the inhibitory glycine receptor', Journal of Neurochemistry, vol. 73, no. 5, pp. 2158 - 2166