Neurotransmitter-gated ion channels are involved in the rapid chemical transmission of nerve impulses at synapses where binding of neurotransmitters to their receptors results in the opening of an integral ion-selective pore in less than 1 millisecond. Speed of transduction, which is an essential feature of the nervous system, is in large part determined by the incorporation of the ion channel into the same protein that contains the neurotransmitter-binding site.
Our aim is to understand the molecular mechanism of action of the Cys–loop family of neurotransmitter-gated ion channels. Malfunction of these proteins is associated with a range of neuronal disorders, such as epilepsy, schizophrenia, learning and attention deficit and drug addiction, and the receptors are the target of a many therapeutically active agents including anesthetics, Alzheimer’s drugs, anti-convulsants, tranquilizers, anti-emetics and insecticides. Understanding the details of Cys-loop activation will clarify how they contribute to brain function, and will allow the development of safer, more effective drugs.
Much of our work uses the 5-HT3 receptor, but we also use a range of other related proteins including GABA- and acetycholine-activated receptors. The techniques we use include molecular biology (e.g. protein engineering), functional studies (e.g. electrophysiology and single cell fluorescent studies), protein chemistry (e.g. radioligand binding and structural determination) and bioinformatics (e.g. homology modelling and ligand docking).
Lab members: Mona Alqazzaz, Fiona Love, Kerry Price, Andrew Thompson, David Weston, Lu Zhou
1. Lummis SCR. 5-HT3 receptors. J Biol Chem. 2012; 287:40239-45
2. Thompson AJ, McGonigle I, Duke R, Johnston GA, Lummis SCR. A single amino acid determines the toxicity of Ginkgo biloba extracts. FASEB J. 2012 :1884-91.
3. Lummis SCR, McGonigle I, Ashby JA, Dougherty DA. Two amino acid residues contribute to a cation-π binding interaction in the binding site of an insect GABA receptor. J Neurosci. 2011;31:12371-6.
4. Thompson AJ, Lummis SC. A single channel mutation alters agonist efficacy at 5-HT3A and 5-HT3AB receptors.Br J Pharmacol. 2013;170:391-402.