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Molecular Characterisation of Neurotransmitter-Gated Ion Channels

The 5-HT3 receptor family of proteins are pentameric (see insert) with each subunit having a similar predicted structure to that shown here. The second transmembrane domain (2) lines the ion pore. The ligand (green) binds close to the characteristic Cys-loop (orange) which is some distance from the pore.

Research Groupings: Neuroscience, psychology and mental health | Developmental and regenerative biology and medicine

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.

The synapse is the site of chemical communication between nerve cells. Here the incoming action potential triggers calcium influx and a release of neurotransmitter; this stimulates opening of ligand-gated ion channels in the postsynaptic cell.

This same property makes these proteins particularly amenable to analysis of receptor function, and our aim is to relate the way these proteins function to their molecular structure.

To do this we are exploring the characteristics of 5-HT₃, GABAA and GABAC receptors, which are all members of the ‘Cys-loop’ ligand-gated ion channel family. These proteins are closely related to the well-studied nicotinic acetylcholine (nACh) receptor, but are amenable to more experimental techniques.

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 immunolabelling) and bioinformatics (e.g. homology modelling and ligand docking).

5-HT docked into the binding site of the 5-HT3 receptor. Important binding residues are labelled, illustrating the aromatic box that is important in all Cys-loop receptors, Potential hydrogen bonds shown in green. From Reeves et al., 2003

The ultimate aim of our research is to understand the mechanism of action of all members of this family of neurotransmitter-gated ion channels.

Lab members
Jamie Ashby, Mariza Dayrell, Ian McGonigle, Katherine Millen, Kerry Price, Andrew Thompson, David Weston, Lu Zhou

References