Prof John Peters

Research

The rapid movement of ions across cell membranes in response to chemical messengers, or neurotransmitters, is the basis of fast communication between neurones in the nervous system and neurones and skeletal muscle cells in the periphery. A fundamental event in this dialogue is the translation of the chemical signal into a brief electrical event, a process mediated by specialised ion transmembrane proteins known as ligand-gated ion channels (LGICs). The efficient operation of such LGICs is essential to normal bodily function and pathologies that include myasthenia gravis, certain forms of epilepsy and psychiatric disorders are the consequence of perturbed function, expression, or abundance, of LGICs.

Channels as molecular pipelines

The fundamental function of the ion channel is to provide an environment, or conduction pathway, through which ions can flow in a highly regulated manner. In the case of the LGICs, the conduction pathway can exist in open and closed conformations, allowing, or preventing, the flow of ions respectively. Neurotransmitter binding regulates the switch from the closed, to the open, conformation. However, it is equally important that the open channel only conducts ions of a specific charge and size, yet it must perform this task against the competing goal of allowing ions to flow incredibly rapidly, typically at a rate of around 10,000,000 charges per second! Our research focuses upon how these conflicting demands are satisfied at the molecular level. Using a combination of molecular biological, electrophysiological and structural techniques, we are building upon the foundations laid down over 20 years ago when the structural determinants of ion conduction in the nicotinic acetylcholine (nACh) receptor were first traced to a transmembrane domain of the receptor termed M2. Subsequent work on the structural cousins of the nACh receptor (i.e. the 5-HT3, GABAA and glycine receptors) have conformed the importance of M2 in ion selectivity and conduction. However, our work has expanded this paradigm by demonstrating that an intracellular domain of the 5-HT3 receptor (the M3-M4 loop) is a crucial determinant of ion conduction. Moreover, the influence of this region extends to representative nACh and glycine receptors. Our data are rationalised by reference to structural models of the nACh receptor that show the intracellular vestibule of the conduction pathway is not a simple, solitary, ‘hole’ (as conventionally viewed). Rather, it contains five narrow portals through which ions must flow to enter, or exit, the channel. This domain of the receptor may provide a novel target for drug action.

The research laboratories at Ninewells Hospital and medical School are run in collaboration with Professor Lambert and Dr Belelli and are currently staffed by 14 researchers. Additional internal collaborations are with Professor Hales.

Current research includes:

Investigating the relationship between the structure and biophysical properties of 5-HT3, nicotinic acetylcholine and glycine receptors.

Nomenclature committees

An active interest in the nomenclature of ion channels and receptors and a member of the nomenclature committee of the International Union and Basic and Clinical Pharmacology (NC-IUPHAR) that has established a comprehensive database. Also co-edit with Steve Alexander and Alistair Mathie the British Journal of Pharmacology 'Guide to Receptors and Channels'

Publications

Peters, J.A., Cooper, M.A., Carland, J.E., Livesey, M.R., Hales, T.G., Lambert, J.J. (2010). Novel structural determinants of single channel conductance and ion selectivity in 5-hydroxytryptamine-type3 and nicotinic acetylcholine receptors. J Physiol 588.4;587-595.

Peters, J.A., Cooper, M.A., Livesey, M.R., Carland, J.E. & Lambert, J.J. (2010). 5-HT3 receptors, In: The Ion Channels. Ed. Kew, J. & Davies, C. Oxford University Press, (New York). Eds. Kew J. & Davies C. pp231-251.

Harmar, A.J., Hills, R.A., Rosser, E.M., Jones, M., Buneman, O.P., Dunbar, D.R., Greenhill, S.D., Hale, V.A., Sharman, J.L., Bonner, T.I., Catterall, W.A., Davenport, A.P., Delagrange, P., Dollery, C.T., Foord, S.M., Gutman, G.A., Laudet, V., Neubig, R.R., Ohlstein, E.H., Olsen, R.W., Peters, J., Pin, J.-P., Ruffolo, R.R., Searls, D.B., Wright, M.W. & Spedding, M. (2009). NC-IUPHAR-DB: the IUPHAR database of G-protein coupled receptors and ion channels. Nucleic Acids Res. 37, D680-685.

Carland, J.E., Cooper, M.A., Sugiharto, S., Jeong, H.J., Lewis, T.M., Barry, P.H., Peters, J.A., Lambert, J.J. & Moorhouse, A.J. (2009). Characterization of the effects of charged residues in the intracellular loop on ion permeation in a1 glycine receptor-channels. J. Biol. Chem. 284, 2023-2030.

Barnes, N.M., Hales, T.G., Lummis SCR & Peters, J.A. (2009). The 5-HT3 receptor: The relationship between structure and function. Neuropharmacology, 56, 273-284.

Collingridge, G.L., Olsen, R.W., Peters, J. & Spedding, M (2009). A nomenclature for ligand-gated ion channels. Neuropharmacology, 56, 2-5.

Livesey, M.R., Cooper, M.A., Carland, J.E., Kozuska, J., Deeb, T.Z., Hales, T.G., Lambert, J.J. & Peters, J.A. (2008). Structural determinants Ca2+ permeability and conduction in the human 5-hydroxytryptamine type 3A receptor. J. Biol. Chem., 283, 19301-19313.

Alexander, S.P.H., Mathie, A. & Peters, J.A. (Eds.) (2008). Guide to Receptors and Ion Channels (3nd. edition). Br. J. Pharmacol., 153, Supplement 2, S1-S209.

Nilius, B., Owsianik, G., Voets, T. & Peters, J.A. (2007). Transient receptor potential (TRP) channels cation channels in disease. Physiol. Rev. 87, 165-217.

Deeb, T.Z., Carland, J.E., Cooper, M.A., Livesey, M.R., Lambert, J.J., Peters, J.A. & Hales, T.G. (2007). Dynamic modification of a mutant cytoplasmic cysteine residue modulates the conductance of the human 5-HT3A receptor. J. Biol. Chem., 282, 6172-6182.

Peters, J.A., Carland, J.E., Cooper, M.A., Livesey, M.R., Deeb, T.Z., Hales, T.G. & Lambert, J.J. (2006). Novel structural determinants of single-channel conductance in nicotinic acetylcholine and 5-hydroxytryptamine type-3 receptors. Biochem. Soc. Trans., 34, 882-886.

Hales, T.G., Dunlop, J.I., Deeb, T.Z., Carland, J.E., Kelley, S.P., Lambert, J.J. & Peters, J.A. (2006). Common determinants of single channel conductance within the large cytoplasmic loop of 5-HT3 and a4b2 nicotinic acetylcholine receptors. J. Biol. Chem., 281, 8062-8071.

Alexander, S.P.H., Mathie, A. & Peters, J.A. (Eds.) (2006). Guide to Receptors and Ion Channels (2nd. edition). Br. J. Pharmacol., 147, Supplement 3, S1-S180.

Key past publications:

Peters, J.A., Hales, T.G. & Lambert, J.J. (2005). Molecular determinants of single-channel conductance and ion selectivity in the Cys-loop family: insights from the 5-HT3 receptor. Trends Pharmacol. Sci., 26, 587-594.

Nilius, B., Voets, T. & Peters, J.A. (2005). TRP channels in disease. Sci. STKE., 295:re8.

Kelley, S.P., Dunlop, J.I., Kirkness, E.F., Lambert, J.J. & Peters, J.A. (2003). A cytoplasmic region determines single channel conductance in 5-HT3 receptors. Nature, 424, 321-324.

Gunthorpe, M.J., Peters, J.A., Gill, C.H., Lambert,J.J. & Lummis, S.C.R. (2000) The 4’lysine in the putative channel lining domain affects desensitisation but not the single channel conductance of recombinant homomeric 5-HT3A receptors. J. Physiol.(Lond.), 522, 187-198

Davies P.A., Pistis, M., Hanna, M.C., Peters, J.A., Lambert, J.J., Hales, T.G. & Kirkness, E.F. (1999) The 5-HT3B subunit is a major determinant of serotonin receptor function. Nature, 397, 359-363.