We work at understanding the functioning of receptors that mediate fast synaptic transmission, and focus on two classes of ion channels in the nicotinic superfamily, nicotinic and glycine receptors. Different types of nicotinic receptors (which are all excitatory and activated by the transmitter acetylcholine) mediate the initiation of muscle contraction by the peripheral terminals of motor neurones in the spinal cord and the regulation of involuntary bodily functions, such as blood pressure at the level of autonomic ganglia. Yet other forms of nicotinic receptors are present in the brain and are affected by the nicotine in tobacco smoke. Glycine receptors are activated by the simplest amino acid, glycine, and are inhibitory, acting to dampen excessive neuronal activity, particularly in the lower levels of the central nervous system, such as the spinal cord. For instance, without glycine transmission there would be no coordination between muscles that have opposite effects on the movement of a limb. In man, inherited mutations in nicotinic or glycine receptors are known to produce neurological disease. Our general aim is to understand in quantitative terms how a receptor functions as a one-molecule machine. This is only possible because, thanks to the techniques of patch clamp and single channel recording, the activity of a single receptor molecule can be seen in real time. This type of work is important not just for neuroscience (i.e. for understanding synaptic transmission), but also for pharmacology. Indeed, to this day concepts that are central to pharmacology and receptor theory, such as partial agonism and efficacy, are well understood (i.e. can be quantitatively formulated) only for receptors that belong to the ligand-gated ion channel class (largely because of past research in this department). Some of the questions being investigated include: * How do differences in the properties of the several types of receptors derive from differences in the sort of protein subunits that make them up (each of which is produced by a different gene)? * How does the binding of the transmitter to the receptor result in channel opening and what portions of the subunits are important in this process? * How many molecules of transmitter need to bind for the channel to open efficiently? * How do disease mutations in the amino acid sequence of subunits impair the working of the receptor? A combination of electrophysiological recording and molecular biology techniques are used in the laboratory in order to obtain in cell cultures or in Xenopus oocytes receptors that are similar to those in the brain of humans and animals. We then record the electrical currents they produce both in their normal form and in forms that have been mutated. While a range of electrophysiological recording techniques are in everyday use in the laboratory, a strong focus is on single channel recording and its interpretation.
Doctor of Philosophy
|St Bartholomews Hospital|
|Universita degli Studi di Milano|
Bachelor of Science
|Universita degli Studi di Ferrara|
I graduated in Pharmaceutical Chemistry from the University of Ferrara in Italy. After research work in Ferrara and Milan on the modulation of transmitter release in the CNS, I was awarded travelling fellowships by the Royal Society and the Italian Ministry of Education to work at St Bartholomew's Hospital Medical College in London. This project (on GABA receptors in the frog visual system) led to the description of what is now called the GABAC receptor and the award of my PhD in 1988. After a career break for family reasons, I worked as a postdoc at UCL, first with Clifford Woolf in the Anatomy Department, then with David Colquhoun in Pharmacology. From there, I joined The School of Pharmacy as a lecturer in Pharmacology in 1997, before moving back to UCL in 2003.