Ian McFadzean

Ian McFadzean

Professor

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Personal profile

Research interests

The common thread running through my research career has been an interest in the mechanisms by which neurotransmitters, and drugs regulate calcium entry into cells. During my PhD work I used electrophysiological techniques to study the mechanisms by which opioid receptor agonists inhibit synaptic transmission in the central nervous system, work which contributed to the development of the hypothesis that pre-synaptic opioid receptors inhibit neurotransmitter release by inhibiting calcium entry into nerve terminals through voltage-operated calcium channels. My interest in this area continued during my post-doctoral work at University College London where I used a neuroblastoma hybrid cell line as a model system, along with whole-cell patch-clamping techniques, to study the intracellular pathways that link receptor activation to inhibition of voltage-operated calcium channels. By injecting antibodies selective against different G-protein subtypes into the cells we were able to show that antibodies against the a-subunit of Go were able to prevent the inhibitory action of neurotransmitters on the calcium currents. This was one of the first demonstrations of this key signalling role for Go in neurones.

 At King’s College London I turned the focus of my research away from neurones and onto smooth muscle cells, but still retained my interest in calcium entry pathways. Again the approach was to develop a model system in which to study drug effects, in this case single smooth muscle cells isolated enzymatically from the anococcygeus muscles of mice. The mechanisms by which excitatory neurotransmitters produced contractions of this and other tonic smooth muscles muscle had not been fully elucidated, though evidence pointed to them increasing calcium entry via poorly defined pathways. In collaboration with Dr Alan Gibson at King’s, I set out to identify the calcium entry pathway activated by contractile agonists and this work culminated with the identification of a store-operated calcium entry pathway that was activated following receptor mediated depletion of internal calcium stores (a process called capacitative calcium entry). This was achieved using a combination of whole-cell patch clamp to measure the small calcium entry current directly and Fura-2 microfluorimetry to monitor the consequential changes in intracellular calcium. Although up to that point store-operated calcium entry had been described in a variety of other cell types, this was arguably the first report of its electrophysiological characterisation in smooth muscle. Since then store-operated calcium entry has been shown to occur in a range of smooth muscles and drugs that inhibit the process have the potential to act as smooth muscle relaxants.

 More recently my work has turned towards using electrophysiological and microfluorimetric techniques to study the pharmacology of airway disease. For example, in collaboration with Dr Dom Spina I have been developing projects to determine whether blockers of potassium ion channels might alter calcium entry into neutrophils. We are also studying the electrophysiology of sensory nerves involved in the cough response with a view to identifying novel targets for the development of antitussives, including pre-synaptic inhibitors of transmission in the afferent arm of the cough circuitry. Thus I find I have come full circle.

Research interests (short)

Electrophysiological analysis of neurotransmitter and drug effects in smooth muscle and neurones.

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Education/Academic qualification

Doctor of Philosophy, Opioid actions in the locus coeruleus, University of Cambridge

Award Date: 1 Jan 1987

Bachelor of Science, University of Strathclyde

Award Date: 1 Jan 1982

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