Postdoctoral Research Fellow
Division of Neuroscience,
Ninewells Hospital and Medical School
Dundee, DD1 9SY
I obtained my BSc and MSc from the University of Manchester in Biomedical Sciences and Molecular Pharmacology respectively. I obtained my PhD from the University of Edinburgh studying the molecular mechanisms underlying iron overload cardiomyopathies.
Cys-loop receptor structure-function
Recent structural models of prokaryotic pentameric ligand gated ion channels (pLGICs) and the C. elegans glutamate activated chloride channel (GluCl) provided us with great insight into the structure of Cys-loop receptors. However, structural information on a large portion of the cytoplasmic domain is still lacking. The large intracellular loop between the third and fourth transmembrane domains harbours residues which determine single channel conductance and current-voltage relationships of some Cys-loop receptors, traditionally thought to be exclusively contained within the pore region. The electric ray (Torpedo marmorata) nicotinic acetylcholine receptor model shows an intracellular extension (cytoplasmic portals) of the ion conduction pathway, lined by these rate limiting residues.
Using the 5-HT3 receptor as a model, I am using molecular biology techniques and electrophysiology to understand more about the structure and function of these cytoplasmic portals.
Mechanisms of opioid analgesics tolerance
Agonists at µ-opioid receptors (MOPrs) such as morphine are effective in the treatment of acute and chronic pain. However, prolonged morphine exposure induces a myriad of side effects including respiratory depression, hyperalgesia and constipation. These side effects are exacerbated by the development of tolerance to opioid analgesia leading to the necessity for escalating drug doses in the treatment of persistent pain. In addition to MOPrs, δ-opioid receptors (DOPrs) and β-arrestin 2 (β-arr2) may also play a role in analgesic tolerance suggesting that these proteins may be good targets for ameliorating this side effect.
Using a combination of molecular biology, biochemistry and electrophysiology, I am trying to understand the molecular mechanisms which underlie analgesic tolerance, and in particular, the role of DOPrs and β-arr2.
Ion channels and cancer
Voltage-gated sodium channels (VGSC) are integral membrane proteins found in excitable tissues such as neurons and cardiomyocytes, where they are vital in the initiation and propagation of action potentials. However, VGSCs are also found in cancers of non-excitable cells, such as those in prostate, breast, lung and colon. In particular, the cardiac isoform of VGSC, NaV1.5, as well as the modulatory β3 subunit, encoded by SCN5A and SCN3B genes respectively, are present in SW620 metastatic colon cancer cells. Pharmacological modulation of NaV1.5 in these cells reduces invasion, suggesting a role for NaV1.5 in metastasis. This means that many clinically relevant drugs which target NaV1.5, have the potential to be re-purposed for treatment of metastatic cancers.
Using a combination of molecular biology, cell biology, biochemistry and electrophysiology, I am investigating the role of NaV1.5 in colon cancer metastasis.
Baptista-Hon DT, Deeb TZ, Othman NA, Sharp D, Hales TG. (2012) The 5-HT3B subunit affects high-potency inhibition of 5-HT3 receptors by morphine. Br J Pharmacol. 165:693-704
Othman NA, Gallacher M, Deeb TZ, Baptista-Hon DT, Perry DC, Hales TG. (2012) Influences on blockade by t-butylbicyclo-phosphoro-thionate of GABA(A) receptor spontaneous gating, agonist activation and desensitization. J Physiol. 590:163-78.
I have given platform and poster presentations at the following major scientific meetings:
- Society for Neuroscience (SfN) Annual Meetings.
- Scottish Neuroscience Group (SNG) Annual Meetings.
Physiological Society Annual Meetings.