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Exploring the structural basis of cell-specific behaviour and pharmacology of potassium channels.


Project Description

Some ion channels, including voltage-gated (Kv) and calcium-activated (KCa) potassium channels, are expressed in several different tissues. However, their functional and pharmacological properties differ between cell types; for example, neuron versus smooth muscle cell. This is largely determined by cell-specific expression of accessory and regulatory proteins, forming specific macromolecular complexes.

This project will explore the structural basis of how channel properties are altered by interacting proteins. Cryo-EM is an ideal technique to address this problem and with access to state-of-the-art facilities (FEI Titan Krios electron microscopes) we can potentially generate high resolution data. Human potassium channel complexes will be expressed and purified from large-scale mammalian cell cultures for structural analysis. Functional studies will be carried out using electrophysiology to measure the effects of protein co-expression and of mutations. This would give a molecular insight into channel regulation and how drugs act on specific complexes, leading to the development of more specific ion channel therapeutic modulators. This research is of particular interest to the pharmaceutical and biotechnology industries, with whom we have active collaborations.

References

JL:
Tiede C, Bedford R, Heseltine SJ, Smith G, Wijetunga I, Ross R, et al. (2017) Affimer proteins are versatile and renewable affinity reagents. Elife 6, e24903.

Wrighton DC, Muench SP, Lippiat JD (2015) Mechanism of inhibition of mouse Slo3 (KCa 5.1) potassium channels by quinine, quinidine and barium. Br J Pharmacol 172, 4355-63.

Jin X, Shah S, Liu Y, Zhang H, Lees M, Fu Z, Lippiat JD, Beech DJ, Sivaprasadarao A, Baldwin SA, Zhang H, & Gamper N (2013) Activation of the Cl- Channel ANO1 by Localized Calcium Signals in Nociceptive Sensory Neurons Requires Coupling with the IP3 Receptor. Sci Signal 6, ra73.

Gorvin CM, Wilmer MJ, Piret SE, Harding B, van den Heuvel LP, Wrong O, Jat PS, Lippiat JD, Levtchenko EN, & Thakker RV (2013) Receptor-mediated endocytosis and endosomal acidification is impaired in proximal tubule epithelial cells of Dent disease patients. Proc Natl Acad Sci U S A 110, 7014-9.


SM:
Rawson S, Bisson C, Hurdiss DL, Fazal A, McPhillie MJ, Sedelnikova SE, Baker PJ, Rice DW, Muench SP. Elucidating the structural basis for differing enzyme inhibitor potency by cryo-EM. 2018. Proc Natl Acad Sci U S A. pii: 201708839
Lee S.C., Postis V.L.G., Knowles T.J., Jamshad M., Parslow R.A., Lin Y., Goldman A., Sridhar P., Overduin M., Muench S.P. & Dafforn T.R. Detergent-free method of membrane protein isolation for biophysical methods. (2016) Nat. Prot. 11(7) 1149-1162

Rawson S., Phillips C., Huss M., Tiburcy F., Wieczorek H., Trinick J., Harrison M.A., Muench S.P. Structure of the vacuolar H+-ATPase rotary motor at subnanometer resolution. (2015) Structure 23(3) 461-471.

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

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