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Understanding the mechanism by which ion channels regulate vesicle fusion

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

P2X receptors were identified in the 1990s as ion channels that are gated in response to extracellular ATP. They have been shown to play roles in taste sensation, bladder emptying, oxygen sensing, inflammation and pain. P2X receptors are therefore attractive drug targets and clinical trials are currently in progress to test the therapeutic value of P2X receptor antagonists. Despite this, relative to other ion channel proteins, we know very little of the molecular structure, interacting partners, membrane trafficking, and physiological roles of P2X receptors. Our research seeks to redress such deficits.

Our approach is stimulated by our recent and surprising finding that P2X receptors can be found on intracellular organelles (Nature, 2007). Recently, we have discovered that activation of a intracellular P2X receptors can result in calcium efflux required for downregulation of Rab activity and efficient vacuole fusion (Nature Cell Biology, 2014). Although Rab GTPases are known to play key roles in the delivery, docking and fusion of different intracellular vesicles, the mechanism by which spatial and temporal regulation of Rab GTPase activity is controlled has been poorly understood. Our findings suggest a novel mechanism by which localized calcium release through a vesicular ion channel controls Rab GTPase activity. Our identification of a novel calcium regulated Rab GAP protein found in a complex with the Rab and P2X receptor provides a solution to this problem. Given that P2X channels and this novel class of calcium dependent Rab GAPs are widely conserved, this work provides fundamental insights into Rab GTPase regulation in vesicular trafficking.

Currently, we aim to employ genetic, biochemical and cell biological approaches to further define the role of intracellular P2X receptors in vacuole fusion, infection and immunity, and to characterize the factors that regulate P2X receptor function in cells.

Associated skills: Molecular biology, live cell imaging, cell culture, genetic screens, proteomics.

Lab website: http://thethompsonlab.wordpress.com/


Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

Parkinson, K., Baines, A., Keller, T., Gruenheit, N., Bragg, L., North, R. & Thompson, C (2014). Calcium-dependent regulation of Rab activation and vesicle fusion by an intracellular P2X ion channel. Nature Cell Biology 16(1), 87-98. eScholarID:219013

PMID:24335649

DOI:10.1038/ncb2887

Baines A, Parkinson K, Sim JA, Bragg L, *Thompson CRL, North RA (2013) Functional properties of five Dictyostelium discoideum P2X receptors. Journal of Biological Chemistry, vol 288(29) p. 20992-1000

Fountain SJ, Parkinson K, Young MT, Cao L, Thompson CR, North RA. (2007). An intracellular P2X receptor required for osmoregulation in Dictyostelium discoideum. Nature, 448(7150), 200-3. eScholarID:1c6865

PMID:17625565

DOI:10.1038/nature05926

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