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Role of junctophilins in Ca2+ handling and inflammatory signaling in sensory neurons

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  • Full or part time
    Dr N Gamper
    Dr I Jayasinghe
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Peripheral sensory neurons collect and transduce to CNS wealth of somatosensory information, including pain. Intracellular Ca2+ plays a paramount role in mediating sensory mechanisms in these neurons. Thus, Ca2+ release from intracellular stores underlies responses of pain-sensing neurons to inflammation. An important organelle for maintenance of cellular Ca2+ homeostasis is endoplasmic reticulum (ER). It serves as a Ca2+ reservoir and releases Ca2+ in response to action of inflammatory mediators. Upon release, ER is then refilled by store-operated Ca2+ entry (SOCE) from the extracellular space. Recent work in the host laboratory identified multiprotein signaling complexes assembled at junctions between the ER and plasma membrane (PM) in the peripheral pain-sensing neurons. Furthermore, our unpublished data suggest that scaffolding protein junctophilin-4 (JPH4) plays a key role in such complexes. We will aim to build upon this foundation to elucidate roles of junctophilins in Ca2+ signaling in sensory neurons. To answer our research questions we will employ cell biology and electrophysiology methods with novel imaging approaches (including super-resolution) and in vivo behavioral tests. Mechanistic understanding of localized intracellular signaling in sensory neurons is necessary to understand principles of somatic sensations; moreover, such understanding will pave a way for future treatments of inflammatory pain.

Funding Notes

BBSRC White Rose Mechanistic Biology DTP 4 year studentship.

Studentships covers UK/EU fees and stipend (c.£14,553) for 4 years to start in Oct 2018. Applicants should have/be expecting at least a 2.1 Hons. degree in a relevant subject. EU candidates require 3 years of UK residency in order to receive full studentship.

Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process and the projects selected by the successful candidates will be funded.

There are 2 stages to the application process. Please see our website for more information: http://www.fbs.leeds.ac.uk/postgraduate/phdopportunities.php

References

1. Jin, X., Shah, S., Liu, Y., Zhang, H., Lees, M., Fu, Z., Lippiat, J.D., Beech, D.J., Sivaprasadarao, A., Baldwin, S.A., 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(290):ra73.

2. Munro, M.L., Jayasinghe, I.D., Wang, Q., Quick, A., Wang, W., Baddeley, D., Wehrens, X.H.T., Soeller, C. The role of Junctophilin-2 in the nanoscale organisation and functional gating of ryanodine receptor clusters in murine cardiomyocytes. J Cell Sci. 2016; 29:4388-4398.

3. Gao, H., Boillat, A., Huang, D., Liang, C., Peers, C., Gamper, N. (2017) Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate. Proc Natl Acad Sci U S A. 114:E6410-E6419.

4. Du, X., Hao, H., Yang, Y., Huang, S., Wang, C., Gigout, S., Ramli, R., Li, X., Jaworska, E., Edwards, I., Deuchars, J., Yanagawa, Y., Qi, J., Guan, B., Jaffe, D.B., Zhang, H., Gamper, N. (2017) Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission. J Clin Invest. 127:1741-1756.

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