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Novel interactions of anaesthetics on oxygen sensitive TASK K+ channels derived from rat chemoreceptor cells

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  • Full or part time
    Prof K Buckler
    Prof J Pandit
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Fully funded 3-year National Institute of Academic Anaesthesia (NIAA) PhD studentship to investigate the novel interactions of anaesthetics on oxygen sensitive TASK K+ channels derived from rat chemoreceptor cells (carotid body). The carotid body is the main oxygen sensor involved in the control of breathing. Hypoxia excites sensory cells in these organs through the inhibition of TASK potassium channels which leads to membrane depolarization, calcium entry, neurosecretion and the excitation of nerve fibers projecting to respiratory control centers in the brainstem. This process is greatly attenuated by many general anaesthetics, particularly volatile anaesthetics. This effect is often compounded by concurrent use of opiates, given for analgesia, which also suppress breathing. Together these agents can compromise a patient’s ability to breathe adequately well into the post- operative period. Inadequate ventilation risks hypoxemia which carries with it a significant risk of morbidity and mortality.

Our research is focused upon trying to understand why anaesthetics depress chemoreceptor function and whether this might be prevented by respiratory stimulants. Recent studies indicate that both volatile anaesthetics and respiratory stimulants target the same TASK potassium channels that are involved in responding to hypoxic stimuli. We are therefore investigating how these agents interact with TASK channels. One hypothesis is that general anaesthetics interact with specific binding sites on the TASK-channels as opposed to simply changing the biophysical properties of the lipid bilayer (the traditional “Meyer &Overton” model of anaesthetic action). The main objective of this project is to try to identify these binding sites, characterize their interaction with anaesthetics, and to investigate the possibility that these sites might also be involved in mediating the effects of lipid based signaling molecules that also regulate TASK channel function and which may be linked to the oxygen sensing process.

The project will involve electrophysiological analysis of ion channel function in the presence of anaesthetics in native carotid body cells and in cell lines heterologously expressing ion channels. It will be co-supervised by Professors Buckler and Pandit (University of Oxford), who are, respectively, leading experts in oxygen sensing and anaesthesia. The project will commence in October 2018 within the Department of Physiology, Anatomy and Genetics at the University of Oxford.

https://www.ox.ac.uk/admissions/graduate/courses/dphil-physiology-anatomy-and-genetics?wssl=1 and https://www.dpag.ox.ac.uk/study/for-graduates/how-when-to-apply and/or https://www.dpag.ox.ac.uk/study/for-graduates/how-when-to-apply

Funding Notes


Applicants should hold or be about to achieve a First or Upper-Second (2.i) class degree in a relevant subject. NIAA Studentships are available to UK nationals and EU students who meet the UK residency requirements.
The studentship is available for 3 years and the successful candidate will receive a stipend of at least £14,553 per annum. Fees will be met in full.

Informal enquiries may be made to Professor Keith Buckler at [Email Address Removed] Interviews will be in mid May 2019.

References

Buckler KJ. TASK channels in arterial chemoreceptors and their role in oxygen and acid sensing.
Pflugers Arch. 2015 May;467(5):1013-25.

O'Donohoe PB, Huskens N, Turner PJ, Pandit JJ, Buckler KJ. A1899, PK-THPP, ML365, and Doxapram inhibit endogenous TASK channels and excite calcium signaling in carotid body type-1 cells. Physiol Rep. 2018 Sep;6(19):e13876

Pang DSJ et al. An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action. Proc Nat Acad Sci 2009; 106: 17546-51

Franks NP. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nature Rev Neurosci 2008; 9, 370-386

Pandit, J.J. and K.J. Buckler, Differential effects of halothane and sevoflurane on hypoxia induced intracellular calcium transients of neonatal rat carotid body type I cells. Br J Anaesth, 2009. 103(5): p. 701-10.

Pandit, J.J., The variable effect of low-dose volatile anaesthetics on the acute ventilatory response to hypoxia in humans: a quantitative review. Anaesthesia, 2002. 57(7): p. 632-43.

Pandit JJ. When anaesthetics collide: antagonism of one agent by another? Anaesthesia. 2017 May;72(5):555-560



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