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


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). TASK channels play a critical role in controlling the excitability of carotid body type-1 cells which, in turn, play an important role in the control of breathing by measuring both blood oxygen and acidity. The ability to detect and respond to hypoxia is blunted by many inhalational anaesthetics which appear to act by stimulating these oxygen sensitive TASK channels thus opposing the effects of hypoxia. Our current research interests concern the mechanisms by which inhalational anaesthetics activate TASK channels. Traditionally general anaesthetics are thought to act additively in producing anaesthesia via a ‘non-receptor’ based mechanism of action (e.g., lipid solubility theory). Whilst investigating the effects of anaesthetics on chemoreceptor oxygen sensing however we have serendipitously observed that not only do anaesthetics vary in their efficacy but that antagonistic effects are observed when some anaesthetics are given in combination (i.e. as is predicted by conventional competitive binding models of receptor function wherein low-efficacy (partial) agonists are predicted to antagonise the effects of high-efficacy agonists). Whilst this is the norm for most drugs it has not hitherto been observed with volatile anaesthetics. This could have profound implications for our understanding of how volatile anaesthetics work at the protein level. Our current research is therefore focused on trying to understand this phenomenon and to explore the possibility that anaesthetics might be interacting with receptor sites on the channel protein that are involved in channel regulation by lipid based signaling molecules.
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The project 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 2019 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

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. Further information about eligibility for Research Council UK funding can be found on the MRC website.
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
Interview dates are scheduled for mid March 2019

References

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
Prabhakar NR. Oxygen sensing by the carotid body chemoreceptors. J Appl Physiol 2000; 88: 2287-95.
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.
Buckler, K.J., B.A. Williams, and E. Honore, An oxygen-, acid- and anaesthetic-sensitive TASK-like background potassium channel in rat arterial chemoreceptor cells. J Physiol, 2000. 525 Pt 1: p. 135-42.
Pandit JJ. When anaesthetics collide: antagonism of one agent by another? Anaesthesia. 2017 May;72(5):555-560

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