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Agonist-induced inhibition of the M-current: involvement of the phosphoinositide cycle

Winks, Joanna Shaw; (2004) Agonist-induced inhibition of the M-current: involvement of the phosphoinositide cycle. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

M-type potassium channels are closed by activation of G protein-coupled receptors which couple to phospholipase C activation. I have investigated the proposed role of the hydrolysis and depletion of phosphatidylinositol-4,5-bisphosphate (PIP2) in the closure of these channels produced by two different agonists (the muscarinic agonist, oxotremorine-M, and the peptide, bradykinin) in primary mammalian sympathetic neurons. Simultaneous electrophysiological recording of the M-current and imaging of the localization of a fluorescent PIP2-binding construct, GFP-PLC-[delta] PH, has provided a valuable tool for investigation of the involvement of PIP2 levels in M-channel closure. I found that over-expression of the neuronal calcium-sensor protein NCS-1, which enhances PIP2 synthesis by increasing the activity of the enzyme PI4-kinase, reduced the net decrease in membrane PIP2 following application of bradykinin and, in parallel, reduced the sensitivity of M channels to closure by bradykinin. This reduction in sensitivity was partly reversed by the PI4-kinase inhibitor wortmannin. I also found that over-expression of the next enzyme in the synthetic pathway, PI5-kinase, reduced both the net decrease in membrane PIP2 and the sensitivity of the M channels to both agonists. This (plus other evidence) suggests that membrane PIP2 depletion is a key factor in the regulation of M channels by both of these agonists.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Agonist-induced inhibition of the M-current: involvement of the phosphoinositide cycle
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10097652
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