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Pharmacological and second messenger-mediated modulation of heterologously expressed and neuronal calcium-dependent potassium currents

Howe, Timothy; (2019) Pharmacological and second messenger-mediated modulation of heterologously expressed and neuronal calcium-dependent potassium currents. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The modulation of calcium-activated and calcium and voltage-dependent potassium channels, by drugs and second messengers, was investigated using the whole cell patch clamp technique in hippocampal slices, primary neuronal cultures, and transiently transfected HEK293 cells. The voltage and Ca2+-sensitive BK channel has emerged as a potential therapeutic target in conditions including multiple sclerosis and Fragile X syndrome. The Selwood lab have developed a compound, VSN-16R, that can rescue functions in mouse models of these diseases, and preliminary evidence suggested VSN-16R might act as a BK channel activator.. In the first part of the project I tested VSN-16R on heterologously expressed BK channels formed from α-subunit homomultimers or from coexpression of the alpha subunit with β subunits, and determined that VSN-16R does not act as an activator of these channels. Additionally, I characterised for the first time the effects of the BK activator NS19504 on heterologously expressed channels incorporating beta subunits, and assessed the effects of VSN-16R in the presence of intracellular reducing agents glutathione and dithiothreitol, and under conditions of oxidative stress produced by extracellular application of H2O2. In the second part of my thesis I aimed to discover the location of discrete subcellular signalling domains involved in the regulation of the slow afterhyperpolarising current (sIAHP) in hippocampal pyramidal neurons by monoaminergic transmitters. Various monoamines, including noradrenaline, converge on a pathway involving the activation of PKA by elevated cAMP levels, which leads to the inhibition of the sIAHP by an unknown mechanism. The results of my experiments provide evidence of subcellular spatial variation in the degree of sIAHP inhibition in response to focal application of the βadrenergic agonist isoproterenol, and to localised uncaging of cAMP on the inhibition of the sIAHP.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Pharmacological and second messenger-mediated modulation of heterologously expressed and neuronal calcium-dependent potassium currents
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: http://discovery.ucl.ac.uk/id/eprint/10069226
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