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An Investigation of Lipid Modulation of Low Voltage Activated Currents in Spiral Ganglion Neurons

Browne, LP; (2016) An Investigation of Lipid Modulation of Low Voltage Activated Currents in Spiral Ganglion Neurons. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Type I spiral ganglion neurons (SGNs) synapse onto cochlear inner hair cells and constitute the majority of afferent fibres in the auditory nerve (AN). Better characterisation of their biophysical properties may identify therapeutic targets for optimising AN sensitivity. This study aimed to characterise the membrane physiology underlying the firing properties of post-hearing onset SGNs and investigated whether their properties could be modified by the presence of native and synthetic lipids. In dissociated ganglionic cultures, SGNs displayed an intrinsic variation in their firing properties; this could be correlated with the magnitudes of specific membrane currents. SGNs were categorised by their response to depolarising current injection; SGNs either adapted to the stimulus rapidly, slowly or not at all. Rapid adaptation, a mechanism that preserves temporal precision throughout the auditory system, was found to be regulated by a dendrotoxin-K (DTX-K) and tityustoxin-Kα (TsTx)-sensitive low-threshold voltage-activated (LVA) K+ current, suggesting contribution by Kv1.1 and Kv1.2 subunits. As Kv1.2 channels were known to be positively modulated by membrane phosphoinositides, we investigated the influence of phosphatidylinositol-4,5- bisphosphate (PIP2) availability on SGN K+ currents. Inhibiting PIP2 production using wortmannin, or sequestration using a palmitoylated peptide (PIP2-PP), slowed or abolished adaptation in SGNs. PIP2-PP specifically reduced SGN LVA currents in a manner that was partly rescued by intracellular dialysis with diC8PIP2, a nonhydrolysable analogue of PIP2. PIP2-PP application induced similar levels of current inhibition in Kv1.1/Kv1.2 channels heterologously expressed in HEK293 cells. Accordingly, the lipid sensitivity of the Kv1.2 channel was further explored with a range of native and synthetic free fatty acids. Polyunsaturated fatty acids were found to be strong inhibitors of Kv1.2 currents, offering further potential candidates for SGN modulation. Collectively, this data identifies Kv1.1 and Kv1.2 containing K+ channels as key regulators of excitability in the AN, and potential targets for pharmacological modulation.

Type: Thesis (Doctoral)
Title: An Investigation of Lipid Modulation of Low Voltage Activated Currents in Spiral Ganglion Neurons
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
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 Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > The Ear Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: http://discovery.ucl.ac.uk/id/eprint/1477267
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