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Title: Mechano-electrical transduction in cochlear hair cells : channel blockers, an anomalous mechano-sensitive current and TRPC knockout mice
Author: Desmonds, Terri
ISNI:       0000 0004 5922 0200
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2016
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Transforming sound vibrations into neural signals, the process of mechano-electrical transduction (MET), is achieved via the movement of rows of stereocilia located atop cochlear hair cells, activating non-selective MET channels. Recording MET currents using whole-cell patch clamp electrophysiology has allowed for various investigations centred on the MET channel. There is a statistically significant difference in MET current amplitudes between mid-apical and mid-basal outer hair cells. The larger MET current, flowing through basal hair cells explains a key contributory element to their increased susceptibility to the ototoxic effects of aminoglycoside antibiotics, as they are thus able to enter these cells more readily, in greater abundance. The cell penetrating peptides D-TAT and D-JNKi1 have been studied in cochlear hair cells. They are both high affinity, voltage dependent, permeant blockers of the MET channel in inner (IHCs) and outer hair cells (OHCs). Whilst ototoxic at higher concentrations, they may have therapeutic potential at lower concentrations, providing ototoprotection against aminoglycoside induced ototoxicity by competitively blocking the MET channel. There is an apical to basal gradient in the OHC MET channel block caused by D-TAT and D-JNKi1, the affinity of the block increasing from apex to base. Compellingly, the first evidence of a gradient in the MET channel properties of IHCs is presented here, a gradient in D-JNKi1 block. Properties of an anomalous mechano-sensitive current, elicited by inverse stimuli relative to the MET current, have been elucidated via the use of the compounds dihydrostreptomycin (DHS) and FM1-43. When compared with the MET current, DHS block of the anomalous current is two orders of magnitude less strong and FM1-43 block has altered voltage dependence. TRPC3/6 knock-out mice, whilst previously thought to have a basal OHC specific MET deficit, have been shown to exhibit normal MET currents. In addition, so too have TRPC1/3/6 and TRPC1/3/5/6 knock-out mice.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP0461 Hearing. Physiological acoustics