Role of presynaptic Kv3 potassium channel subunits in forming native potassium channels and adapting synaptic transmission and auditory processing

Lead Research Organisation: University of Leicester
Department Name: Neuroscience, Psychology and Behaviour


This proposal is a training collaboration between synaptic and ion channel physiologists at the University of Leicester and Autifony Therapeutics pharmacologists based in London and Verona. The aim is to test novel compounds known to modify the gating and activity of Kv3 potassium channels. These actions influence the excitability of neurons, where Kv3 channels act as delayed rectifiers in repolarizing action potentials. The compounds are potential therapeutic agents for tinnitus and other hyperexcitability disorders. It is suspected that several of the compounds have differential actions on some of the four Kv3 subunits (each specified by a different gene, kcnc1-4). Indeed heteromeric channels are commonly trafficked and expressed in differing neuronal locations, so giving the possibility of differential action of specific lead compounds in particular areas of the brain. In the auditory brainstem only Kv3.1 and Kv3.3 are expressed, but the proportion of Kv3.1 is greater in medial nuclei while Kv3.3 dominates in lateral nuclei, so we can exploit this to test the lead compounds on native Kv3 channels of differing subunit composition (and we can modify that composition by using transgenic knockout mice which lack one or other subunit). Kv3.3 subunits are also associated with presynaptic terminals; since we can conduct presynaptic recordings from the calyx of Held giant synapse, we can test the hypothesis that these drugs may have different pre- and post-synaptic effects. So this project will provide important insights into the distribution and function of Kv3 channel subunits and provide Autifony with detailed knowledge of the mechanisms by which their lead compounds act on neuronal excitability and synaptic transmission and suggest further refinement of the pharmacology.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M016501/1 01/10/2015 30/09/2019
1698521 Studentship BB/M016501/1 01/10/2015 30/09/2019 Amy Richardson
Description This research has uncovered the presence of a high voltage activated potassium channel subunit on the presynaptic membrane of neurons in the auditory system. The subunit is likely required for the formation of functional channels at the synapse. This subunit is a potential target for compounds developed by Autifony aimed to increase neuronal activity in cases of age related hearing loss to compensate for diminished inputs to the brain from the ear. This research has been used as preliminary data for new funding to examine how mutations in this channel impact hearing.
Exploitation Route This protein has been implicated in a number of different diseases (spinocerebellar ataxia, schizophrenia, tinnitus, hearing loss) and knowing the presynaptic location of the protein and its role in the brain can be used to determine mechanisms of disease.
Sectors Pharmaceuticals and Medical Biotechnology

Description Research findings have been presented to the public as an example of how basic research can impact individuals with hearing loss. Key findings have influenced drug targeting in partnership with Autifony.
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

Description Project grant
Amount £736,887 (GBP)
Funding ID BB/R001154/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2017 
End 10/2020
Description Travel grant
Amount £500 (GBP)
Organisation Physiological Society 
Sector Charity/Non Profit
Country Global
Start 08/2017 
End 09/2017
Description Brain awareness day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Schools and general public were invited to the university to take part in a neuroscience day in which researchers, including myself present their work via posters, demonstrations and talks.
Year(s) Of Engagement Activity 2016,2017