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

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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.