Dendritic voltage-gated K+ channels, or Kv channels, are fundamental components of dendritic signalling. Dendritic Kv channels control the characteristics of backpropagating action potentials, and thus influence synaptic efficacy. In addition, these channels can influence the spread of postsynaptic potentials to the soma, influencing the integration of synaptic input and the response of neurons to external stimuli. Lastly dendritic Kv channels can dramatically influence Ca2+ signalling in dendrites, which can have far reaching implications for neuronal plasticity. This proposal is aimed at determining the fundamental mechanisms that determine dendritic function through the regulation of the abundance, distribution and function of dendritic Kv channels. We will focus our studies on the Kv2.1 Kv channel, which underlies a major component of the dendritic delayed rectifier current. This proposal is aimed at determining the dynamic cellular mechanisms that localize Kv2.1 at important sites of Ca2+ signalling in neurons, the phosphorylation sites on Kv2.1 that regulate localization and function, and the role of these Kv2.1-associated neuronal Ca2+ signalling proteins, and other Kv2.1-interacting proteins, in Kv2.1 localization and function. These studies will yield important insights into the reciprocal physiological regulation of Kv2.1 channel activity and Ca2+ signalling in the soma and dendrites of mammalian central neurons. As regulation of dendritic Kv channel activity influences action potential duration, amplitude and frequency, and synaptic efficacy, understanding the mechanisms controlling the composition of Kv channel complexes at the molecular level, anticipated from our proposed studies, will provide insights into the normal and abnormal function of neurons. It will thus contribute to the eventual understanding and treating of a variety of neurological disorders, including diseases associated with altered neuronal excitability such as genetic and acquired epilepsy, cognitive disorders, and affective disorders.
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