Normal neuronal function requires the proper assembly, localization, and regulation of ion channel proteins. When these systems break down, neurons are no longer able to properly respond to synaptic inputs. In this proposal, we will be examining the molecular basis for the proper regulation of neuronal dendritic function. In hippocampal CA1 pyramidal neurons, an A channel that is located in distal dendrites, and regulated by multiple protein kinase systems, is a critical site for controlling the active properties of dendrites. Many important questions remain, however, to understand the molecular processes involved in controlling dendritic function The first important question concerns the molecular composition of these A channels. Shal subunit proteins have been proposed to constitute an important component of A channels in neurons.
In Specific Aim 1, we will use molecular genetic and immunological methods to identify specific subunit proteins that are used to form the hippocampal dendritic A channel. Another important question concerns the mechanisms operating to produce a dendritic localization for the A channels. For other channels and receptors, PDZ binding sequences have been implicated in specific anchoring of membrane proteins to the cytoskeleton.
In Specific Aim 2, we will test if Shal subunit proteins contain a novel PDZ binding sequence at their C-terminus. Finally, we would like to understand how kinase systems act to regulate A channels.
In Specific Aim 3, we will continue our work on phosphorylation sites in the Shal subunit protein rKv4.2 to determine the functional consequences of phosphorylation of these channels by different kinase systems.
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