Binding of Endophilin Endocytic Proteins to AMPA Receptors and Neuronal Voltage-gated Potassium (Kv) Channels: Regulation of Synaptic Plasticity

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This Discovery Grant is focused on the cellular biology of ion channels and regulation of nervous tissue excitability and learning and memory. The voltage-gated potassium (Kv) channels and ligand-gated glutamate receptors called AMPARs perform many functions in the human brain, including maintenance of resting membrane potential and regulation of memory-forming synaptic plasticity, respectively. Several members of the Kv-family of potassium channels, namely the Kv1.5, Kv4.2 and HERG channels, and AMPARs are expressed in an area of the brain, called the hippocampus, which is responsible for encoding and storing memory.****Increasing evidence suggest that some proteins normally involved in the recycling of tiny membrane vesicles can regulate the density of specific membrane receptors and ion channels present on the surfaces of nerve cells. The recycling proteins of the endophilin-family contain a specific region that preferentially binds to protein sequences enriched with proline amino acids.  Endophilin proteins are also known to bind to other endocytic protein machineries, including dynamin 2, and to the immediate-early gene called Arc/Arg3.1 (Arc), which also serves as a marker for recently activated nerve cells.  Arc has also been shown to regulate the surface expression of AMPARs, and genetic ablation of Arc leads to memory retention deficits. Recently we reported that the adenosine A1 receptor (A1R) causes clathrin-mediated internalization of AMPARs, which underlies A1R-mediated reduction in hippocampal synaptic transmission. ***However, it is not yet known whether a similar mechanism for endophilin-Arc-driven AMPAR internalization also occurs for Kv channels in the brain.  Since the cytoplasmic regions of some Kv channels contain appropriate patterns for endophilin binding, we will investigate the possibility that some Kv channels are directly coupled to endophilin. This interaction can facilitate the recycling of these Kv channels to and from the nerve surface, which can affect nerve excitability and action of memory-forming molecules, such as the AMPARs.***The proposal is centered on these three aims: ***1) To determine whether endophilin regulates the recycling and overall function of the Kv channels and AMPARs in nerve cells;***2) To determine whether the proline-rich regions of Kv channels and AMPARs are targets for endophilin binding; and ***3) To determine whether the endophilin interactions with Kv and AMPARs influence the excitability and memory-forming capacity of neurons within the brain's memory center.***These studies will provide new insight into the physiology of Kv channels and AMPARs, regulation of nervous communication, and factors that contribute to learning and memory in the brain.  In long term, this work will assist in the evaluation of specific potassium channels as targets to prevent excessive neuronal excitability, such as seen with seizures and subsequent memory loss.**