IBN 98-06215 ARAI Neurons throughout the brain contain a calcium-activated protease called 'calpain' that can cleave various intracellular proteins. It has been shown that the moderate increase in intracellular calcium produced by a few bursts of synaptic activity is sufficient to activate this enzyme. Such activity under the proper circumstances induces a long lasting enhancement of synaptic transmission called 'long-term potentiation' (LTP), which is thought to be one of the mechanisms responsible for encoding memory. Suppression of calpain in fact prevents both LTP and memory formation, which suggests that this enzyme plays an essential role in these processes. Expression of LTP is now commonly thought to involve a change in currents through AMPA receptors, a subtype within the glutamate receptor family, that mediates excitatory synaptic transmission between most neurons in higher brain regions. It is thus of particular interest that AMPA receptors were recently found to be cleaved by calpain near their intracellular C-terminal, and that the domain removed by proteolysis contains target sites for kinases and a site which anchors the receptor to cytoskeletal proteins. The goal of this project is to identify whether and in what way C-terminal modification of the AMPA receptor by calpain alters the functional properties of this receptor. It will be specifically tested (1) whether direct application of activated calpain into neurons changes the time course of the current flow through the receptors, (2) whether AMPA receptors truncated at their C-terminal exhibit characteristic alterations in their physiological properties, and (3) whether modulation of AMPA receptors by kinases is altered after truncation. The proposed experiments supported by this POWRE award represent a new direction for Dr. Arai and will give her the opportunity to learn new skills in the field of molecular biology which will complement her expertise in neurophysiology. Acquiring thes e skills will be critical for her career goal to start an independent research laboratory, to expand her research scope, and to develop further her leadership in the field of AMPA receptor research and synaptic plasticity.
