CAM KINASE AUTOREGULATION AND ROLE IN SYNAPTIC FUNCTION

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DESCRIPTION (Investigator's Abstract): The long-term goal of this research is to define the molecular basis of memory. To accomplish this goal a reductionist approach will be used and the assumption is made that learning and memory in vertebrate neurons is initiated and expressed by molecules at synapses (synaptic plasticity). Numerous proteins are required to form functional synapses. The applicant has concentrated on one of the most abundant, CaM-kinase. CaM-kinase is highly concentrated at both presynaptic and postsynaptic elements where it constitutes a large percentage of the protein (40 percent) of isolated postsynaptic densities. CaM-kinase is activated when neuronal activity permits Ca++-influx into the intracellular compartment, either from external or internal Ca++ stores. When activated, CaM-kinase phosphorylates several neuronal proteins controlling a variety of functions. Interestingly, CaM-kinase also phosphorylates itself (autophosphorylation). Autophosphorylation changes CaM-kinase into an enzyme which no longer requires Ca++-influx for activity, and in a simple theoretical sense "remembers" the past activity of the synapse by recording Ca++-influx in the amount of autophosphorylated CaM-kinase. This activity can then be expressed for some period of time after the Ca++ concentrations have returned to resting levels. Ca++ plays an important role in many forms of short and long-term neuronal plasticity, which are believed to be the cellular basis for learning and memory. The applicant has been studying the role of Ca++-activated protein kinases (e.g., CaM-kinase) in the hippocampal slice model of cellular learning called long-term potentiation (LTP). Initial experiments have shown that CaM-kinase plays some, as yet unknown, role in the induction process of LTP.