Calcium signaling plays a central yet surprisingly flexible role in the function of neurons, contributing to neurotransmission, synaptic plasticity, ad neuronal death. Calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII) is a multifunctional Ser/Thr protein kinase that is essential for normal hippocampal synaptic plasticity and spatial learning in mice. CaMKII is believed to decode the frequency of calcium transients (i.e. neuronal activity) in to graded levels of activity. Unlike the role of CaMKII in physiologica calcium signaling, its role in pathological calcium signaling is largely unknown. Aberrant calcium signaling accompanies multiple disease states associated with glutamate, the major excitatory neurotransmitter in the brain. Excessive glutamate release accompanies acute disease states (e.g. ischemia and brain trauma) as well as chronic neurodegenerative disorders (delayed neuronal death with ischemia and epilepsy). Exactly what CaMKII is doing in excitotoxicity is unknown; however, there are clues worth noting. First, CaMKII is highly expressed (1-2% of total protein) in regions of the brain highly susceptible to excitotoxicity. Second, ischemic duration correlates to CaMKII inactivation and neuronal death. Third, preventing CaMKII from activating during excitotoxicity prevents neuronal death; a process that also prevents CaMKII from undergoing activity-dependent inactivation and aggregation. Fourth, we have recently published that inhibiting CaMKII directly induces neuronal apoptosis via calcium dysregulation and hyperexcitability to aberrant glutamate signaling. In this application, we propose to understand novel mechanisms underlying CaMKII substrate phosphorylation, inactivation and aggregation in both highly controlled biochemical experiments and in living cells. In addition, we propose to determine if CaMKII inactivation in astrocytes disrupts normal glial-neuronal communication; a process our preliminary data indicates leads to astrocyte degeneration. These experiments will not only advance our understanding of CaMKII signaling during pathological calcium signaling, but they will also shed new light on basic mechanisms related to CaMKII structure, substrate phosphorylation, and protein aggregation. Conclusions from these studies may also identify novel therapeutic targets and mechanisms to disrupt neuronal and glia death induced by glutamate excitotoxicity.
CaMKII is serine/threonine protein kinase that undergoes aggregation and inactivation following excitotoxic calcium signaling associated with ischemia and epilepsy. The long-term goal of these studies is to identify molecular mechanisms and therapeutic strategies to disrupt CaMKII's vulnerability to excitotoxic glutamate-signaling; a process we also believe will reveal novel insights into synaptic plasticity and the function of CaMKII in physiological calcium signaling.
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