Several studies have reported JNK1 activation following Influenza A infection

ge of LTP-inducing frequencies of postsynaptic calcium spikes. A major finding of the current research is the regulation of total amount of calcium ions on the frequency-sensitivity of synaptic plasticity. This may explain why the quantitative characteristics of postsynaptic calcium, required for triggering either LTP or LTD, have been difficult to determine. It is simply because there is no such absolute thresholding frequency or amount of post-synaptic calcium ions for synaptic changes in either direction. Rather, the synaptic connection is regulated based on a cell-type- or individual cell- specific manner. One important underlying evidence is that not all NMDA receptors are equivalent. The diverse compositions of NMDA receptors expressed in different cells, or in a single cell but at distinct developmental stages, confer various channel properties. This affects the transient property of calcium influx, therefore, controlling the induction of LTP or LTD. Furthermore, NMDA receptor subunit composition is also regulated by the excitation history of the spine, therefore previous activities can regulate further excitations. High frequency stimulations induce short but potent elevations of free intracellular calcium concentration, and these specific calcium transients impose a specific temporal constraint for calcium decoding proteins, such as calmodulin. We show that calmodulin activation depends on calcium input frequencies. With a constant total input of calcium ions, high frequency signals stimulate calmodulin more efficiently. Calcium Spikes Modulate Synaptic Plasticity Not only Calmodulin activates CaMKII, its availability also influences how CaMKII responds to calcium input frequencies . This finding suggests the importance of calmodulin buffer proteins, such as neurogranin, on the regulation of synaptic plasticity, because calmodulin concentration is always a limiting factor. Finally, there may be active recruitment processes for calmodulin taking place in specific locations within a spine, for instance, in the area near calcium channels in the post-synaptic-density. Calmodulin may be recruited from other calmodulin binding proteins to CaMKII, because of the increased affinity between CaMKII and calmodulin induced by high-frequency stimulation. Calmodulin may also be translocated via process mediated by actin filament, since synaptic activity can regulate actin polymerization. According to our simulation results, calmodulin recruitment can actively reduce the calcium-spike frequency required for CaMKII activation. Furthermore, the more calmodulin is accessible, the longer CaMKII will be activated, which may play an important role in modulating synaptic plasticity. It has often been believed that CaMKII-frequency sensitivity is due to its multimeric structure and intersubunit autophosphorylation. High frequency calcium pulses successfully induce the activation of large GFT505 site amounts of calmodulin, and this enhances its probability of binding to neighboring subunits of CaMKII, thus inducing CaMKII autophosphorylation. This autophosphorylation promotes high affinity calmodulin binding, thus CaMKII responds to higher frequency signals with a positive feedback. We demonstrate here that even without autophosphorylation on Thr286, CaMKII shows frequency sensitivity to a certain extent. This is mainly due to the activation of calmodulin. Because at higher calcium-input frequencies, more calmodulin is activated and more CaMKII subunit can theref