The broad objective of this study is to gain insight into the molecular mechanisms underlying long-term potentiation (UP) as a model for memory formation. This proposal will focus on the regulation of the voltage gated potassium channel Kv4.2 by calcium/calmodulin dependent kinase II (CaMKII) and the role of such regulation in LTP To embark on such a study will require bridging biochemical, anatomical, molecular,and physiological techniques. These approaches will be greatly facilitated by our laboratory's development of phospho- specific antibodies that recognize Kv4.2 only when it is phosphorylated at either of the two CaMKII phosphorylation sites. In the first two specific aims, these phospho-specific antibodies will be used to determine whether Kv4.2 phosphorylation can be regulated by modulation of CaMKII activity and to determine anatomically which brain circuits recruit CaMKII phosphorylation of Kv4.2 as a potential means for synaptic plasticity.
The third aim will identify the potential functional effects of CaMKII phosphorylation on Kv4.2 function by comparing channel biophysical properties of the native channel to one lacking the CaMKII sites. Finally, we will return to the use of phospho- specific antibodies to monitor changes in Kv4.2 phosphorylation that occur when hippocampal slices undergo long-term potentiation. Taken together, these data may provide a novel mechanism by which CaMKII affects memo formation.
| Varga, Andrew W; Yuan, Li-Lian; Anderson, Anne E et al. (2004) Calcium-calmodulin-dependent kinase II modulates Kv4.2 channel expression and upregulates neuronal A-type potassium currents. J Neurosci 24:3643-54 |
