Dendritic ion channel trafficking in plasticity

描述（由申请人提供）：突触反应和膜兴奋性的长期变化是神经元可塑性的不同形式，被认为是记忆的基础。突触传导变化的性质和机制已被广泛研究。然而，与突触可塑性相关的兴奋性和EPSP-spike耦合经常发生变化。内在可塑性是神经可塑性的另一个组成部分，其机制尚不清楚。

DESCRIPTION (provided by applicant): Long-term changes in synaptic responses and membrane excitability are different forms of neuronal plasticity thought to underlie memory. The nature of and mechanisms underlying the synaptic conductance changes have been extensively investigated. However, there are often changes in excitability and EPSP-spike coupling associated with synaptic plasticity. The mechanisms involved in intrinsic plasticity, the other component of neural plasticity, remain unknown. One mechanism through which plastic changes in membrane excitability can be achieved is via kinase dependent regulation of ion channel surface expression or trafficking. Kv4.2 subunits-mediated A-type K currents (IA) emerged as a key player controlling signal propagation and membrane excitability. We have recently made an unexpected finding that CaMKII activity increases the cell surface expression of Kv4.2 in COS cells. Furthermore, we demonstrated that Kv4.2 is a substrate for CaMKII, identified the exact sites of phosphorylation, and showed that direct phosphorylation of these sites is necessary for CaMKII-mediated upregulation of K channel expression. These results lead to the intriguing idea that synaptic activity and/or CaMKII phosphorylation drives new K channels into the plasma membrane of neurons, consequently regulating and establishing the dendritic distribution of A-type K channels. In concert with the potentiation of synaptic conductances, promotion of K channel surface expression may provide a homeostatic mechanism by reducing overall excitability of a neuron. For this proposal I will test experimentally the above hypotheses, and extend our studies to a mouse model for Angelman syndrome (AS). The implications of these studies are more general in that they can be applied as a molecular model for the trafficking and regulation of other ion channels by protein kinases during neuronal plasticity. Moreover, the studies proposed above represent our efforts to define the precise dendritic mechanisms involved in an animal model for human neurological diseases.