The Cyclin-Dependent Kinase 5 Activators p35 and p39 Interact with the α-Subunit of Ca2+/Calmodulin-Dependent Protein Kinase II and α-Actinin-1 in a Calcium-Dependent Manner

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Abstract
Cyclin-dependent kinase 5 (Cdk5) is a critical regulator of neuronal migration in the developing CNS, and recent studies have revealed a role for Cdk5 in synaptogenesis and regulation of synaptic transmission. Deregulation of Cdk5 has been linked to the pathology of neurodegenerative diseases such as Alzheimer9s disease. Activation of Cdk5 requires its association with a regulatory subunit, and two Cdk5 activators, p35 and p39, have been identified. To gain further insight into the functions of Cdk5, we identified proteins that interact with p39 in a yeast two-hybrid screen. In this study we report that α-actinin-1 and the α-subunit of Ca2+/calmodulin-dependent protein kinase II (CaMKIIα), two proteins localized at the postsynaptic density, interact with Cdk5 via their association with p35 and p39. CaMKIIα and α-actinin-1 bind to distinct regions of p35 and p39 and also can interact with each other. The association of CaMKIIα and α-actinin-1 to the Cdk5 activators, as well as to each other, is stimulated by calcium. Further, the activation of glutamate receptors increases the association of p35 and p39 with CaMKIIα, and the inhibition of CaMKII activation diminishes this effect. The glutamate-mediated increase in association of p35 and CaMKIIα is mediated in large part by NMDA receptors, suggesting that cross talk between the Cdk5 and CaMKII signal transduction pathways may be a component of the complex molecular mechanisms contributing to synaptic plasticity, memory, and learning.