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The Journal of Neuroscience, September 15, 2002, 22(18):7879-7891
The Cyclin-Dependent Kinase 5 Activators p35 and p39 Interact
with the  -Subunit of Ca2+/Calmodulin-Dependent Protein
Kinase II and -Actinin-1 in a Calcium-Dependent Manner
Rani
Dhavan1, *,
Paul L.
Greer1, *,
Maria A.
Morabito1,
Lianna R.
Orlando2, and
Li-Huei
Tsai1, 3
1 Department of Pathology, Harvard Medical School,
Boston, Massachusetts 02115, 2 Department of Neurology,
Massachusetts General Hospital, Boston, Massachusetts 02114, and
3 Howard Hughes Medical Institute, Boston, Massachusetts
02115
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 Alzheimer's 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  -actinin-1 and the -subunit of
Ca2+/calmodulin-dependent protein kinase II
(CaMKII), two proteins localized at the postsynaptic density,
interact with Cdk5 via their association with p35 and p39. CaMKII
and -actinin-1 bind to distinct regions of p35 and p39 and
also can interact with each other. The association of CaMKII
and -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 CaMKII, and the
inhibition of CaMKII activation diminishes this effect. The
glutamate-mediated increase in association of p35 and CaMKII 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.
Key words:
Cdk5; p35; p39; CaMKII; actinin; synapses; calcium; yeast
two-hybrid; NMDA
*
R.D. and P.L.G. contributed equally to this work.
Copyright © 2002 Society for Neuroscience 0270-6474/02/22187879-13$05.00/0
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