AKT and CDK5/P35 mediate brain derived neurotrophic factor induction of DARPP-32 in medium size spiny neurons in vitro

doi:10.1074/jbc.M606508200

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Papers In Press, published online ahead of print January 5, 2007
J. Biol. Chem, 10.1074/jbc.M606508200
Submitted on July 10, 2006
Accepted on January 5, 2007

AKT and CDK5/P35 mediate brain derived neurotrophic factor induction of DARPP-32 in medium size spiny neurons in vitro

Alexey Bogush, Steve Pedrini, Joshua Pelta-Heller, Tung Chan, Qian Yang, Zixu Mao, Emily Sluzas, Tracy Gieringer, and Michelle E. Ehrlich

Farber Institute for Neurosciences/Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Corresponding Author: michelle.ehrlich{at}jefferson.edu

Mature striatal medium size spiny neurons express the dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa (DARPP-32), but little is known about the mechanisms regulating its levels, or the specification of fully differentiated neuronal subtypes. Cell extrinsic molecules that increase DARPP-32 mRNA and/or protein levels include brain-derived neurotrophic factor (BDNF), retinoic acid (RA) and estrogen (E2). DARPP-32 induction by BDNF in vitro requires phosphatidylinositide 3-kinase (PI3K), but inhibition of phosphorylation of protein kinase B (PKB)/Akt does not entirely abolish expression of DARPP-32. Moreover, the requirement for Akt has not been established. Using pharmacologic inhibitors of PI3K, Akt, and cyclin-dependent kinase 5 (cdk5), and constitutively active and dominant negative PI3K, Akt, cdk5 and p35 viruses in cultured striatal neurons, we measured BDNF-induced levels of DARPP-32 protein and/or mRNA. We demonstrate that both the PI3K/Akt/mTOR (mammalian target of rapamycin) and the cdk5/p35 signal transduction pathways contribute to the induction of DARPP-32 protein levels by BDNF, and that the effects are on both the transcriptional and translational levels. It also appears that PI3K is upstream of cdk5/p35, and its activation can lead to an increase in p35 protein levels. These data support the presence of multiple signal transduction pathways mediating expression of DARPP-32 in vitro, including a novel, important pathway via which PI3K regulates the contribution of cdk5/p35.

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