TY - JOUR
T1 - Differential regulation of the Cdk5-dependent phosphorylation sites of inhibitor-1 and DARPP-32 by depolarization
AU - Nguyen, Chan
AU - Hosokawa, Tomohisa
AU - Kuroiwa, Mahomi
AU - Ip, Nancy Y.
AU - Nishi, Akinori
AU - Hisanaga, Shin Ichi
AU - Bibb, James A.
PY - 2007/11
Y1 - 2007/11
N2 - While cyclin-dependent kinase 5 (Cdk5) is of growing importance to neuronal signaling, its regulation remains relatively unexplored. Examination of the mechanism by which NMDA modulates the phosphorylation of protein phosphatase inhibitor-1 at Ser6 and Ser67 and dopamine- and cAMP-regulated phosphoprotein Mr 32 000 at Thr75 revealed that generalized depolarization, rather than specific activation of NMDA receptors, was sufficient to induce decreases in these Cdk5 sites. Although no evidence for the involvement of the Cdk5 cofactors p35 or p39, or for L- and T-type voltage-gated Ca2+ channels, was found, evaluation of the role of phosphatases and extracellular cations revealed differential regulation of the three sites. NMDA-induced decreases in the phosphorylation of Thr75 of dopamine- and cAMP-regulated phosphoprotein Mr 32 000 required protein phosphatase 1/2A activity and extracellular Ca2+. In contrast, the effects on Ser6 and Ser67 of inhibitor-1 were not cation specific; either Na+ or Ca2+ sufficed. Furthermore, while the decrease in phosphorylation of Ser6 was partially dependent on protein phosphatase 2B, that of Ser67 was independent of the major protein serine/threonine phosphatases, likely indicating the presence of a pathway by which NMDA inhibits Cdk5 activity. Thus, in the striatum the regulation of phosphorylation of Cdk5-dependent sites by NMDA occurs through multiple distinct pathways.
AB - While cyclin-dependent kinase 5 (Cdk5) is of growing importance to neuronal signaling, its regulation remains relatively unexplored. Examination of the mechanism by which NMDA modulates the phosphorylation of protein phosphatase inhibitor-1 at Ser6 and Ser67 and dopamine- and cAMP-regulated phosphoprotein Mr 32 000 at Thr75 revealed that generalized depolarization, rather than specific activation of NMDA receptors, was sufficient to induce decreases in these Cdk5 sites. Although no evidence for the involvement of the Cdk5 cofactors p35 or p39, or for L- and T-type voltage-gated Ca2+ channels, was found, evaluation of the role of phosphatases and extracellular cations revealed differential regulation of the three sites. NMDA-induced decreases in the phosphorylation of Thr75 of dopamine- and cAMP-regulated phosphoprotein Mr 32 000 required protein phosphatase 1/2A activity and extracellular Ca2+. In contrast, the effects on Ser6 and Ser67 of inhibitor-1 were not cation specific; either Na+ or Ca2+ sufficed. Furthermore, while the decrease in phosphorylation of Ser6 was partially dependent on protein phosphatase 2B, that of Ser67 was independent of the major protein serine/threonine phosphatases, likely indicating the presence of a pathway by which NMDA inhibits Cdk5 activity. Thus, in the striatum the regulation of phosphorylation of Cdk5-dependent sites by NMDA occurs through multiple distinct pathways.
KW - Cyclin-dependent kinase 5
KW - Depolarization
KW - Dopamine- and cAMP-regulated phosphoprotein
KW - N-methyl-d-aspartate
KW - Protein phosphatase
KW - Protein phosphatase inhibitor-1
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U2 - 10.1111/j.1471-4159.2007.04868.x
DO - 10.1111/j.1471-4159.2007.04868.x
M3 - Article
C2 - 17868322
AN - SCOPUS:35448931445
SN - 0022-3042
VL - 103
SP - 1582
EP - 1593
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 4
ER -