PMID- 10604473
OWN - NLM
STAT- MEDLINE
DCOM- 20000104
LR  - 20161124
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 402
IP  - 6762
DP  - 1999 Dec 9
TI  - Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons.
PG  - 669-71
AB  - The physiological state of the cell is controlled by signal transduction
      mechanisms which regulate the balance between protein kinase and protein
      phosphatase activities. Here we report that a single protein can, depending on
      which particular amino-acid residue is phosphorylated, function either as a
      kinase or phosphatase inhibitor. DARPP-32 (dopamine and cyclic AMP-regulated
      phospho-protein, relative molecular mass 32,000) is converted into an inhibitor
      of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at
      threonine 34. We find that DARPP-32 is converted into an inhibitor of PKA when
      phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5
      phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75
      DARPP-32 inhibits PKA in vitro by a competitive mechanism. Decreasing phospho-Thr
      75 DARPP-32 in striatal slices, either by a Cdk5-specific inhibitor or by using
      genetically altered mice, results in increased dopamine-induced phosphorylation
      of PKA substrates and augmented peak voltage-gated calcium currents. Thus
      DARPP-32 is a bifunctional signal transduction molecule which, by distinct
      mechanisms, controls a serine/threonine kinase and a serine/threonine
      phosphatase.
FAU - Bibb, J A
AU  - Bibb JA
AD  - Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University,
      New York, New York 10021, USA.
FAU - Snyder, G L
AU  - Snyder GL
FAU - Nishi, A
AU  - Nishi A
FAU - Yan, Z
AU  - Yan Z
FAU - Meijer, L
AU  - Meijer L
FAU - Fienberg, A A
AU  - Fienberg AA
FAU - Tsai, L H
AU  - Tsai LH
FAU - Kwon, Y T
AU  - Kwon YT
FAU - Girault, J A
AU  - Girault JA
FAU - Czernik, A J
AU  - Czernik AJ
FAU - Huganir, R L
AU  - Huganir RL
FAU - Hemmings, H C Jr
AU  - Hemmings HC Jr
FAU - Nairn, A C
AU  - Nairn AC
FAU - Greengard, P
AU  - Greengard P
LA  - eng
GR  - P01 DA010044/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Dopamine and cAMP-Regulated Phosphoprotein 32)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Recombinant Proteins)
RN  - 2ZD004190S (Threonine)
RN  - EC 2.7.11.1 (Cyclin-Dependent Kinase 5)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.22 (CDC2 Protein Kinase)
RN  - EC 2.7.11.22 (Cdk5 protein, mouse)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
CIN - Nature. 1999 Dec 9;402(6762):588-9. PMID: 10604460
MH  - Animals
MH  - CDC2 Protein Kinase/metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors/metabolism
MH  - Cyclin-Dependent Kinase 5
MH  - Cyclin-Dependent Kinases/*metabolism
MH  - Dopamine/*metabolism
MH  - Dopamine and cAMP-Regulated Phosphoprotein 32
MH  - Enzyme Inhibitors/chemistry/metabolism
MH  - In Vitro Techniques
MH  - Mice
MH  - Nerve Tissue Proteins/*metabolism
MH  - Neurons/enzymology/*metabolism
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Recombinant Proteins/metabolism
MH  - *Signal Transduction
MH  - Threonine/metabolism
EDAT- 1999/12/22 09:00
MHDA- 2001/03/23 10:01
CRDT- 1999/12/22 09:00
PHST- 1999/12/22 09:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/12/22 09:00 [entrez]
AID - 10.1038/45251 [doi]
PST - ppublish
SO  - Nature. 1999 Dec 9;402(6762):669-71. doi: 10.1038/45251.