PMID- 10217279
OWN - NLM
STAT- MEDLINE
DCOM- 19990506
LR  - 20201209
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 72
IP  - 5
DP  - 1999 May
TI  - Role of calcineurin and protein phosphatase-2A in the regulation of DARPP-32
      dephosphorylation in neostriatal neurons.
PG  - 2015-21
AB  - DARPP-32, a dopamine- and cyclic AMP-regulated phosphoprotein of Mr 32 kDa, is
      phosphorylated on Thr34 by cyclic AMP-dependent protein kinase, resulting in its 
      conversion to a potent inhibitor of protein phosphatase-1 (PP-1). Conversely,
      Thr34-phosphorylated DARPP-32 is dephosphorylated and inactivated in vitro by
      calcineurin and protein phosphatase-2A (PP-2A). We have investigated the relative
      contributions of these protein phosphatases to the regulation of DARPP-32
      dephosphorylation in mouse neostriatal slices. Cyclosporin A (5 microM), a
      calcineurin inhibitor, maximally increased the level of phosphorylated DARPP-32
      by 17+/-2-fold. Okadaic acid (1 microM), an inhibitor of PP-1 and PP-2A, had a
      smaller effect, increasing phospho-DARPP-32 by 5.1+/-1.3-fold. The effect of
      okadaic acid on DARPP-32 phosphorylation was shown to be due to inhibition of
      PP-2A activity. Incubation of slices in the presence of cyclosporin A plus either
      okadaic acid or calyculin A, another PP-1/PP-2A inhibitor, caused a synergistic
      increase in the level of phosphorylated DARPP-32. The use of Ca2(+)-free/EGTA
      medium mimicked the effects of cyclosporin A on DARPP-32 phosphorylation,
      supporting the conclusion that the action of cyclosporin on DARPP-32
      phosphorylation was attributable to blockade of the Ca2(+)-dependent activation
      of calcineurin. The results indicate that calcineurin and PP-2A, but not PP-1,
      act synergistically to maintain a low level of phosphorylated DARPP-32 in
      neostriatal slices.
FAU - Nishi, A
AU  - Nishi A
AD  - Department of Physiology, Kurume University School of Medicine, Fukuoka, Japan.
FAU - Snyder, G L
AU  - Snyder GL
FAU - Nairn, A C
AU  - Nairn AC
FAU - Greengard, P
AU  - Greengard P
LA  - eng
GR  - P01 DA010044/DA/NIDA NIH HHS/United States
GR  - MH-40899/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Calcineurin Inhibitors)
RN  - 0 (Dopamine and cAMP-Regulated Phosphoprotein 32)
RN  - 0 (Drug Combinations)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Marine Toxins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Oxazoles)
RN  - 0 (Phosphoproteins)
RN  - 1W21G5Q4N2 (Okadaic Acid)
RN  - 7D07U14TK3 (calyculin A)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - EC 3.1.3.16 (Calcineurin)
RN  - EC 3.1.3.16 (Phosphoprotein Phosphatases)
RN  - EC 3.1.3.16 (Protein Phosphatase 1)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
SB  - IM
MH  - Animals
MH  - Calcineurin/*physiology
MH  - Calcineurin Inhibitors
MH  - Cyclosporine/pharmacology
MH  - Dopamine and cAMP-Regulated Phosphoprotein 32
MH  - Drug Combinations
MH  - Drug Synergism
MH  - Enzyme Inhibitors/pharmacology
MH  - In Vitro Techniques
MH  - Male
MH  - Marine Toxins
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neostriatum/cytology/*metabolism
MH  - Nerve Tissue Proteins/*metabolism
MH  - Neurons/*metabolism
MH  - Okadaic Acid/pharmacology
MH  - Oxazoles/pharmacology
MH  - Phosphoprotein Phosphatases/antagonists & inhibitors/*physiology
MH  - *Phosphoproteins
MH  - Phosphorylation
MH  - Protein Phosphatase 1
MH  - Protein Phosphatase 2
EDAT- 1999/04/27 00:00
MHDA- 1999/04/27 00:01
CRDT- 1999/04/27 00:00
PHST- 1999/04/27 00:00 [pubmed]
PHST- 1999/04/27 00:01 [medline]
PHST- 1999/04/27 00:00 [entrez]
AID - 10.1046/j.1471-4159.1999.0722015.x [doi]
PST - ppublish
SO  - J Neurochem. 1999 May;72(5):2015-21. doi: 10.1046/j.1471-4159.1999.0722015.x.