Greengard, Paul

Publication Detail

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Amplification of dopaminergic signaling by a positive feedback loop.

A Nishi; J A Bibb; G L Snyder; H Higashi; A C Nairn; P Greengard (Profiled Author: Greengard, Paul)

Department of Physiology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. nishia@med.kurume-u.ac.jp
Proceedings of the National Academy of Sciences of the United States of America 2000;97(23):12840-5.

Dopamine and cAMP-regulated phosphoprotein of M(r) 32,000 (DARPP-32) plays an obligatory role in most of the actions of dopamine. In resting neostriatal slices, cyclin-dependent kinase 5 (Cdk5) phosphorylates DARPP-32 at Thr-75, thereby reducing the efficacy of dopaminergic signaling. We report here that dopamine, in slices, and acute cocaine, in whole animals, decreases the state of phosphorylation of striatal DARPP-32 at Thr-75 and thereby removes this inhibitory constraint. This effect of dopamine is achieved through dopamine D1 receptor-mediated activation of cAMP-dependent protein kinase (PKA). The activated PKA, by decreasing the state of phosphorylation of DARPP-32-Thr-75, de-inhibits itself. Dopamine D2 receptor stimulation has the opposite effect. The ability of activated PKA to reduce the state of phosphorylation of DARPP-32-Thr-75 is apparently attributable to increased protein phosphatase-2A activity, with Cdk5 being unaffected. Together, these results indicate that via positive feedback mechanisms, Cdk5 signaling and PKA signaling are mutually antagonistic.

2 Originating Grant

• 1.

  GREENGARD, PAUL

  DRUGS OF ABUSE - ROLE OF PROTEIN PHOSPHORYLATION

  1 March 1997 - 29 February 2016

  NATIONAL INSTITUTE ON DRUG ABUSE

  Total Funding: $ 24,977,507

• 2.

  Greengard, Paul

  REGION SPECIFIC PHOSPHOPROTEINS IN THE BASAL GANGLIA

  1 July 1985 - 30 June 2005

  NATIONAL INSTITUTE OF MENTAL HEALTH

  Total Funding: $ 27,221,874

Scientific Context

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