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Amplification of dopaminergic signaling by a positive feedback loop
Open accessAbstract
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.
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Citations
Cited by
The principal features and mechanisms of dopamine modulation in the prefrontal cortex
Seamans, J. K., & Yang, C. R. (2004) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2004.05.006 · Cited by 1,592
Neve, K. A., Seamans, J. K., & Trantham‐Davidson, H. (2004) · Journal of Receptors and Signal Transduction · doi:10.1081/lrst-200029981 · Cited by 837
DARPP-32: An Integrator of Neurotransmission
Svenningsson, P., Nishi, A., Fisone, G., Girault, J.-A., Nairn, A. C., & Greengard, P. (2004) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.44.101802.121415 · Cited by 720
Self-citationCaffeine as a psychomotor stimulant: mechanism of action
Fisone, G., Borgkvist, A., & Usiello, A. (2004) · Cellular and Molecular Life Sciences (CMLS) · doi:10.1007/s00018-003-3269-3 · Cited by 538
Agnati, L. F., Ferré, S., Lluis, C., Franco, R., & Fuxe, K. (2003) · Pharmacological Reviews · doi:10.1124/pr.55.3.2 · Cited by 323
Metadata
- Authors
- Nishi, A., Bibb, J. A., Snyder, G. L., Higashi, H., Nairn, A. C., & Greengard, P.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2000-10-24
- Volume
- 97
- Issue
- 23
- Pages
- 12840-12845
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1983285634
- Cited by
- 238
- References
- 0
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- green
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- Nishi, A., Bibb, J. A., Snyder, G. L., Higashi, H., Nairn, A. C., & Greengard, P. (2000). Amplification of dopaminergic signaling by a positive feedback loop. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.220410397
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