DARPP-32 (dopamine and cyclic adenosine 3',5'-mono-phosphate-regulated phosphoprotein, 32 kDa) is a specific inhibitor of PP1. It is expressed at high concentrations in medium spiny neurons of the neostriatum where it plays a central role in integrating responses to dopamine (acting via the cAMP) and glutamate (acting via Ca2+) in dopaminoceptive neurons (Figure 3, right). Diseases associated with defects in dopaminergic neurotransmission include Parkinson's disease, Huntington's disease, ADHD, and schizophrenia.
Activation of the cAMP pathway in dopaminoceptive neurons leads to increased phosphorylation of
DARPP-32 on Thr 34 and inhibition of PP1. This results in increased phosphorylation of neurotransmitter receptors, voltage-gated ion channels, an electrogenic ion pump (Na+/K+ ATPase), and a transcription factor (CREB).
In contrast, glutamate acting through NMDA receptors promotes dephosphorylation of brain proteins through activation of a protein phosphatase cascade involving PP2B and PP1. Activation of NMDA receptors elevates Ca2+ which activates PP2B. This leads to DARPP-32 dephosphorylation by PP2B and activation of PP1 through relief of inhibition by DARPP-32.
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