FIGURE 10.

Schemes showing the regulation of DARPP-32 phosphorylation and nuclear translocation by dopamine D1 receptor/PKA and glutamate/NMDA and AMPA receptor (AMPAR)/Ca²⁺ signaling. A, DARPP-32 phosphorylation patterns under unstimulated, dopamine D1 receptor (D1R)/PKA-activated, and NMDA/AMPA receptor/Ca²⁺-activated conditions. The relative levels of phosphorylation of Thr-34 (T34), Thr-75 (T75), Ser-97 (S97), and Ser-130 (S130) are indicated by the size of the circled P. B, right side of figure illustrated with blue arrows, activation of dopamine D1 receptor/PKA signaling induces DARPP-32 Thr-34 phosphorylation and DARPP-32 dephosphorylation at Thr-75 and Ser-97 by PP2A/B56δ. Left side of figure illustrated with red arrows, activation of NMDA or AMPA receptors followed by an increase in intracellular Ca²⁺ induces DARPP-32 dephosphorylation at all four sites: Thr-34 dephosphorylation by calcineurin (PP2B); Thr-75, Ser-97, and Ser-130 dephosphorylation by PP2A/PR72. PKA and Ca²⁺ signals induce Ser-97 dephosphorylation via different mechanisms of PP2A activation, leading to the nuclear accumulation of different forms of DARPP-32 (green arrows). After D1 dopamine receptor stimulation and activation of PKA, DARPP-32 phosphorylated at Thr-34 translocates to the nucleus where it retains the ability to inhibit PP1 and potentiate dopamine signaling. After glutamate receptor activation, DARPP-32 translocates to the nucleus in a form where Thr-34 is in the dephosphorylated state and thus unable to inhibit PP1.