Drug-stimulated ERK activity is regulated by dephosphorylation through a network of phosphatases whose activities are regulated by PKA.36 The striatal-enriched protein tyrosine phosphatase (STEP; PTPN5 protein tyrosine phosphatase, nonreceptor type 5 striatum-enriched) inactivates ERK by dephosphorylating a tyrosine residue within its activation loop. The ability of STEP/PTPN5 to dephosphorylate ERK is lost by PKA-mediated phosphorylation of STEP/PTPN5 at a regulatory serine within its ERK-binding domain. This serine can be dephosphorylated by protein phosphatase 1 (PP1), and PKA-phosphorylated DARPP-32 inhibits PP1. Therefore, in the absence of DARPP-32 inhibition, PP1 can dephosphorylate STEP/PTPN5, allowing it to bind, dephosphorylate, and inactivate ERK. In addition to suppressing STEP activity, DARPP-32 also mediates drug-induced increases in ERK activity by promoting the phosphorylation and activation of MEK. These mechanisms explain why in DARPP-32 knockout mice, cocaine, amphetamine, nicotine, THC, or morphine fail to increase ERK phosphorylation in the NAc.21
