DARPP-32/protein phosphatase 1 regulates Rasgrp2 as a novel component of dopamine D1 receptor signaling in striatum. (January 2023)

• Record Type: Journal Article
• Authors: Kuroiwa, Mahomi; Shuto, Takahide; Nagai, Taku; Amano, Mutsuki; Kaibuchi, Kozo; Nairn, Angus C.; Nishi, Akinori
• Is Part Of: Neurochemistry international. Volume 162(2023)
• Publication Date: 2023-01
• Subjects: DARPP-32 -- PP1 -- PKA -- Rasgrp2 -- Rap1gap -- Striatum; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2022.105438
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: Dopamine regulates psychomotor function by D1 receptor/PKA-dependent phosphorylation of DARPP-32. DARPP-32, phosphorylated at Thr34 by PKA, inhibits protein phosphatase 1 (PP1), and amplifies the phosphorylation of other PKA/PP1 substrates following D1 receptor activation. In addition to the D1 receptor/PKA/DARPP-32 signaling pathway, D1 receptor stimulation is known to activate Rap1/ERK signaling. Rap1 activation is mediated through the phosphorylation of Rasgrp2 (guanine nucleotide exchange factor; activation) and Rap1gap (GTPase-activating protein; inhibition) by PKA. In this study, we investigated the role of PP1 inhibition by phospho-Thr34 DARPP-32 in the D1 receptor-induced phosphorylation of Rasgrp2 and Rap1gap at PKA sites. The analyses in striatal and NAc slices from wild-type and DARPP-32 knockout mice revealed that the phosphorylation of Rasgrp2 at Ser116/Ser117 and Ser586, but not of Rasgrp2 at Ser554 or Rap1gap at Ser441 or Ser499 induced by a D1 receptor agonist, is under the control of the DARPP-32/PP1. The results were supported by pharmacological analyses using a selective PP1 inhibitor, tautomycetin. In addition, analyses using a PP1 and PP2A inhibitor, okadaic acid, revealed that all sites of Rasgrp2 and Rap1gap were regulated by PP2A. Thus, the interactive machinery of DARPP-32/PP1 may contribute to efficient D1 receptor signaling via Rasgrp2/Rap1 in the striatum. Highlights: PP1 inhibition by phospho-Thr34 DARPP-32 induces efficient Rasgrp2 phosphorylation by PKA. A selective PP1 inhibitor reveals that Rasgrp2 at Ser116/Ser117 and Ser586 are substrates for PP1. DARPP-32/PP1 signaling interacts with the Rap1 pathway via Rasgrp2 phosphorylation.