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

Mahomi Kuroiwa; Takahide Shuto; Taku Nagai; Mutsuki Amano; Kozo Kaibuchi; Angus C Nairn; Akinori Nishi

doi:10.1016/j.neuint.2022.105438

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

Neurochem Int. 2023 Jan:162:105438. doi: 10.1016/j.neuint.2022.105438. Epub 2022 Nov 6.

Authors

Mahomi Kuroiwa¹, Takahide Shuto¹, Taku Nagai², Mutsuki Amano³, Kozo Kaibuchi⁴, Angus C Nairn⁵, Akinori Nishi⁶

Affiliations

¹ Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, 830-0011, Japan.
² Division of Behavioral Neuropharmacology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan.
³ Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, 466-8550, Japan.
⁴ Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, 466-8550, Japan; Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan.
⁵ Department of Psychiatry, Yale School of Medicine, Connecticut Mental Health Center, New Haven, CT, 06519, United States.
⁶ Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, 830-0011, Japan. Electronic address: nishia@kurume-u.ac.jp.

PMID: 36351540
DOI: 10.1016/j.neuint.2022.105438

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.

Keywords: DARPP-32; PKA; PP1; Rap1gap; Rasgrp2; Striatum.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Corpus Striatum* / metabolism
Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
Mice
Neostriatum* / metabolism
Phosphorylation
Protein Phosphatase 1 / metabolism
Protein Phosphatase 1 / pharmacology
Receptors, Dopamine D1 / metabolism
Signal Transduction

Substances

Protein Phosphatase 1
Dopamine and cAMP-Regulated Phosphoprotein 32
Receptors, Dopamine D1