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

被引：1

作者：

Kuroiwa, Mahomi ^{[1
]}

Shuto, Takahide ^{[1
]}

Nagai, Taku ^{[2
]}

Amano, Mutsuki ^{[3
]}

Kaibuchi, Kozo ^{[3
,4
]}

Nairn, Angus C. ^{[5
]}

Nishi, Akinori ^{[1
]}

机构：

[1] Kurume Univ, Dept Pharmacol, Sch Med, Kurume, Fukuoka 8300011, Japan

[2] Fujita Hlth Univ, Int Ctr Brain Sci, Div Behav Neuropharmacol, Toyoake, Aichi 4701192, Japan

[3] Nagoya Univ, Grad Sch Med, Dept Cell Pharmacol, Nagoya, Aichi 4668550, Japan

[4] Fujita Hlth Univ, Int Ctr Brain Sci, Div Cell Biol, Toyoake, Aichi 4701192, Japan

[5] Connecticut Mental Hlth Ctr, Yale Sch Med, Dept Psychiat, New Haven, CT 06519 USA

来源：

NEUROCHEMISTRY INTERNATIONAL | 2023年 / 162卷

基金：

日本学术振兴会;

关键词：

DARPP-32; PP1; PKA; Rasgrp2; Rap1gap; Striatum; INNERVATED BRAIN-REGIONS; CALDAG-GEFI; EXCHANGE FACTORS; PROTEIN-KINASE; PHOSPHOPROTEIN; PHOSPHORYLATION; PURIFICATION; TAUTOMYCETIN; ACTIVATION; INHIBITOR;

D O I：

10.1016/j.neuint.2022.105438

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：8

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