SKF83959, an Agonist of Phosphatidylinositol-Linked D1-Like Receptors, Promotes ERK1/2 Activation and Cell Migration in Cultured Rat Astrocytes

Chao Huang,Jingjing Wu,Rujia Liao,Wei Zhang,Alexander A Mongin

doi:10.1371/journal.pone.0049954

Chao Huang, Jingjing Wu + Show 3 more

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https://doi.org/10.1371/journal.pone.0049954

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Journal: PloS one	Publication Date: Nov 19, 2012
Citations: 21	License type: CC BY 4.0

Affiliation: Nantong University, Suzhou Kowloon Hospital

Abstract

Extracellular signal-regulated kinase 1/2 (ERK1/2) is a member of the mitogen-activated protein kinase family. It can mediate cell migration. Classical dopamine receptor-mediated ERK1/2 phosphorylation is widely studied in neurons. Here, we report that ERK1/2 phosphorylation is also modulated by putative phosphatidylinositol-linked D1-like receptors in cultured rat astrocytes. 6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959), an agonist of the putative phosphatidylinositol-linked D1-like receptors, was found to enhance ERK1/2 phosphorylation, which then promoted the migration of cultured astrocytes. The SKF83959-induced ERK1/2 phosphorylation was found to be Ca2+-independent based on the following observations: i. chelating intracellular Ca2+ did not inhibit ERK1/2 phosphorylation and astrocyte migration; ii. blockage of the release of intracellular Ca2+ from the endoplasmic reticulum by an inhibitor of inositol 1,4,5-trisphosphate (IP3) receptor did not attenuate ERK1/2 phosphorylation. However, inhibition of phospholipase C (PLC), the upstream molecule of internal Ca2+ release, disabled SKF83959’s ability to elevate the level of ERK1/2 phosphorylation. Both non-selective protein kinase C (PKC) inhibitor and PKCδ selective inhibitor prevented ERK1/2 phosphorylation increase and astrocyte migration, but PKCα inhibitor did not. This suggests that Ca2+-independent and diacylglycerol-dependent PKCδ acts downstream of putative phosphatidylinositol-linked D1-like receptor activation and mediates SKF83959-induced elevation of ERK1/2 phosphorylation in order to modulate astrocyte migration. In conclusion, our results demonstrate that SKF83959-induced increases in ERK1/2 phosphorylation and astrocyte migration are dependent on PLC-PKCδ signals. This might help us to further understand the functions of the putative phosphatidylinositol-linked D1-like receptors in the nervous system.

Highlights

Dopamine (DA) can regulate emotion, cognition, locomotion, and endocrine function [1,2]
Our present study demonstrates that SKF83959 promotes Extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation by augmenting phospholipase C (PLC)-protein kinase Cd (PKCd) signaling in cultured rat astrocytes
Because ERK1/2 affects astrocyte migration [18,24], we evaluated the effects of SKF83959 on astrocyte migration

Summary

Introduction

Dopamine (DA) can regulate emotion, cognition, locomotion, and endocrine function [1,2]. The roles of DA are mediated by distinct DA receptors (D1–D5). Among these receptors, classical cyclase-coupled D1 receptors are linked to Gs protein that can stimulate cyclic AMP (cAMP) formation [3]. Noncyclase-coupled D1-like receptors are connected to Gq protein to promote phospholipase C (PLC) activation and the subsequent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) [4]. Non-cyclase-coupled D1-like receptor was named phosphatidylinositol (PI)-linked D1-like receptor because of its ability to activate Gq/PLC/inositol 1,4,5-triphosphate (IP3) signals [5]. SKF83959, an agonist of the putative PI-linked D1-like receptor can be used to identify new roles of atypical DA receptors in the nervous system [6,7,8].

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