Modulation of Astrocytic Glutamine Synthetase by Endocannabinoid 2-Arachidonoylglycerol in JNK-Independent Pathway.

Jing Wang,Shenghong Wang,Hua Zhang

doi:10.3389/fpain.2021.682051

Abstract

Background and Objective: The glutamine synthetase (GS), an astrocyte-specific enzyme, plays an important role in neuroprotection through the glutamate/glutamine shuttle and can be modulated by endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) through extracellular signal-regulated protein kinase ½ (ERK1/2) and p38 signaling pathways. However, the role of c-Jun N-terminal kinase (JNK) signaling pathway in the modulation of GS in astrocytes by 2-AG is not clear.Materials and Methods: The expression of GS and JNK in astrocytes following the exposure to lipopolysaccharide (LPS) was examined with Western blotting and immunochemistry.Results: The results revealed that short-term exposure to LPS activated GS and increased phosphorylation of JNK in astrocytes in a time-dependent manner. Treatment with 2-AG reversed the changes in GS but had no effect on the activation of JNK.Conclusions: These findings suggest that the activation of JNK induced by LPS is not involved in the modulation of astrocytic GS by 2-AG.

Highlights

The astrocytic glutamine synthetase (GS) can modulate the extracellular concentration of glutamate by converting glutamate into glutamine and is verified to be involved in a variety of neurological disorders such as neurodegenerative diseases and chronic pain [1]
The previous study indicates that 2-AG is involved in the modulation of synaptic function, neuroprotection, and stimulation of mitogen-activated protein kinase (MAPK) family by binding to and activating the G-protein-coupled receptors (GPCR), cannabinoid receptor type 1 (CB1R), and cannabinoid receptor type 2 (CB2R), which are expressed in astrocytes [6, 7]
The data showed that the exposure to LPS induced time-dependent biphasic changes in the expression of GS in astrocytes, i.e., in contrast to baseline (0 min), expression of GS began to increase at 30 min (1.62 ± 0.08, p < 0.01), peaked at 1 h (1.86 ± 0.08, p < 0.001), declined to control level at 2–3 h, and decreased at 6 h (0.57 ± 0.05, p < 0.01; Figures 1A,B)

Summary

Introduction

The astrocytic glutamine synthetase (GS) can modulate the extracellular concentration of glutamate by converting glutamate into glutamine and is verified to be involved in a variety of neurological disorders such as neurodegenerative diseases and chronic pain [1]. A variety of Astrocytic Glutamine Synthetase and Endocannabinoid studies indicate that the activation of CB1R or CB2R produced effects of anti-inflammation, antinociception, and neuroprotection [8], and activation of MAPK signaling [9]. Our recent study indicates that astrocytic MAPK subunits, extracellular signal-regulated protein kinase 1⁄2 (ERK1/2) and p38, are involved in the modulation of GS by CB1R and CB2R [10]. The glutamine synthetase (GS), an astrocyte-specific enzyme, plays an important role in neuroprotection through the glutamate/glutamine shuttle and can be modulated by endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) through extracellular signal-regulated protein kinase 1⁄2 (ERK1/2) and p38 signaling pathways. The role of c-Jun N-terminal kinase (JNK) signaling pathway in the modulation of GS in astrocytes by 2-AG is not clear

Methods

Results

Conclusion