Role of G Protein-Coupled Receptors in Microglial Activation: Implication in Parkinson's Disease.

Chao Gu,Mei Wang,Yan Chen,Zengyan Zhu,Yajing Chen,Chun-Feng Liu

doi:10.3389/fnagi.2021.768156

Abstract

Parkinson’s disease (PD) is one of the prevalent neurodegenerative diseases associated with preferential loss of dopaminergic (DA) neurons in the substantia nigra compacta (SNc) and accumulation of α-synuclein in DA neurons. Even though the precise pathogenesis of PD is not clear, a large number of studies have shown that microglia-mediated neuroinflammation plays a vital role in the process of PD development. G protein-coupled receptors (GPCRs) are widely expressed in microglia and several of them act as regulators of microglial activation upon corresponding ligands stimulations. Upon α-synuclein insults, microglia would become excessively activated through some innate immune receptors. Presently, as lack of ideal drugs for treating PD, certain GPCR which is highly expressed in microglia of PD brain and mediates neuroinflammation effectively could be a prospective source for PD therapeutic intervention. Here, six kinds of GPCRs and two types of innate immune receptors were introduced, containing adenosine receptors, purinergic receptors, metabotropic glutamate receptors, adrenergic receptors, cannabinoid receptors, and melatonin receptors and their roles in neuroinflammation; we highlighted the relationship between these six GPCRs and microglial activation in PD. Based on the existing findings, we tried to expound the implication of microglial GPCRs-regulated neuroinflammation to the pathophysiology of PD and their potential to become a new expectation for clinical therapeutics.

Highlights

Microglia are the main resident macrophages in the central nervous system (CNS), which originate from the yolk sac and merge into CNS at the early stage development (McGeer et al, 1988; Colonna and Butovsky, 2017; Prinz et al, 2019)
Damaged DA neurons in turn stimulate microglial activation, resulting in a positive feedback loop of microglial activation and DA neuronal death (Glass et al, 2010). It is still undetermined whether neuroinflammation is the cause of Parkinson’s disease (PD) pathogenesis or a downstream response of neuronal damage, some studies reported that inhibiting microglial action or clear activated microglia is neuroprotective and could relieve some motor symptoms in PD animal models (Gu et al, 2018), suggesting targeting neuroinflammation might show new lights on the research of PD pathogenesis
This study suggested the key role of NLR protein 3 (NLRP3) in PD pathogenesis

Summary

Introduction

Microglia are the main resident macrophages in the central nervous system (CNS), which originate from the yolk sac and merge into CNS at the early stage development (McGeer et al, 1988; Colonna and Butovsky, 2017; Prinz et al, 2019). Stimulation of A1 receptors inhibits microglial morphological activation through suppressing ATP-induced Ca2+ influx (Luongo et al, 2014), indicating the possible beneficial role of A1 receptors in microglia-mediated neuroinflammation.

Results

Conclusion