TABLE 1.
Reported microglial GPCRs and their potential roles in PD.
| Microglial GPCRs | Sub-types | Ligands | Reported mechanisms | References |
| Adenosine receptors | A1 | Adenosine, paeoniflorin (agonist) | Promoting ATP-induced Ca2+ influx, neuroinflammation inhibition | Liu et al. (2006), Brothers et al. (2010), Luongo et al. (2014), Bagga et al. (2016) |
| A2A | Preladenant SCH58261 Caffeine (antagonist) | Microglial activation inhibition, neuroprotective effects in MPTP model, increase of A2A in MPTP or LPS-treated model | Orr et al. (2009), Brothers et al. (2010), Gyoneva et al. (2014), Bagga et al. (2016), Madeira et al. (2016) | |
| A2B | Adenosine, BAY60-6583 (agonist) | Promoting p-CREB and p-p38 | Koscsó et al. (2012), Merighi et al. (2017) | |
| A3 | Adenosine, Cl-IB-MECA (agonist) | Suppressing Akt and NF-κB activation | Hammarberg et al. (2003), Lee et al. (2006) | |
| Purinergic receptors | P2Y1 | ATP and ADP (agonist) | Increasing Ca2+ release from intracellular stores, promoting pro-inflammatory factors production | De Simone et al. (2010), Orellana et al. (2013) |
| P2Y12 | ADP (agonist) | TGF-β-induced microglial migration | De Simone et al. (2010) | |
| P2Y6 | UDP (agonist) | P2Y6 upregulation in LPS-induced microglia, ERK1/2 activation, promoting MPTP-induced neuronal cell death | Yang et al. (2017), Qian et al. (2018), Anwar et al. (2020) | |
| P2Y12 | P2Y12–/–mice | GTP-RhoA/ROCK2 signaling activation in P2Y12–/– mice | Yu et al. (2019) | |
| P2Y13 | P2Y13–/–microglia | IL-1β release is increased remarkably in P2Y13–/– microglia | Kyrargyri et al. (2020) | |
| Metabotropic glutamate receptors | mGlu5 | CHPG (agonist) | Inhibiting α-synuclein-mediated neuroinflammation | Zhang Y.N. et al. (2021) |
| Triptolide | Inhibiting microglial activation via increasing mGlu5 receptor expression | Huang et al. (2018) | ||
| mGluR5–/–mice | Increasing number of both microglia and astrocytes | Carvalho et al. (2019) | ||
| Adrenergic receptors | α2 | Dexmedetomidine (agonist) | Suppressing LPS-induced release of pro-inflammatory cytokines, regulating microglial polarization induced by 6-OHDA | Yamanaka et al. (2017), Zhang et al. (2017) |
| β2 | Terbutaline, Salmeterol, Clenbuterol, Formoterol (agonist) | Enhancing intracellular cAMP level, inhibit microglia-mediated neuroinflammation, activating classical cAMP/PKA/CREB as well as the PI3K and p38 MAPK signaling pathways, β2AR/β-arrestin2-dependent pathway, inhibiting microglial activation in LPS-challenged inflammatory PD mouse model | Fujita et al. (1998), Qian et al. (2011), Peterson et al. (2014), Sharma et al. (2019), O’Neill et al. (2020) | |
| Cannabinoid receptors | CB1 | Endocannabinoid, WIN55212-2, HU210 (agonist), SR141716A (antagonist) | Inhibiting NADPH and ROS, increasing pro-inflammatory factors (TNF-α, IL-1β, and IL-6) and chemokines (MCP-1 and CX3CL1) | Chung et al. (2011), Lou et al. (2018) |
| CB2 | Upregulation of microglial CB2 receptors in PD model | Concannon et al. (2015), Concannon et al. (2016), Gómez-Gálvez et al. (2016), Navarrete et al. (2018) | ||
| WIN55212-2, Cannabinoids, CP55940 (agonist) | NRF2, ERK1/2, cPLA2, and NF-κB inhibition, neurotoxin-mediated neuroinflammation inhibition | Ribeiro et al. (2013), Galán-Ganga et al. (2020) | ||
| GPR55 | KIT77 (agonist) | Reduce protein synthesis of mPGES-1 and COX-2 | Saliba et al. (2018) | |
| Melatonin receptors | MT1 | Ramelteon (agonist) | Enhancing PDHA1-mediated enhancement of oxidative phosphorylation | Gu et al. (2021) |
| MT1/MT2 | Agomelatine, Ramelteon, Melatonin, (agonist) | Suppressing NF-κB nuclear translocation, promoting Nrf2 nuclear accumulation | Molteni et al. (2013), Wang et al. (2019) |