Activation of other receptors by SPMs
A few studies have reported the possibility of other GPCR involvement. Among them, GPR101 mediates the pro-resolving effects of RvD5n-3 DPA in arthritis and infection (Flak et al. 2020). Besides, SPMs have been reported to activate non-GPCRs receptors, such as nuclear receptors.
In a dose-dependent manner, PD1 enhances PPARγ transcriptional activation reporter activity in human neuron-glia (HNG) cells co-transfected with hPPARγ-GAL4 and MH100-tk-Luc (Zhao et al. 2011). This suggests that PD1 is capable of enhancing the peroxisome proliferator-activated receptor gamma (PPARγ) (Fig. 2). The transcriptional activity of PPARγ was significantly increased after treatment with 100 nM PD1. RvD1 was also assumed to be a ligand for PPARγ and inhibited IκBα degradation and NF-κB p65 nuclear translocation in an LPS-induced lung injury model, which was partially reversed by the PPARγ inhibitor GW9662 (Fig. 2) (Liao et al. 2012). Recently, it has been reported that LXA4 binds to the nuclear aryl hydrocarbon receptor (AhR) (Fig. 2) (Asha et al. 2020).
A GPCR that acts directly on MaR1 has not yet been identified. However, MaR1 blocks TRPV1-mediated currents in neurons, acts as a ligand for the retinoid-associated orphan receptor α (RORα), and inhibits TLR4 signalling (Fig. 2) (Park 2015), Chiang et al. found that MaR1 can activate LGR6, a member of the glycoprotein hormone receptor subfamily of rhodopsin-like GPCRs (Chiang et al. 2019b), which initiates cAMP, impedance changes, and stimulate an innate immune response against PMNs, monocytes and macrophages (Chiang et al. 2019b).