Functional profiling of the G protein-coupled receptor C3aR1 reveals ligand-mediated biased agonism

Complement C3aR signaling: Immune and metabolic modulation and its impact on Alzheimer's disease

“…Additionally, an obstacle in targeting C3aR lies in the lack of effective pharmacological approaches. The commonly used antagonist, SB290157, also displays agonistic effects [18,100], posing difficulties in accurately assessing the impact of pharmacological inhibition of the receptor in animal models. This challenge was further hampered by the absence of structural information of the receptor to design efficient inhibitory molecules.…”

“…While some evidence in the literature suggests that C3aR activation triggers Gαi-family, other studies indicate that Gαs and Gαq are involved [14][15][16][17][18]. In a recent study it was identified that C3aR primarily couples to Gαi/o/z subtype to inhibit cAMP accumulation and mediate calcium influx [18]. The most reported downstream effect of C3aR activation is an increase in intracellular calcium [19][20][21], but other molecular pathways such as GSK3β, Wnt, ERK, JAK/STAT, and HIF1α signaling are also found to be downstream of C3aR activation [22][23][24][25][26].…”

“…This disassociation promotes the generation and promotion of subsequent downstream signaling through second messengers such as cAMP and calcium depending on the Gα subtype. While some evidence in the literature suggests that C3aR activation triggers Gαi-family, other studies indicate that Gαs and Gαq are involved [14][15][16][17][18]. In a recent study it was identified that C3aR primarily couples to Gαi/o/z subtype to inhibit cAMP accumulation and mediate calcium influx [18].…”

“…GPCR signaling is terminated by phosphorylation of the cytoplasmic loops and C-terminal tail, catalyzed by G-protein coupled receptor kinases (GRKs), which leads to recruitment of β-arrestin causing desensitization and internalization of the receptor. The recruitment of β-arrestin to C3aR has been reported in multiple studies [16,18,27], however knowledge about the molecular players involved in the initiation of the termination of C3aR signaling is limited. Majority of our current understanding of C3aR regulation comes from studies performed in mast cells, in which GRK-2 and GRK-3 are implicated in the phosphorylation of C3aR [28].…”

“…Furthermore, molecular modeling demonstrated that the C-terminal -AR motif of TLQP-21 interacts with three specific residues (R161, R340, and D417) of C3aR to form salt bridges [14,17,33]. The fact that the two ligands bind to the same pocket of C3aR suggests that they may participate in competitive binding and are thus antagonistic to each other [18,36].…”