Recombinant SER-2 expressed in HEK293 cells demonstrated dual signaling pathways:
cAMP Inhibition: Tyramine reduced cAMP by 80% via Gαᵢ/o coupling .
Calcium Mobilization: SER-2 triggered Ca²⁺ influx (EC₅₀ = 1.2 μM), while SER-2A showed weaker activity .
Antagonist profiling revealed:
| Antagonist | Ki (nM) |
|---|---|
| LSD | 2.1 |
| Yohimbine | 85 |
| Chlorpromazine | 1,200 |
Genetic studies in C. elegans revealed SER-2’s roles in:
Pharyngeal Pumping: SER-2 antagonizes serotonin (5-HT)-stimulated pumping. ser-2 mutants failed to suppress 5-HT-induced pumping upon tyramine exposure .
Foraging Behavior: ser-2(pk1357) mutants exhibited defective nose-touch response during reversals, indicating SER-2 regulates sensorimotor integration .
Feeding Suppression: SER-2 in NSM neurons mediates tyramine/octopamine-dependent inhibition of feeding via 5-HT modulation .
Post-translational arginine methylation by PRMT-5 enhances SER-2 signaling:
While SER-2 is nematode-specific, insect TAR1 receptors share functional similarities:
| Receptor | Organism | Signaling Pathway | Key Function |
|---|---|---|---|
| SER-2 | C. elegans | Gαᵢ/o, Ca²⁺ | Pharyngeal pumping, foraging |
| TAR1 | Drosophila | Gαᵢ/o | Olfactory behavior |
| TAR2 | Drosophila | Gαq, Ca²⁺ | Malpighian tubule function |
Isoform-Specific Pharmacology: SER-2A’s reduced octopamine sensitivity (vs. SER-2) highlights IL3’s role in ligand discrimination .
Neural Circuit Integration: SER-2 in NSM neurons mediates cross-talk between tyraminergic and serotonergic pathways to regulate feeding .
Methylation-Dependent Activation: PRMT-5-mediated methylation increases SER-2’s efficacy in vivo, linking epigenetic regulation to GPCR function .