G protein-coupled receptors (GPCRs) are involved in regulation of manifold physiological processes through coupling to heterotrimeric G proteins upon ligand stimulation. Classical therapeutically active drugs simultaneously initiate several downstream signaling pathways, whereas biased ligands, which stabilize subsets of receptor conformations, elicit more selective signaling. This concept of functional selectivity of a ligand has emerged as an interesting property for the development of new therapeutic molecules. Biased ligands are expected to have superior efficacy and/or reduced side effects by regulating biological functions of GPCRs in a more precise way. In the last decade, 5-HT_7 receptor (5-HT_7R) has become a promising target for the treatment of neuro-psychiatric disorders, sleep and circadian rhythm disorders, and pathological pain. In this study, we showed that Serodolin is unique among a number of agonists and antagonists tested: it behaves as an antagonist/inverse agonist on G_s signaling while inducing ERK activation through a (i-arrestin-dependent signaling mechanism that requires c-SRC activation. Moreover, we showed that Serodolin clearly decreases hyperalgesia and pain sensation in response to inflammatory, thermal, and mechanical stimulation. This antinociceptive effect could not be observed in 5-HT_7R knockout (KO) mice and was fully blocked by administration of SB269-970, a specific 5-HT_7R antagonist, demonstrating the specificity of action of Serodolin. Physiological effects of 5-HT_7R stimulation have been classically shown to result from G_s-dependent adenylyl cyclase activation. In this study, using a beta-arrestin-biased agonist, we provided insight into the molecular mechanism triggered by 5-HT_7R and revealed its therapeutic potential in the modulation of pain response.
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