I8-arachnotocin-an arthropod-derived G protein-biased ligand of the human vasopressin V(2) receptor.

The neuropeptides oxytocin (OT) and vasopressin (VP) and their G protein-coupled receptors OTR, V(1a)R, V(1b)R, and V(2)R form an important and widely-distributed neuroendocrine signaling system. In mammals, this signaling system regulates water homeostasis, blood pressure, reproduction, as well as social behaviors such as pair bonding, trust and aggression. There exists high demand for ligands with differing pharmacological profiles to study the physiological and pathological functions of the individual receptor subtypes. Here, we present the pharmacological characterization of an arthropod (Metaseiulus occidentalis) OT/VP-like nonapeptide across the human OT/VP receptors. I8-arachnotocin is a full agonist with respect to second messenger signaling at human V(2)R (EC(50) 34 nM) and V(1b)R (EC(50) 1.2 µM), a partial agonist at OTR (EC(50) 790 nM), and a competitive antagonist at V(1a)R [pA(2) 6.25 (558 nM)]. Intriguingly, I8-arachnotocin activated the Gα(s) pathway of V(2)R without recruiting either β-arrestin-1 or β-arrestin-2. I8-arachnotocin might thus be a novel pharmacological tool to study the (patho)physiological relevance of β-arrestin-1 or -2 recruitment to the V(2)R. These findings furthermore highlight arthropods as a novel, vast and untapped source for the discovery of novel pharmacological probes and potential drug leads targeting neurohormone receptors.