A journey toward understanding the vasopressin type 2 receptor function; impact of small molecules and structural biology

Arginine-vasopressin (AVP) is well known for its antidiuretic effect, which is mediated through activation of the kidney V2 receptor subtype (V2R). Here, we provide a detailed overview of the evolution of our understanding of this system, from the pioneering work of Schafer and Oliver to recent studies that characterize its physiological, pharmacological, and molecular mechanistic features. Recent breakthroughs in cryo-electron microscopy (cryo-EM) have significantly advanced our understanding of how V2R interacts with its cognate ligand. Furthermore, these structural insights help explain how small molecules developed over the past three decades bind to and modulate receptor activity. Together, these advances open new therapeutic perspectives for the treatment of V2R-associated diseases.