The fifth neurohypophysial hormone receptor is structurally related to the V2-type receptor but functionally similar to V1-type receptors

The neurohypophysial peptides of the vasopressin (VP) and oxytocin (OT) families regulate salt and water homeostasis and reproduction through distinct G protein-coupled receptors. The current thinking is that there are four neurohypophysial hormone receptors (V1aR, V1bR, V2R, and OTR) in vertebrates, and their evolutionary history is still debated. We report the identification of a fifth neurohypophysial hormone receptor (V2bR) from the holocephalan elephant fish. This receptor is similar to conventional V2R (V2aR) in sequence, but induced Ca²⁺ signaling in response to vasotocin (VT), the non-mammalian VP ortholog; such signaling is typical of V1-type receptors. In addition, V1aR, V1bR and OTR were also isolated from the elephant fish. Further screening revealed that orthologous V2bRs are widely distributed throughout the jawed vertebrates, and that the V2bR family is subdivided into two subfamilies: the fish specific type-1, and a type-2 that is characteristically found in tetrapods. Analysis suggested that the mammalian V2bR may have lost its function. Based on molecular phylogenetic, synteny and functional analyses, we propose a new evolutionary history for the neurohypophysial hormone receptors in vertebrates as follows: the first duplication generated V1aR/V1bR/OTR and V2aR/V2bR lineages; after divergence from the V2bR lineage, the V2aRs evolved to use cAMP as a second messenger, while the V2bRs retained the original Ca²⁺ signaling system. Future studies on the role of V2bR in the brain, heart, kidney and reproductive organs, in which it is highly expressed, will open a new research field in VP/VT physiology and evolution.