Identification of amino acid residues that direct differential ligand selectivity of mammalian and nonmammalian V1a type receptors for arginine vasopressin and vasotocin: Insights into molecular coevolution of V1a type receptors and their ligands

Sujata Acharjee, Jean Luc Do-Rego, Dayoung Oh, Ryun Sup Ahn, Han Choe, Hubert Vaudry, Kyungjin Kim, Jae Young Seong, Hyuk Bang Kwon

Research output: Contribution to journalArticle

37 Scopus citations


Arginine vasotocin (VT) is the ortholog in all nonmammalian vertebrates of arginine vasopressin (AVP) in mammals. We have previously cloned an amphibian V1a-type vasotocin receptor (VT1R) that exhibited higher sensitivity for VT than AVP, while the mammalian V1a type receptor (V1aR) responded better to AVP than VT. In the present study, we identified the amino acid residues that confer differential ligand selectivity for AVP and VT between rat V1aR and bullfrog VT1R (bfVT1R). A chimeric rat V1aR having transmembrane domain (TMD) VI to the carboxyl-terminal tail (C-tail) of bfVT1R showed a reverse ligand preference for AVP and VT, whereas a chimeric VT1R with TMD VI to the C-tail of rat V1aR showed a great increase in sensitivity for AVP. A single mutation (Ile 315(6.53) to Thr) in TMD VI of V1aR increased the sensitivity for VT, while a single mutation (Phe313(6.51) to Tyr or Pro 334(7.33) to Thr) reduced sensitivity toward AVP. Interestingly the triple mutation (Phe313(6.51) to Tyr, Ile6.53 to Thr, and Pro7.33 to Thr) of V1aR increased sensitivity to VT but greatly reduced sensitivity to AVP, behaving like bfVT1R. Further, like V1aR, a double mutant (Tyr306(6.51) to Phe and Thr327(7.33) to Pro) of bfVT1R showed an increased sensitivity to AVP. These results suggest that Phe/Tyr6.51, Ile/Thr6.53, and Pro/Thr7.33 are responsible for the differential ligand selectivity between rat V1aR and bfVT1R. This information regarding the molecular interaction of VT/AVP with their receptors may have important implications for the development of novel AVP analogs.

Original languageEnglish (US)
Pages (from-to)54445-54453
Number of pages9
JournalJournal of Biological Chemistry
Issue number52
StatePublished - Dec 24 2004


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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