Comparison of the pharmacological profiles of arginine vasopressin and oxytocin analogs at marmoset, macaque, and human vasopressin 1a receptor

Biomed Pharmacother. 2020 Jun:126:110060. doi: 10.1016/j.biopha.2020.110060. Epub 2020 Mar 4.

Abstract

Arginine vasopressin (AVP) and oxytocin (OT) are nonapeptides that bind to G-protein coupled receptors and influence social behaviors. Consensus mammalian AVP and OT (Leu8-OT) sequences are highly conserved. In marmosets, an amino acid change in the 8th position of the peptide (Pro8-OT) exhibits unique structural and functional properties. There is ∼85 % structural homology between the OT receptor (OTR) and vasopressin 1a receptor (V1aR) resulting in significant cross-reactivity between the ligands and receptors. Chinese hamster ovary (CHO) cells expressing marmoset (mV1aR), macaque (qV1aR), or human vasopressin receptor 1a (hV1aR) were used to assess AVP, Leu8-OT and Pro8-OT pharmacological profiles. To assess activation of Gq, functional assays were performed using Fluo-3 to measure ligand-induced Ca2+ mobilization. In all three V1aR-expressing cell lines, AVP was more potent than the OT ligands. To assess ligand-induced hyperpolarization, FLIPR Membrane Potential (FMP) assays were performed. In all three V1aR lines, AVP was more potent than the OT analogs. The distinctive U-shaped concentration-response curve displayed by AVP may reflect enhanced desensitization of the mV1aR and hV1aR, which is not observed with qV1aR. Evaluation of Ca2+-activated potassium (K+) channels using the inhibitors apamin, paxilline, and TRAM-34 demonstrated that both intermediate and large conductance Ca2+-activated K+ channels contributed to membrane hyperpolarization, with different pharmacological profiles identified for distinct ligand-receptor combinations. Taken together, these data suggest differences in ligand-receptor signaling that may underlie differences in social behavior. Integrative studies of behavior, genetics and ligand-receptor interaction will help elucidate the connection between receptor pharmacology and social behaviors.

Keywords: Arginine vasopressin; Calcium-activated potassium channels; Oxytocin; Vasopressin receptor 1a; g-protein coupled receptor.

MeSH terms

  • Animals
  • Arginine Vasopressin* / analogs & derivatives
  • Arginine Vasopressin* / pharmacology
  • CHO Cells
  • Calcium / metabolism
  • Callithrix
  • Cricetulus
  • Humans
  • Ligands
  • Macaca
  • Oxytocin* / analogs & derivatives
  • Oxytocin* / pharmacology
  • Potassium Channels, Calcium-Activated / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Oxytocin / genetics
  • Receptors, Oxytocin / metabolism*
  • Receptors, Vasopressin / genetics
  • Receptors, Vasopressin / metabolism*
  • Social Behavior
  • Species Specificity

Substances

  • Ligands
  • Potassium Channels, Calcium-Activated
  • Receptors, G-Protein-Coupled
  • Receptors, Oxytocin
  • Receptors, Vasopressin
  • Arginine Vasopressin
  • Oxytocin
  • Calcium