Tyr115 is the key residue for determining agonist selectivity in the V1a vasopressin receptor
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Using a three-dimensional model of G protein-coupled receptors (GPCR), we have previously succeeded in docking the neurohypophysial hormone arginine-vasopressin (AVP) into the V1a receptor. According to this model, the hormone is completely embedded in the transmembrane part of the receptor. Only the side chain of the Arg residue at position 8 projects outside the transmembrane core of the receptor and possibly interacts with a Tyr residue located in the first extracellular loop at position 115. Residue 8 varies in the two natural neurohypophysial hormones, AVP and oxytocin (OT); similarly, different residues are present at position 115 in the different members of the AVP/OT receptor family. Here we show that Arg8 is crucial for high affinity binding of AVP to the rat V1a receptor. Moreover, when Tyr115 is replaced by an Asp and a Phe, the amino acids naturally occurring in the V2 and in the OT receptor subtypes, the agonist selectivity of the V1a receptor switches accordingly. Our results indicate that the interaction between peptide residue 8 and the receptor residue at position 115 is not only crucial for agonist high affinity binding but also for receptor selectivity.
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AVP has similar affinity for OTRs, V1aRs, and V1bRs, whereas OT may have a higher affinity for OTRs than for V1aRs or V1bRs.
“AVP has a similar affinity for OTRs, V1aRs, and V1bRs while OT may have a higher affinity for OTRs than V1aRs or V1bRs [28; 29; 30; 31; 32; 33].”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [28]
There can be differences of around 10-100 fold in the selectivity of OTRs and AVP receptors for OT and AVP.
“Nevertheless, it appears that there can be differences of around 10–100 fold in the selectivity of OTRs and AVP receptors for OT and AVP.”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [28]
The F103Y residue is homologous to Tyr115 in V1aR, which is critical for AVP binding and may confer increased binding affinity for AVP to Saimiri OTR.
“Vargas-Pinilla et al. (2015) identified this residue as homologous to Tyr115 in V1aR, which is critical for AVP binding and may confer increased binding affinity for AVP to Saimiri OTR (Chini et al., 1995).”
From Neuropeptide diversity and the regulation of social behavior in New World primates (2016) · cites this paper as Chini et al., 1995
Most critical sites for AVP-V1aR binding are conserved, with one notable exception.
“Like the OTR, most of the critical sites for AVPV1aR binding are conserved (Barberis et al., 1998; Chini et al., 1995; Mouillac et al., 1995; Thibonnier et al., 2000), with one notable exception.”
From Neuropeptide diversity and the regulation of social behavior in New World primates (2016) · cites this paper as Chini et al., 1995
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- Authors
- Chini, B., Mouillac, B., Ala, Y., Balestre, M. N., Trumpp‐Kallmeyer, S., Hoflack, J., Elands, J., Hibert, M., Manning, M., & Jard, S.
- Affiliations
- Inserm (FR)
- Venue
- The EMBO Journal
- Published
- 1995-05-01
- Volume
- 14
- Issue
- 10
- Pages
- 2176-2182
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC398323
- OpenAlex
- W1866285812
- Cited by
- 179
- References
- 33
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 4 · 2015: 1 · 2014: 2 · 2013: 8 · 2012: 5
- FWCI
- 5.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- National Institutes of Health
- National Institute of General Medical Sciences (GM25280, R01GM025280)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- vasopressin V1a receptor, vasopressin, oxytocin, agonist selectivity, ligand-receptor interactions, G protein-coupled receptors, receptor modeling, hormone binding affinity, V2 receptor
- MeSH terms
- Amino Acid Sequence, Animals, Arginine Vasopressin, Binding Sites, Dose-Response Relationship, Drug, Humans, Ligands, Models, Molecular, Molecular Sequence Data, Oligopeptides, Structure-Activity Relationship, Signal Transduction, Receptors, Vasopressin, Receptors, Oxytocin, Rats
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