Atypical signaling and functional desensitization response of MAS receptor to peptide ligands
Open accessAbstract
MAS is a G protein-coupled receptor (GPCR) implicated in multiple physiological processes. Several physiological peptide ligands such as angiotensin-(1-7), angiotensin fragments and neuropeptide FF (NPFF) are reported to act on MAS. Studies of conventional G protein signaling and receptor desensitization upon stimulation of MAS with the peptide ligands are limited so far. Therefore, we systematically analyzed G protein signals activated by the peptide ligands. MAS-selective non-peptide ligands that were previously shown to activate G proteins were used as controls for comparison on a common cell based assay platform. Activation of MAS by the non-peptide agonist (1) increased intracellular calcium and D-myo-inositol-1-phosphate (IP1) levels which are indicative of the activation of classical Gαq-phospholipase C signaling pathways, (2) decreased Gαi mediated cAMP levels and (3) stimulated Gα12-dependent expression of luciferase reporter. In all these assays, MAS exhibited strong constitutive activity that was inhibited by the non-peptide inverse agonist. Further, in the calcium response assay, MAS was resistant to stimulation by a second dose of the non-peptide agonist after the first activation has waned suggesting functional desensitization. In contrast, activation of MAS by the peptide ligand NPFF initiated a rapid rise in intracellular calcium with very weak IP1 accumulation which is unlike classical Gαq-phospholipase C signaling pathway. NPFF only weakly stimulated MAS-mediated activation of Gα12 and Gαi signaling pathways. Furthermore, unlike non-peptide agonist-activated MAS, NPFF-activated MAS could be readily re-stimulated the second time by the agonists. Functional assays with key ligand binding MAS mutants suggest that NPFF and non-peptide ligands bind to overlapping regions. Angiotensin-(1-7) and other angiotensin fragments weakly potentiated an NPFF-like calcium response at non-physiological concentrations (≥100 µM). Overall, our data suggest that peptide ligands induce atypical signaling and functional desensitization of MAS.
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MasR activation by Ang-1-7 and BIO101 probably does not induce the same signaling cascade.
“Consequently, MasR activation by Ang-1-7 and BIO101 probably does not induce the same signaling cascade.24,29,30”
Peptidic ligands such as TXA-127/Ang-1-7 and non-peptidic ligands such as BIO101 bind to an overlapping but not identical pocket.
“it has been shown that peptidic ligands such as TXA-127/Ang-1-7 and non peptidic ligands such as BIO101 (20-hydroxyecdysone) bind to an overlapping but not identical pocket.29”
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Lobo, S. M., Plantefève, G., Nair, G., Joaquim Cavalcante, A., Franzin de Moraes, N., Nunes, E., Barnum, O., Berdun Stadnik, C. M., Lima, M. P., Lins, M., et al. (2024) · eClinicalMedicine · doi:10.1016/j.eclinm.2023.102383 · Cited by 27 · see citing works
- Authors
- Tirupula, K. C., Desnoyer, R., Speth, R. C., & Karnik, S. S.
- Affiliations
- Cleveland Clinic (US)
- Nova Southeastern University (US)
- Corresponding author
- Karnik, Sadashiva S.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-07-28
- Volume
- 9
- Issue
- 7
- Pages
- e103520
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4113456
- OpenAlex
- W2002671750
- Cited by
- 47
- References
- 64
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 5 · 2023: 6 · 2022: 1 · 2021: 8 · 2020: 1 · 2019: 4 · 2018: 5 · 2017: 5 · 2015: 7
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- NSUWorks (Nova Southeastern University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Ipsen
- National Heart, Lung, and Blood Institute (HL115964, R01HL132351, R01HL083243, HL57470, R01HL057470, R01HL115964)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Keywords
- Mas receptor, G protein-coupled receptors, peptide ligands, neuropeptide FF, angiotensin-(1-7), Gαq/11 signaling, phospholipase C, Gαi signaling, cyclic AMP, intracellular calcium, constitutive activity, inverse agonists, ligand binding
- MeSH terms
- Proto-Oncogene Mas, Amino Acid Sequence, Angiotensin I, Binding Sites, Calcium, Humans, Inositol Phosphates, Ligands, Models, Molecular, Molecular Sequence Data, Mutation, Neuropeptides, Oligopeptides, Peptide Fragments, Peptides, Protein Binding, Proto-Oncogene Proteins, Signal Transduction, Protein Structure, Secondary, Microscopy, Confocal, Intracellular Space, Receptors, G-Protein-Coupled, HEK293 Cells
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