Effects of the β‐agonist, isoprenaline, on the down‐regulation, functional responsiveness and trafficking of β2‐adrenergic receptors with N‐terminal polymorphisms
Open accessAbstract
The β2-AR (β2-adrenergic receptor) is an important target for respiratory and CVD (cardiovascular disease) medications. Clinical studies suggest that N-terminal polymorphisms of β2-AR may act as disease modifiers. We hypothesized that polymorphisms at amino acids 16 and 27 result in differential trafficking and down-regulation of β2-AR variants following β-agonist exposure. The functional consequences of the four possible combinations of these polymorphisms in the human β2-AR (designated β2-AR-RE, β2-AR-GE, β2-AR-RQ and β2-AR-GQ) were studied using site-directed mutagenesis and recombinant expression in HEK-293 cells (human embryonic kidney cells). Ligand-binding assays demonstrated that after 24 h exposure to 1 μM isoprenaline, isoforms with Arg16 (β2-AR-RE and β2-AR-RQ) underwent increased down-regulation compared with isoforms with Gly16 (β2-AR-GE and β2-AR-GQ). Consistent with these differences in down-regulation between isoforms, prolonged isoprenaline treatment resulted in diminished cAMP response to subsequent isoprenaline challenge in β2-AR-RE relative to β2-AR-GE. Confocal microscopy revealed that the receptor isoforms had similar co-localization with the early endosomal marker EEA1 following isoprenaline treatment, suggesting that they had similar patterns of internalization. None of the isoforms exhibited significant co-localization with the recycling endosome marker Rab11 in response to isoprenaline treatment. Furthermore, we found that prolonged isoprenaline treatment led to a higher degree of co-localization of β2-AR-RE with the lysosomal marker LAMP1 (lysosome-associated membrane protein 1) compared with that of β2-AR-GE. Taken together, these results indicate that a mechanism responsible for differential responses of these receptor isoforms to the β-agonist involves differences in the efficiency with which agonist-activated receptors are trafficked to the lysosomes for degradation, or differences in degradation in the lysosomes.
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Isoproterenol predominantly binds β2-ADRs that primarily couple to the Gαs subunit in MEG01 cells and platelets.
“Isoproterenol (ISO), which predominantly binds to β2-ADRs that primarily couple to the Gαs subunit in both MEG01 cells (Fig. S5G) and in platelets (Fig. S5H) (Koryakina et al., 2012)”
From A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors (2020) · cites this paper as Koryakina et al., 2012
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A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors
Nemet, I., Saha, P. P., Gupta, N., Zhu, W., Romano, K. A., Skye, S. M., Cajka, T., Mohan, M. L., Li, L., Wu, Y., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.016 · Cited by 784 · see citing works
- Authors
- Koryakina, Y., Jones, S. M., Cornett, L. E., Seely, K., Brents, L., Prather, P. L., Kofman, A., & Kurten, R. C.
- Affiliations
- Arkansas Children's Hospital (US)
- University of Arkansas for Medical Sciences (US)
- University of Virginia (US)
- Corresponding author
- Koryakina, Yulia
- ORCID
- Venue
- Cell Biology International
- Publisher
- Wiley
- Published
- 2012-12
- Volume
- 36
- Issue
- 12
- Pages
- 1171-1183
- ISSN
- 1065-6995 (ISSN-L)
- 1095-8355
- PMC
- PMC4018189
- OpenAlex
- W2004462370
- Cited by
- 12
- References
- 52
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 1
- FWCI
- 0.51
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cell Biology International (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Center for Research Resources (2 P20 RR-16460, P20RR016460, S10RR019395, 1 S10 RR 19395)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- beta2-adrenergic receptor, isoproterenol, receptor down-regulation, receptor internalization, receptor trafficking, lysosomal degradation, cAMP signaling, receptor isoforms, disease modifiers
- MeSH terms
- rab11 GTP-Binding Proteins, Cyclic AMP, Adrenergic beta-Agonists, Humans, Isoproterenol, Polymorphism, Genetic, Down-Regulation, Receptors, Adrenergic, beta-2, Protein Isoforms, rab GTP-Binding Proteins, Protein Transport, Lysosomal-Associated Membrane Protein 1, HEK293 Cells
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