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Hetero-oligomerization between beta2- and beta3-adrenergic receptors generates a beta-adrenergic signaling unit with distinct functional properties.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2004 Jul 02; Vol. 279 (27), pp. 28756-65. Date of Electronic Publication: 2004 Apr 27. - Publication Year :
- 2004
-
Abstract
- The ability of the closely related beta(2)- and beta(3)-adrenergic receptors (AR) to form hetero-oligomers was assessed by bioluminescence resonance energy transfer. Quantitative bioluminescence resonance energy transfer titration curves revealed that the beta(2)AR has identical propensity to hetero-oligomerize with the beta(3)AR than to form homo-oligomers. To determine the influence of heterooligomerization, a HEK293 cell line stably expressing an excess of beta(3)AR over beta(2)AR was generated so that all beta(2)AR are engaged in hetero-oligomerization with beta(3)AR, providing a tool to study the effect of hetero-oligomerization on beta(2)AR function in the absence of any beta(2)AR homooligomer. The hetero-oligomerization had no effect on the ligand binding properties of various beta(2)AR ligands and did not affect the potency of isoproterenol to stimulate adenylyl cyclase. Despite the unaltered ligand binding properties of the beta(2/3)AR hetero-oligomer, the stable association of the beta(2)AR with the beta(3)AR completely blocked agonist-stimulated internalization of the beta(2)AR. Given that the beta(3)AR is resistant to agonist-promoted endocytosis, the results indicate that the beta(3)AR acted as a dominant negative of the beta(2)AR endocytosis process. Consistent with this notion, the beta(2/3)AR hetero-oligomer displayed a lower propensity to recruit beta-arrestin-2 than the beta(2)AR. The hetero-oligomerization also led to a change in G protein coupling selectivity. Indeed, in contrast to beta(2)AR and beta(3)AR, which regulate adenylyl cyclase and extracellular signal-regulated kinase activity through a coupling to G(s) and G(i/o), no G(i/o) coupling was observed for the beta(2/3)AR hetero-oligomer. Together, these results demonstrate that hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic signaling unit that possesses unique functional properties.
- Subjects :
- Adenylyl Cyclases metabolism
Animals
COS Cells
Cell Line
Cell Membrane metabolism
Cyclic AMP metabolism
Dimerization
Dose-Response Relationship, Drug
Endocytosis
Fluorescence Resonance Energy Transfer
Genes, Dominant
Genetic Vectors
Humans
Kinetics
Ligands
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases metabolism
Pertussis Toxin pharmacology
Protein Binding
Protein Structure, Tertiary
Receptors, Adrenergic, beta-2 metabolism
Receptors, Adrenergic, beta-3 metabolism
Signal Transduction
Receptors, Adrenergic, beta-2 chemistry
Receptors, Adrenergic, beta-3 chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 279
- Issue :
- 27
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15123695
- Full Text :
- https://doi.org/10.1074/jbc.M313310200