Characterization of Agonist Stimulation of cAMP-Dependent Protein Kinase and G Protein-Coupled Receptor Kinase Phosphorylation of the β2-Adrenergic Receptor Using Phosphoserine-Specific Antibodies

2004 ◽  
Vol 65 (1) ◽  
pp. 196-206 ◽  
Author(s):  
Tuan M. Tran ◽  
Jackie Friedman ◽  
Eyad Qunaibi ◽  
Faiza Baameur ◽  
Robert H. Moore ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Receptor Kinase ◽  
Dependent Protein Kinase ◽  
Agonist Stimulation ◽  
Dependent Protein ◽  
Β2 Adrenergic Receptor ◽  
Kinase Phosphorylation ◽  
G Protein Coupled ◽  
Stimulation Of

Abstract P427: Inhibition Of PP2A By Insulin Impairs Beta-Adrenergic Receptor Function

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Anita Sahu ◽  
Sromona D Mukherjee ◽  
Conner P Witherow ◽  
Kate Stenson ◽  
John Tesmer ◽  
...  
Keyword(s):  
Cross Talk ◽  
Adrenergic Receptor ◽  
Receptor Kinase ◽  
Receptor Function ◽  
Knock Down ◽  
Phosphatase 2A ◽  
Β2 Adrenergic Receptor ◽  
Β Blocker ◽  
Phosphoinositide 3 Kinase ◽  
G Protein Coupled

Insulin impairs β2-adrenergic receptor (β2AR) function via trans-phosphorylation through G protein-coupled receptor kinase 2 (GRK2). However, less is known about dephosphorylation mechanisms mediated by protein phosphatase 2A (PP2A) during this insulin-β2AR cross-talk. Pharmacologic or genetic inhibition of phosphoinositide 3-kinase γ (PI3Kγ) unexpectedly resulted in significant reduction of insulin-mediated β2AR phosphorylation. Interestingly, β2AR-associated phosphatase activity was inhibited by insulin but was reversed by knock-down of PI3Kγ showing negative regulation of PP2A by PI3Kγ. Co-immunoprecipitation and surface plasmon resonance studies using purified proteins showed that GRK2 and PI3Kγ form a complex and could be recruited to β2ARs as GRK2 interacts with insulin receptor substrate (IRS) following insulin treatment. Further, co-immunoprecipitation studies showed that PI3Kγ directly interacted with both IRS-1 and IRS-2 but only IRS-2 interaction with PI3Kγ significantly increased following insulin stimulation. These results indicated that PI3Kγ could also be directly recruited to the receptor complex by IRS-2. Consistently, β-blocker pretreatment did not reduce insulin-mediated β2AR phosphorylation indicating agonist- and Gβγ-independent non-canonical regulation of receptor function. Mechanistically, PI3Kγ inhibits PP2A activity at the βAR complex by phosphorylating an intracellular inhibitor of PP2A (I2PP2A). Knock-down or CRISPR ablation of endogenous I2PP2A unlocked PP2A inhibition mediating β2AR dephosphorylation showing an unappreciated acute regulation of PP2A in mediating insulin-β2AR cross-talk.

Members of the G Protein-Coupled Receptor Kinase Family That Phosphorylate the β2-Adrenergic Receptor Facilitate Sequestration†

Biochemistry ◽  
1996 ◽  
Vol 35 (13) ◽  
pp. 4155-4160 ◽  
Author(s):  
Luc Ménard ◽  
Stephen S. G. Ferguson ◽  
Larry S. Barak ◽  
Lucie Bertrand ◽  
Richard T. Premont ◽  
...  
Keyword(s):  
G Protein ◽  
Adrenergic Receptor ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Kinase Family ◽  
Β2 Adrenergic Receptor ◽  
G Protein Coupled

Selected Contribution: Long-term effects of β2-adrenergic receptor stimulation on alveolar fluid clearance in mice

2002 ◽  
Vol 93 (5) ◽  
pp. 1875-1880 ◽  
Author(s):  
C. Sartori ◽  
X. Fang ◽  
D. W. McGraw ◽  
P. Koch ◽  
M. E. Snider ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Fluid Transport ◽  
Alveolar Fluid Clearance ◽  
Camp Production ◽  
Long Term Effects ◽  
Agonist Stimulation ◽  
Β2 Adrenergic Receptor ◽  
Stimulation Of ◽  
Alveolar Edema

Stimulation of active fluid transport with β-adrenergic receptor (βAR) agonists can accelerate the resolution of alveolar edema. However, chronic βAR-agonist administration may cause βAR desensitization and downregulation that may impair physiological responsiveness to βAR-agonist stimulation. Therefore, we measured baseline and terbutaline- (10−3 M) stimulated alveolar fluid clearance in mice that received subcutaneously (miniosmotic pumps) either saline or albuterol (2 mg · kg−1 · day−1) for 1, 3, or 6 days. Continuous albuterol administration increased plasma albuterol levels (10−5 M), an effect that was associated with 1) a significant decrease in βAR density and 2) attenuation, but not ablation, of maximal terbutaline-induced cAMP production. Forskolin-mediated cAMP-release was unaffected. Continuous albuterol infusion stimulated alveolar fluid clearance on day 1 but did not increase alveolar fluid clearance on days 3 and 6. However, terbutaline-stimulated alveolar fluid clearance in albuterol-treated mice was not reduced compared with saline-treated mice. Despite significant reductions in βAR density and agonist-mediated cAMP production by long-term βAR-agonist exposure, maximal βAR-agonist-mediated increase in alveolar fluid clearance is not diminished in mice.

scholarly journals Palmitoylated Cysteine 341 Modulates Phosphorylation of the β2-Adrenergic Receptor by the cAMP-dependent Protein Kinase

1996 ◽  
Vol 271 (35) ◽  
pp. 21490-21497 ◽  
Author(s):  
Serge Moffett ◽  
Lynda Adam ◽  
Hélène Bonin ◽  
Thomas P. Loisel ◽  
Michel Bouvier ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Adrenergic Receptor ◽  
Dependent Protein Kinase ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Β2 Adrenergic Receptor

scholarly journals β2 Adrenergic Receptor Complexes with the L-Type Ca2+ Channel CaV1.2 and AMPA-Type Glutamate Receptors: Paradigms for Pharmacological Targeting of Protein Interactions

2020 ◽  
Vol 60 (1) ◽  
pp. 155-174 ◽  
Author(s):  
Kwun Nok Mimi Man ◽  
Manuel F. Navedo ◽  
Mary C. Horne ◽  
Johannes W. Hell
Keyword(s):  
Protein Interactions ◽  
Adrenergic Receptor ◽  
Cell Types ◽  
Dependent Protein Kinase ◽  
Regulatory Pathways ◽  
Receptor Complexes ◽  
Functional Implications ◽  
Dependent Protein ◽  
Β2 Adrenergic Receptor ◽  
Β Adrenergic Receptors

Formation of signaling complexes is crucial for the orchestration of fast, efficient, and specific signal transduction. Pharmacological disruption of defined signaling complexes has the potential for specific intervention in selected regulatory pathways without affecting organism-wide disruption of parallel pathways. Signaling by epinephrine and norepinephrine through α and β adrenergic receptors acts on many signaling pathways in many cell types. Here, we initially provide an overview of the signaling complexes formed between the paradigmatic β2 adrenergic receptor and two of its most important targets, the L-type Ca2+ channel CaV1.2 and the AMPA-type glutamate receptor. Importantly, both complexes contain the trimeric Gs protein, adenylyl cyclase, and the cAMP-dependent protein kinase, PKA. We then discuss the functional implications of the formation of these complexes, how those complexes can be specifically disrupted, and how such disruption could be utilized in the pharmacological treatment of disease.

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