A Long Lasting β1 Adrenergic Receptor Stimulation of cAMP/Protein Kinase A (PKA) Signal in Cardiac Myocytes

Fu, Qin; Kim, Sungjin; Soto, Dagoberto; Arcangelis, Vania De; DiPilato, Lisa M.; Liu, Shubai; Xu, Bing; Shi, Qian; Zhang, Jin; Xiang, Yang

doi:10.1074/jbc.m113.542589

Cited by 30 publications

(33 citation statements)

References 33 publications

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“…In a classic view, βARs are desensitized in HF due in part to the reduced β 1 AR density at the cell surface, 34 rendering the heart unable to respond to catecholamine stimulation 6 . However, recent progress suggests that βARs can continuously signal at the cell surface 7 and after catecholamine-induced endocytosis. 8 Studies show that βARs are accumulated at the endosome under chronic elevation of sympathetic activity in HF.…”

Section: Discussionmentioning

confidence: 99%

“…5 The disturbed βAR signaling and reduced PKA phosphorylation result in blunted contractile response following administration of βAR agonists. 6 Interestingly, recent progress suggests that βAR can continuously signal both at the cell surface 7 and after catecholamine-induced endocytosis. 8 These βAR signals may play a role in adaptive cardiac hypertrophic remodeling and promote compensatory contractility in the heart.…”

Section: Introductionmentioning

confidence: 99%

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Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure

Barbagallo

Reddy

et al. 2016

Circulation Research

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Rationale In heart failure, myofilament proteins display abnormal phosphorylation, which contributes to contractile dysfunction. The mechanisms underlying the dysregulation of protein phosphorylation on myofilaments is not clear. Objective This study aims to understand the mechanisms underlying altered phosphorylation of myofilament proteins in heart failure. Methods and Results We generate a novel genetically encoded protein kinase A (PKA) biosensor anchored onto the myofilaments in rabbit cardiac myocytes to examine PKA activity at the myofilaments in responses to adrenergic stimulation. We show that PKA activity is shifted from the sarcolemma to the myofilaments in hypertrophic failing rabbit myocytes. In particular, the increased PKA activity on the myofilaments is due to an enhanced β2 adrenergic receptor (β2AR) signal selectively directed to the myofilaments together with a reduced phosphodiesterase activity associated with the myofibrils. Mechanistically, the enhanced PKA activity on the myofilaments is associated with downregulation of caveolin-3 in the hypertrophic failing rabbit myocytes. Reintroduction of caveolin-3 in the failing myocytes is able to normalize the distribution of β2AR signal by preventing PKA signal access to the myofilaments, and to restore contractile response to adrenergic stimulation. Conclusions In hypertrophic rabbit myocytes, selectively enhanced β2AR signaling toward the myofilaments contributes to elevated PKA activity and PKA phosphorylation of myofilament proteins. Reintroduction of caveolin-3 is able to confine β2AR signaling and restore myocyte contractility in response to β-adrenergic stimulation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure

Barbagallo

Reddy

et al. 2016

Circulation Research

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“…Sensitivity of the cell to cyclic AMP is regulated primarily by phosphodiesterases (PDE), which adjust the intensity and confine the three-dimensional geometry of the cyclic AMP signal to select subcellular compartments [97-100]. In the case of the ß 1 -AR, the concentration and diffusion of cyclic AMP generated by the ß 1 -AR signaling pathway was regulated at the level of the ß 1 -AR receptosome by phosphodiesterase 4D8 (PDE4D8), which binds to receptosomal SAP97 [101, 102]. The inclusion of PDE4D8 into the ß 1 -AR receptosome provides a powerful regulatory feedback enzyme that focuses the output of cyclic AMP to within the ß 1 -AR microenvironment [102, and Fig.…”

Section: Role Of Cross-talk and Feedback Regulatory Mechanisms In mentioning

confidence: 99%

“…In the case of the ß 1 -AR, the concentration and diffusion of cyclic AMP generated by the ß 1 -AR signaling pathway was regulated at the level of the ß 1 -AR receptosome by phosphodiesterase 4D8 (PDE4D8), which binds to receptosomal SAP97 [101, 102]. The inclusion of PDE4D8 into the ß 1 -AR receptosome provides a powerful regulatory feedback enzyme that focuses the output of cyclic AMP to within the ß 1 -AR microenvironment [102, and Fig. 2].…”

Section: Role Of Cross-talk and Feedback Regulatory Mechanisms In mentioning

confidence: 99%

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Barcoding of GPCR trafficking and signaling through the various trafficking roadmaps by compartmentalized signaling networks

Bahouth

Nooh

2017

Cellular Signalling

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Proper signaling by G protein coupled receptors (GPCR) is dependent on the specific repertoire of transducing, enzymatic and regulatory kinases and phosphatases that shape its signaling output. Activation and signaling of the GPCR through its cognate G protein is impacted by G protein-coupled receptor kinase (GRK)-imprinted “barcodes” that recruit ß-arrestins to regulate subsequent desensitization, biased signaling and endocytosis of the GPCR. The outcome of agonist-internalized GPCR in endosomes is also regulated by sequence motifs or “barcodes” within the GPCR that mediate its recycling to the plasma membrane or retention and eventual degradation as well as its subsequent signaling in endosomes. Given the vast number of diverse sequences in GPCR, several trafficking mechanisms for endosomal GPCR have been described. The majority of recycling GPCR, are sorted out of endosomes in a “sequence-dependent pathway” anchored around a type-1 PDZ-binding module found in their C-tails. For a subset of these GPCR, a second “barcode” imprinted onto specific GPCR serine/threonine residues by compartmentalized kinase networks was required for their efficient recycling through the “sequence-dependent pathway”. Mutating the serine/threonine residues involved, produced dramatic effects on GPCR trafficking, indicating that they played a major role in setting the trafficking itinerary of these GPCR. While endosomal SNX27, retromer/WASH complexes and actin were required for efficient sorting and budding of all these GPCR, additional proteins were required for GPCR sorting via the second “barcode”. Here we will review recent developments in GPCR trafficking in general and the human ß1-adrenergic receptor in particular across the various trafficking roadmaps. In addition, we will discuss the role of GPCR trafficking in regulating endosomal GPCR signaling, which promote biochemical and physiological effects that are distinct from those generated by the GPCR signal transduction pathway in membranes.

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Terbutaline attenuates LPS ‐induced injury of pulmonary microvascular endothelial cells by cAMP /Epac signaling

Duan

Yang

et al. 2021

Drug Dev Res

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Acute lung injury (ALI), characterized by an acute onset of severe hypoxemia, is a common and devastating syndrome usually triggered by lipopolysaccharide (LPS) infection from bacteria. This study is intended to explore whether terbutaline can alleviate LPS‐induced human pulmonary microvascular endothelial cell (HPMVEC) injury through cAMP/Epac signaling. LPS was utilized to induce ALI in HPMVECs, and after exposure of LPS‐induced HPMVECs to terbutaline, the cellular functions including cell viability and apoptosis were measured by cell counting kit‐8 and terminal deoxynucleotidyl transferase dUTP nick‐end labeling. The protein expression related to cAMP/Epac signaling, apoptosis, and that of tight junction and inflammatory factors were evaluated at the same time. The effects of terbutaline on cellular functions were confirmed again after the addition of antagonists of cAMP and Epac, respectively. The levels of both cAMP and Epac reduced by LPS was concentration‐dependently increased by terbutaline. The apoptosis and endothelial cell permeability damage of LPS‐induced HPMVECs were enhanced after the addition of KT‐5720 and ESI‐09. The beneficial effects of terbutaline on alleviating the inflammation and apoptosis in HPMVECs injured by LPS are mediated by cAMP/Epac signaling, and this evidence would demonstrate the potential of terbutaline in the treatment of ALI.

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A Long Lasting β1 Adrenergic Receptor Stimulation of cAMP/Protein Kinase A (PKA) Signal in Cardiac Myocytes

Cited by 30 publications

References 33 publications

Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure

Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure

Barcoding of GPCR trafficking and signaling through the various trafficking roadmaps by compartmentalized signaling networks

Terbutaline attenuates LPS ‐induced injury of pulmonary microvascular endothelial cells by cAMP /Epac signaling

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