Inhibitors of phosphoinositide 3-kinase cause defects in the postendocytic sorting of β2-adrenergic receptors

Awwad, Hibah O.; Iyer, Varsha; Rosenfeld, Jennifer L.; Millman, Ellen E.; Foster, Estrella; Moore, Robert H.; Knoll, Brian J.

doi:10.1016/j.yexcr.2007.04.034

Cited by 8 publications

(7 citation statements)

References 41 publications

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“…Consistent with these observations, the involvement of PI3K is implicated in P2Y purinergic receptor resensitization [114, 115]. The role of PI3K in resensitization is increasingly evident by defects caused by PI3K inhibitors in postendocytic sorting of β 2 -adrenergic receptors [116]. …”

Section: Gpcr Resensitizationmentioning

confidence: 80%

G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function

Mohan¹,

Vasudevan²,

Gupta³

et al. 2013

CMP

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G-protein coupled receptors (GPCRs) are seven transmembrane receptors that are pivotal regulators of cellular responses including vision, cardiac contractility, olfaction, and platelet activation. GPCRs have been a major target for drug discovery due to their role in regulating a broad range of physiological and pathological responses. GPCRs mediate these responses through a cyclical process of receptor activation (initiation of downstream signals), desensitization (inactivation that results in diminution of downstream signals), and resensitization (receptor reactivation for next wave of activation). Although these steps may be of equal importance in regulating receptor function, significant advances have been made in understanding activation and desensitization with limited effort towards resensitization. Inadequate importance has been given to resensitization due to the understanding that resensitization is a homeostasis maintaining process and is not acutely regulated. Evidence indicates that resensitization is a critical step in regulating GPCR function and may contribute towards receptor signaling and cellular responses. In light of these observations, it is imperative to discuss resensitization as a dynamic and mechanistic regulator of GPCR function. In this review we discuss components regulating GPCR function like activation, desensitization, and internalization with special emphasis on resensitization. Although we have used β-adrenergic receptor as a proto-type GPCR to discuss mechanisms regulating receptor function, other GPCRs are also described to put forth a view point on the universality of such mechanisms.

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Section: Gpcr Resensitizationmentioning

confidence: 80%

G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function

Mohan¹,

Vasudevan²,

Gupta³

et al. 2013

CMP

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“…Several components of this machinery require 3-phosphorylated phosphoinositides for membrane attachment (Cullen and Korswagen, 2011), and a previous study (Awwad et al, 2007) Vps34 represents an endosomal target that controls b2AR signaling. Chemical inhibitors used in previous studies of b2AR trafficking (Sorensen et al, 1999;Naga Prasad et al, 2001;Awwad et al, 2007) [wortmannin (WM) and LY294002] have additional cellular targets (Knight, 2010). In the current study, we employed more specific manipulations to examine the trafficking and signaling effects of endosomal PI3P and Vps34, and revealed previously unrecognized roles of this critical endosomal kinase in GPCR signaling.…”

Section: Introductionmentioning

confidence: 82%

“…b2-adrenoceptors internalize rapidly after ligand-induced activation via clathrin-coated pits and have the ability to recycle to the PM with remarkably high efficiency via a retromer-dependent pathway (Goodman et al, 1996;Temkin et al, 2011). Several components of this machinery require 3-phosphorylated phosphoinositides for membrane attachment (Cullen and Korswagen, 2011), and a previous study (Awwad et al, 2007) Vps34 represents an endosomal target that controls b2AR signaling. Chemical inhibitors used in previous studies of b2AR trafficking (Sorensen et al, 1999;Naga Prasad et al, 2001;Awwad et al, 2007) [wortmannin (WM) and LY294002] have additional cellular targets (Knight, 2010).…”

Section: Introductionmentioning

confidence: 97%

Endosomal Phosphatidylinositol 3-Kinase Is Essential for Canonical GPCR Signaling

et al. 2016

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G protein-coupled receptors (GPCRs), the largest family of signaling receptors, are critically regulated by endosomal trafficking, suggesting that endosomes might provide new strategies for manipulating GPCR signaling. Here we test this hypothesis by focusing on class III phosphatidylinositol 3-kinase (Vps34), which is an essential regulator of endosomal trafficking. We verify that Vps34 is required for recycling of the β2-adrenoceptor (β2AR), a prototypical GPCR, and then investigate the effects of Vps34 inhibition on the canonical cAMP response elicited by β2AR activation. Vps34 inhibition impairs the ability of cells to recover this response after prolonged activation, which is in accord with the established role of recycling in GPCR resensitization. In addition, Vps34 inhibition also attenuates the short-term cAMP response, and its effect begins several minutes after initial agonist application. These results establish Vps34 as an essential determinant of both short-term and long-term canonical GPCR signaling, and support the potential utility of the endosomal system as a druggable target for signaling.

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“…The 22-h treatment time was chosen to insure that receptor levels were at steady state between degradation and synthesis. Previous work with this cell line indicated that receptor degradation approaches maximum at approximately eight after addition of agonist (Awwad et al 2007). …”

Section: Resultsmentioning

confidence: 78%

The effects of acute and chronic nadolol treatment on β2AR signaling in HEK293 cells

Peng

Bond

Knoll

2011

Naunyn-Schmied Arch Pharmacol

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Nadolol (NAD) is a β-adrenergic receptor blocker with inverse agonist activity at βARs. Previous studies in our laboratory showed that chronic treatment with NAD decreased airway resistance response (R (aw)) to the muscarinic agonist methacholine in a murine model of asthma while acute treatment with NAD increased R (aw) (Callaerts-Vegh et al., Proc Natl Acad Sci U S A 101:4948-4953, 2004). Chronic treatment with NAD also caused decreased airway inflammation and mucin content in a murine asthma model (Nguyen et al., Am J Respir Cell Mol Biol 38:256-262, 2008). In this study, we examined the effects of nadolol on β(2)AR levels and signaling components downstream of the β(2)AR using a line of HEK293 cells expressing human β(2)ARs. Chronic treatment with NAD increased β(2)AR protein levels and decreased receptor degradation, consistent with receptor stabilization by the inverse agonist. Basal cAMP levels decreased after 5 min of treatment with NAD but increased after a 24-h treatment. A 5-min treatment with NAD decreased forskolin-stimulated phosphorylation at the β(2)AR PKA site Ser 262 while a 24-h treatment with NAD increased it. In contrast, chronic treatment with NAD had no effect on phosphorylation of the β(2)AR GRK site at Ser 355, 356. Chronic treatment with NAD upregulated cellular levels of G(α)s but had no effect on G(α)i. Chronic NAD treatment therefore increases cellular cAMP levels by mechanisms that include the upregulation of β(2)AR and G(α)s. This effect may explain in part the beneficial effects of chronic nadolol treatment on airway contractility.

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Inhibitors of phosphoinositide 3-kinase cause defects in the postendocytic sorting of β2-adrenergic receptors

Cited by 8 publications

References 41 publications

G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function

G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function

Endosomal Phosphatidylinositol 3-Kinase Is Essential for Canonical GPCR Signaling

The effects of acute and chronic nadolol treatment on β2AR signaling in HEK293 cells

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