β-Agonists and asthma: too much of a good thing?

Shore, Stephanie A.; Drazen, Jeffrey M.

doi:10.1172/jci19642

Cited by 39 publications

(19 citation statements)

References 20 publications

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“…2B). In some cell types, ␤ 2 -adrenoceptors can also couple to Gi protein as well as to Gs protein (47). It has been reported that stimulation of ␤ 2 -adrenoceptors inhibits apoptosis via a Gi-coupled pathway (12).…”

Section: Resultsmentioning

confidence: 99%

Activation of PI3K-Akt pathway mediates antiapoptotic effects of β-adrenergic agonist in airway eosinophils

Machida¹,

Inoue²,

Matsumoto³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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beta-Adrenoceptor agonists reportedly decrease spontaneous apoptosis of peripheral blood eosinophils; however, its signaling pathway is unknown. Survival signals can be elicited by the activation of phosphatidylinositol 3-kinase (PI3K) and Akt, both of which are known to be potent regulators of apoptosis, and Akt in turn inactivates Forkhead transcription factors, including FKHR (Forkhead in rhabdomyosarcoma). We have investigated the effect of beta-agonists on apoptosis of local eosinophils isolated from the airways and the involvement of PI3K, Akt, and FKHR in its survival signal. Eosinophils obtained from immunized mice by bronchoalveolar lavage after allergen provocation underwent apoptosis in a time-dependent manner. Incubation of eosinophils with isoproterenol or formoterol dose-dependently inhibited both spontaneous eosinophil apoptosis and apoptosis induced by Fas receptor activation. Incubation with cAMP or forskolin also inhibited eosinophil apoptosis. The PI3K inhibitors wortmannin and LY-294002 and an Akt inhibitor, 1-L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, but not a mitogen-activated protein kinase kinase inhibitor PD-98059, blocked isoproterenol-mediated eosinophil survival. Wortmannin also inhibited cAMP-mediated eosinophil survival. Isoproterenol rapidly induced phosphorylation of Akt and FKHR in eosinophils in a PI3K-dependent manner. These findings indicate that the PI3K-Akt-FKHR pathway conveys a critical survival signal induced by beta-agonists in airway eosinophils.

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Section: Resultsmentioning

confidence: 99%

Activation of PI3K-Akt pathway mediates antiapoptotic effects of β-adrenergic agonist in airway eosinophils

Machida¹,

Inoue²,

Matsumoto³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…This striking inability of the receptors to couple to G-proteins depicting desensitization is observed in various pathologies including heart failure and asthma [31-34] wherein β-adrenergic receptors are desensitized [32, 33]. GPCR desensitization is initiated via the phosphorylation of activated receptors by the family of seven GRKs [30].…”

Section: Gpcr Desensitizationmentioning

confidence: 99%

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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“…Specifically, genes encoding for phospholipase A 2 (PLA2G4A), leukotriene C 4 synthase (LTC4S), CysLT 1 receptor (CYSLTR1), CysLT 2 receptor (CYSLTR2), 5-LO-activating protein (ALOX5AP), 5-LO (ALOX5), and two cytochrome P450 isoforms (CYP3A4 and CYP2C9) were evaluated. Additionally, the b 2 -adrenergic receptor (ADRB2) was assessed because mechanistically, the b 2 -adrenergic receptor may influence response to leukotriene modifiers via the so-called crosstalk between the activation of G s receptors causing airway smooth muscle relaxation, and G q -receptors that cause muscle contraction [16,17]. Finally, the glucocorticoid receptor (NR3C1) was considered because glucocorticoids induce the upregulation of 5-LO.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast

Klotsman

York

Pillai

et al. 2007

Pharmacogenetics and Genomics

104

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The overall mean response to montelukast may be skewed towards a response phenotype by a small subset (<15%) of asthma patients. CYSLTR2 and ALOX5 polymorphisms may predispose a minority of individuals to excessive cysteinyl-leukotriene concentrations, yielding a distinct asthma phenotype most likely to respond to leukotriene modifier pharmacotherapy. These findings require replication to establish validity and clinical utility.

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β-Agonists and asthma: too much of a good thing?

Cited by 39 publications

References 20 publications

Activation of PI3K-Akt pathway mediates antiapoptotic effects of β-adrenergic agonist in airway eosinophils

Activation of PI3K-Akt pathway mediates antiapoptotic effects of β-adrenergic agonist in airway eosinophils

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

Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast

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