Antithetic regulation by β-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway β-agonist paradox

McGraw, Dennis W.; Almoosa, Khalid F.; Rutgeerts, Paul; Kobilka, Brian K.; Liggett, Stephen B.

doi:10.1172/jci18193

Cited by 122 publications

(80 citation statements)

References 26 publications

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“…LTB 4 , like a number of other arachidonic acid metabolites, is increased in inflammatory states such as asthma, with elevated local levels in the airway (20). The high-affinity receptor for LTB 4 , LTB4R, is well recognized as being expressed on neutrophils and other leukocytes (eosinophils, T-lymphocytes) and, when activated by its endogenous agonist, promotes leukocyte migration to the lung and participates in activation and degranulation (21). To our knowledge, LTB4R expression on human ASM cells has not been previously identified.…”

Section: Discussionmentioning

confidence: 99%

“…Other reports, though, have shown significant contraction of lung parenchymal strips by nanomolar concentrations of LTB 4 (24). Some studies have concluded that LTB 4 antagonists have minor effects on leukocyte accumulation but decrease bronchial hyperreactivity (25,26), another showed decreased leukocyte recruitment but no effect on pulmonary function (27), and another found that antigen-induced bronchoconstriction was decreased but eosinophil accumulation and acute bronchial hyperreactivity were unaffected (28).…”

Section: Discussionmentioning

confidence: 99%

“…We show here three forms of the transcribed LTB4R and two additional variations in the 5ЈUTR, which may alter the rate of transcription. The two splice variants involving the coding region lack domains that are likely necessary for LTB 4 binding to the receptor. However, both have intact G protein coupling domains (second and third intracellular loops) and thus may act as dominant-negative proteins during wild-type LTB4R signaling.…”

Section: Discussionmentioning

confidence: 99%

“…There are several well recognized phenomena in GPCR signaling events, at both the in vitro and clinical levels, which have revealed a complexity beyond that initially expected. One issue has been the recognition that one receptor can regulate another through any number of heterologous mechanisms (4,5). This ''cross-talk'' appears to be necessary for the cell to integrate the large number of GPCR signaling events underway at any given time (6,7).…”

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confidence: 99%

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Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors

Einstein¹,

Jordan²,

Zhou³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) are the largest signaling family in the genome, serve an expansive array of functions, and are targets for Ϸ50% of current therapeutics. In many tissues, such as airway smooth muscle (ASM), complex, unexpected, or paradoxical responses to agonists/antagonists occur without known mechanisms. We hypothesized that ASM express many more GPCRs than predicted, and that these undergo substantial alternative splicing, creating a highly diversified receptor milieu. Transcript arrays were designed detecting 434 GPCRs and their predicted splice variants. In this cell type, 353 GPCRs were detected (including 111 orphans), with expression levels varying by Ϸ900-fold. Receptors used for treating airway disease were expressed lower than others with similar signaling properties, indicating potentially more effective targets. A disproportionate number of Class-A peptide-group receptors, and those coupling to G q/11 or Gs (vs. Gi), was found. Importantly, 192 GPCRs had, on average, five different expressed receptor isoforms because of splicing events, including alternative splice donors and acceptors, novel introns, intron retentions, exon(s) skips, and novel exons, with the latter two events being most prevalent. The consequences of splicing were further investigated with the leukotriene B4 receptor, known for its aberrant responsiveness in lung. We found transcript expression of three variants because of alternative donor and acceptor splice sites, representing in-frame deletions of 38 and 100 aa, with protein expression of all three isoforms. Thus, alternative splicing, subject to conditional, temporal, and cell-type regulation, is a major mechanism that diversifies the GPCR superfamily, creating local recepteromes with specialized environments.pharmacogenetics ͉ signal transduction ͉ splice variants

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors

Einstein¹,

Jordan²,

Zhou³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been shown previously that persistent activation of the Gs signaling pathway can augment muscarinic M 3 receptor-mediated inositol phosphate production 40 . At first glance, the results reported herein might appear to be in good accordance with this earlier report as we detected enhanced muscarinic M 3 receptor signaling in the presence of cAMP elevating agents such as CTX ( Fig.…”

Section: Dynamic Mass Redistribution Faithfully Reports Signaling Of mentioning

confidence: 97%

Deconvolution of complex G protein–coupled receptor signaling in live cells using dynamic mass redistribution measurements

et al. 2010

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β2 Adrenergic receptor activation induces microglial NADPH oxidase activation and dopaminergic neurotoxicity through an ERK‐dependent/protein kinase A‐independent pathway

Zhang

et al. 2009

Glia

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Activation of the β2 adrenergic receptor (β2AR) on immune cells has been reported to possess anti-inflammatory properties, however, the pro-inflammatory properties of β2AR activation remain unclear. In this study, using rat primary mesencephalic neuron-glia cultures, we report that salmeterol, a long-acting β2AR agonist, selectively induces dopaminergic (DA) neurotoxicity through its ability to activate microglia. Salmeterol selectively increased the production of reactive oxygen species (ROS) by NADPH oxidase (PHOX), the superoxide-producing enzyme in microglia. A key role of PHOX in mediating salmeterol-induced neurotoxicity was demonstrated by the inhibition of DA neurotoxicity in cultures pretreated with diphenylene-iodonium (DPI), an inhibitor of PHOX activity. Mechanistic studies revealed the activation of microglia by salmeterol results in the selective phosphorylation of ERK, a signaling pathway required for the translocation of the PHOX cytosolic subunit p47phox to the cell membrane. Furthermore, we found ERK inhibition, but not protein kinase A (PKA) inhibition, significantly abolished salmeterol-induced superoxide production, p47phox translocation, and its ability to mediate neurotoxicity. Together, these findings indicate that β2AR activation induces microglial PHOX activation and DA neurotoxicity through an ERK-dependent/PKA-independent pathway.

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Antithetic regulation by β-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway β-agonist paradox

Cited by 122 publications

References 26 publications

Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors

Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors

Deconvolution of complex G protein–coupled receptor signaling in live cells using dynamic mass redistribution measurements

β2 Adrenergic receptor activation induces microglial NADPH oxidase activation and dopaminergic neurotoxicity through an ERK‐dependent/protein kinase A‐independent pathway

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