Inverse agonism: from curiosity to accepted dogma, but is it clinically relevant?

Parra, Sergio; Bond, Richard A.

doi:10.1016/j.coph.2006.10.005

Cited by 39 publications

(39 citation statements)

References 30 publications

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“…It is now known that many if not all GPCRs, including the ␤ 2 -AR, can signal in the absence of agonist, a phenomenon known as constitutive activity (16,22). Simultaneous with this discovery of constitutive signaling was the identification of compounds termed inverse agonists.…”

Section: Discussionmentioning

confidence: 99%

β ₂ -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

Nguyen¹,

Lin²,

Parra³

et al. 2009

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

106

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Chronic regular use of ␤2-adrenoceptor (␤2-AR) agonists in asthma is associated with a loss of disease control and increased risk of death. Conversely, we have found that administration of ␤2-AR inverse agonists results in attenuation of the asthma phenotype in an allergen-driven murine model. Besides antagonizing agonistinduced signaling and reducing signaling by empty receptors, ␤-AR inverse agonists can also activate signaling by novel pathways. To determine the mechanism of the ␤-AR inverse agonists, we compared the asthma phenotype in ␤2-AR-null and wild-type mice. Antigen challenge of ␤2-AR-null mice produced results similar to what was observed with chronic ␤2-AR inverse agonist treatment, namely, reductions in mucous metaplasia, airway hyperresponsiveness (AHR), and inflammatory cells in the lungs. These results indicate that the effects of ␤2-AR inverse agonists are caused by inhibition of ␤2-AR signaling rather than by the induction of novel signaling pathways. Chronic administration of alprenolol, a ␤-blocker without inverse agonist properties, did not attenuate the asthma phenotype, suggesting that it is signaling by empty receptors, rather than agonist-induced ␤2-AR signaling, that supports the asthma phenotype. In conclusion, our results demonstrate that, in a murine model of asthma, ␤2-AR signaling is required for the full development of three cardinal features of asthma: mucous metaplasia, AHR, and the presence of inflammatory cells in the lungs.airway hyperresponsiveness ͉ ␤-blocker ͉ inverse agonist ͉ mucous metaplasia ͉ inflammation

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Section: Discussionmentioning

confidence: 99%

β ₂ -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

Nguyen¹,

Lin²,

Parra³

et al. 2009

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

106

View full text Add to dashboard Cite

show abstract

“…Although many examples of inverse agonism are well known pharmacologically [12][13][14], this issue has largely been ignored clinically. This may be at least partly due to the dogma that, as therapeutic drugs, neutral antagonists must be better than partial or inverse agonists because they do not change the resting state existing as a "gifted harmony" and inhibit only agonist-dependent signals.…”

Section: Inverse Agonism: Why It Has Not Been Featuredmentioning

confidence: 99%

“…3) [12][13][14]. A constitutively active mutation of a GPCR [13,19,20] is one of the representative situations that induce spontaneous GPCR activation.…”

Section: Fig 2 the Classification Of Gpcr Ligandsmentioning

confidence: 99%

Inverse agonism: the classic concept of GPCRs revisited [Review]

2016

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Abstract. In the classical two-state model, G protein-coupled receptors (GPCRs) are considered to exist in equilibrium between an active and an inactive conformation. Thus, even at the resting state, some subpopulation of GPCRs is in the active state, which underlies the basal activity of the GPCRs. In this review, we discuss inverse agonists, which are defined as GPCR ligands that shift the equilibrium toward the inactive state and thereby suppress the basal activity. Theoretically, if constitutive activation plays an essential role in the pathogenesis of a disease, only inverse agonists, and not neutral antagonists, can reverse this pathophysiological activation. Although many pharmacological examples of inverse agonism have been identified, its clinical importance is still unclear and debated. Thus, even though inverse agonism of angiotensin receptor blockers (ARBs) has been discussed for more than 10 years, its clinical relevance remains to be completely clarified.

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“…Ligand-independent activation of G protein-coupled receptors (GPCRs), known as constitutive activity, is an established biologic phenomenon that results from the spontaneous isomerization of receptors from inactive to active states (Lefkowitz et al, 1993;Parra and Bond, 2007). The two-state model of receptor activation (Leff, 1995), which condenses the vast array of possible receptor conformations into either an active (R*) or inactive (R) form, provides the simplest conceptual framework for understanding constitutive activity and, in turn, inverse agonism.…”

Section: Introductionmentioning

confidence: 99%

Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation

Vecchio

Tan

Gregory

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Aberrant ligand-independent G protein-coupled receptor constitutive activity has been implicated in the pathophysiology of a number of cancers. The adenosine A 2B receptor (A 2B AR) is dynamically upregulated under pathologic conditions associated with a hypoxic microenvironment, including solid tumors. This, in turn, may amplify ligand-independent A 2B AR signal transduction. The contribution of A 2B AR constitutive activity to disease progression is currently unknown yet of fundamental importance, as the preferred therapeutic modality for drugs designed to reduce A 2B AR constitutive activity would be inverse agonism as opposed to neutral antagonism. The current study investigated A 2B AR constitutive activity in a heterologous expression system and a native 22Rv1 human prostate cancer cell line exposed to hypoxic conditions (2% O 2 ). (4-chlorophenyl)piperazide-1-sulfonyl)phenyl)-1-propylxanthine), mediated a concentration-dependent decrease in baseline cAMP levels in both cellular systems. Proliferation of multiple prostate cancer cell lines was also attenuated in the presence of PSB-603. Importantly, both the decrease in baseline cAMP accumulation and the reduction of proliferation were not influenced by the addition of adenosine deaminase, demonstrating that these effects are not dependent on stimulation of A 2B ARs by the endogenous agonist adenosine. Our study is the first to reveal that wild-type human A 2B ARs have high constitutive activity in both model and native cells. Furthermore, our findings demonstrate that this ligand-independent A 2B AR constitutive activity is sufficient to promote prostate cancer cell proliferation in vitro. More broadly, A 2B AR constitutive activity may have wider, currently unappreciated implications in pathologic conditions associated with a hypoxic microenvironment.

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Inverse agonism: from curiosity to accepted dogma, but is it clinically relevant?

Cited by 39 publications

References 30 publications

β ₂ -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

β ₂ -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

Inverse agonism: the classic concept of GPCRs revisited [Review]

Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation

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Inverse agonism: from curiosity to accepted dogma, but is it clinically relevant?

Cited by 39 publications

References 30 publications

β 2 -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

β 2 -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

Inverse agonism: the classic concept of GPCRs revisited [Review]

Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation

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β ₂ -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

β ₂ -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model