A Novel Bioassay for Detecting GPCR Heterodimerization: Transactivation of Beta 2 Adrenergic Receptor by Bradykinin Receptor

Haack, Karla K.V.; Tougas, Michelle; Jones, Kymry T.; El‐Dahr, Samir S.; Radhakrishna, Harish; McCarty, Nael A.

doi:10.1177/1087057109360254

Cited by 19 publications

(14 citation statements)

References 21 publications

(24 reference statements)

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“…There are many other examples showing that blocking only one type of G i/o -protein coupled receptors for endogenous ligands involved in preconditioning, such as adenosine, bradykinin or opioids, can fully abolish the ischemia-tolerant state (Yellon and Downey, 2003;Downey et al, 2007). Transactivation of receptors (Mukhin et al, 2006;Dalton et al, 2009;Haack et al, 2010) and/or their crosstalk (Dzimiri, 2002;Peart and Gross, 2003;Peart et al, 2005;Yao et al, 2006;Shen et al, 2007) seem to be the most likely explanation. Transactivation of G-protein coupled receptors can occur via their heterodimerization on cell membrane that is a formation of a complex of two receptors (Rediger et al, 2009;Pasternak and Pan, 2011).…”

Section: Discussionmentioning

confidence: 93%

Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia

Maslov¹,

Нарыжная²,

Tsibulnikov³

et al. 2013

Life Sciences

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Section: Discussionmentioning

confidence: 93%

Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia

Maslov¹,

Нарыжная²,

Tsibulnikov³

et al. 2013

Life Sciences

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“…Additionally, coexpression of B2R is sufficient to hinder β 2 AR's ability to respond to its selective ligand (Figure 2C, bottom). Thus, in this case the B2R is a negative allosteric modulator of β 2 AR [7]. We know that B2R and β 2 AR are physically associated in Xenopus oocytes, and in these cells, B2R coexpression alters β 2 AR pharmacology as well as activating this receptor directly in the absence of a β 2 AR-selective ligand (Figure 2C, top).…”

Section: Functional Consequences Of Gpcr Dimerizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In the case of the β 2 AR, our previous work has shown that both in vitro and in vivo , binding of bradykinin (BK) to B2R transactivates β 2 AR [7]. Control experiments show that this transactivation is second messenger independent, and is a result of conformational changes in both receptors [7]. Figure 2C shows that upon coexpression of B2R and β 2 AR, stimulation with BK leads to activation of both a calcium activated chloride channel (as indicated by the sharp current spike) and CFTR (as indicated by the slow current wave); the former is via B2R-mediated activation of Gαq signaling, and the latter is via heterodimer-mediated activation of Gαs signaling [7].…”

Section: Introductionmentioning

confidence: 99%

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Functional Consequences of GPCR Heterodimerization: GPCRs as Allosteric Modulators

Haack

McCarty

2011

Pharmaceuticals

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G Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins in the human genome, are the targets of approximately 25% of all marketed pharmaceuticals, and the focus of intensive research worldwide given that this superfamily of receptors is as varied in function as it is ubiquitously expressed among all cell types. Increasing evidence has shown that the classical two part model of GPCR signaling (one GPCR, one type of heterotrimeric G protein) is grossly oversimplified as many GPCRs can couple to more than one type of G protein, each subunit of the heterotrimeric G protein can activate different downstream effectors, and, surprisingly, other GPCRs can affect receptor behavior in G protein-independent ways. The concept of GPCR heterodimerization, or the physical association of two different types of GPCRs, presents an unexpected mechanism for GPCR regulation and function, and provides a novel target for pharmaceuticals. Here we present a synopsis of the functional consequences of GPCR heterodimerization in both in vitro and in vivo studies, focusing on the concept of GPCRs as allosteric modulators. Typically, an allosteric modulator is a ligand or molecule that alters a receptor's innate functional properties, but here we propose that in the case of GPCR heterodimers, it is the physical coupling of two receptors that leads to changes in cognate receptor signaling.

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“…This cell typespecific divergence on cell proliferation by ␤ 2 -AR agonists raises questions about whether there is cross-talk between ␤ 2 -AR and other receptor-linked signaling cascades. A link between ␤ 2 -AR and other GPCRs, including ␣ 2 -AR, bradykinin, oxytocin, and cannabinoid receptors (CBRs), has been described previously (Uberti et al, 2005;Haack et al, 2010;Hudson et al, 2010;Wrzal et al, 2012). Of significance, CBRs have been reported to modulate ␤ 2 -AR activity (Gardiner et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid Receptor Activation Correlates with the Proapoptotic Action of the β₂-Adrenergic Agonist (R,R′)-4-Methoxy-1-Naphthylfenoterol in HepG2 Hepatocarcinoma Cells

Paul

Ramamoorthy

Scheers

et al. 2012

J Pharmacol Exp Ther

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Inhibition of cell proliferation by fenoterol and fenoterol derivatives in 1321N1 astrocytoma cells is consistent with ␤ 2 -adrenergic receptor (␤ 2 -AR) stimulation. However, the events that result in fenoterol-mediated control of cell proliferation in other cell types are not clear. Here, we compare the effect of the ␤ 2 -AR agonists (R,RЈ)-fenoterol (Fen) and (R,RЈ)-4-methoxy-1-naphthylfenoterol (MNF) on signaling and cell proliferation in HepG2 hepatocarcinoma cells by using Western blotting and [ 3 H]thymidine incorporation assays. Despite the expression of ␤ 2 -AR, no cAMP accumulation was observed when cells were stimulated with isoproterenol or Fen, although the treatment elicited both mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt activation. Unexpectedly, isoproterenol and Fen promoted HepG2 cell growth, but MNF reduced proliferation together with increased apoptosis. The mitogenic responses of Fen were attenuated by 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118,551), a ␤ 2 -AR antagonist, whereas those of MNF were unaffected. Because of the coexpression of ␤ 2 -AR and cannabinoid receptors (CBRs) and their impact on HepG2 cell proliferation, these G␣ i /G␣ o -linked receptors may be implicated in MNF signaling. Cell treatment with (R)-(ϩ)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN 55,212-2), a synthetic agonist of CB 1 R and CB 2 R, led to growth inhibition, whereas inverse agonists of these receptors blocked MNF mitogenic responses without affecting Fen signaling. MNF responses were sensitive to pertussis toxin. The ␤ 2 -ARdeficient U87MG cells were refractory to Fen, but responsive to the antiproliferative actions of MNF and WIN 55,212-2. The data indicate that the presence of the naphthyl moiety in MNF results in functional coupling to the CBR pathway, providing one of the first examples of a dually acting ␤ 2 -AR-CBR ligand.

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A Novel Bioassay for Detecting GPCR Heterodimerization: Transactivation of Beta 2 Adrenergic Receptor by Bradykinin Receptor

Cited by 19 publications

References 21 publications

Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia

Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia

Functional Consequences of GPCR Heterodimerization: GPCRs as Allosteric Modulators

Cannabinoid Receptor Activation Correlates with the Proapoptotic Action of the β₂-Adrenergic Agonist (R,R′)-4-Methoxy-1-Naphthylfenoterol in HepG2 Hepatocarcinoma Cells

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A Novel Bioassay for Detecting GPCR Heterodimerization: Transactivation of Beta 2 Adrenergic Receptor by Bradykinin Receptor

Cited by 19 publications

References 21 publications

Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia

Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia

Functional Consequences of GPCR Heterodimerization: GPCRs as Allosteric Modulators

Cannabinoid Receptor Activation Correlates with the Proapoptotic Action of the β2-Adrenergic Agonist (R,R′)-4-Methoxy-1-Naphthylfenoterol in HepG2 Hepatocarcinoma Cells

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Product

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Cannabinoid Receptor Activation Correlates with the Proapoptotic Action of the β₂-Adrenergic Agonist (R,R′)-4-Methoxy-1-Naphthylfenoterol in HepG2 Hepatocarcinoma Cells