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Molecular Pharmacology

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Research ArticleArticle

Interdicting Gq Activation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms

Richard Carr III, Cynthia Koziol-White, Jie Zhang, Hong Lam, Steven S. An, Gregory G. Tall, Reynold A. Panettieri Jr. and Jeffrey L. Benovic
Molecular Pharmacology January 2016, 89 (1) 94-104; DOI: https://doi.org/10.1124/mol.115.100339
Richard Carr III
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (R.C., J.L.B.); Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Airways Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania (C.K.W., J.Z., R.A.P.); Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (H.L., S.S.A.); and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York (G.G.T.)
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Cynthia Koziol-White
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (R.C., J.L.B.); Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Airways Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania (C.K.W., J.Z., R.A.P.); Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (H.L., S.S.A.); and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York (G.G.T.)
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Jie Zhang
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (R.C., J.L.B.); Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Airways Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania (C.K.W., J.Z., R.A.P.); Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (H.L., S.S.A.); and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York (G.G.T.)
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Hong Lam
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (R.C., J.L.B.); Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Airways Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania (C.K.W., J.Z., R.A.P.); Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (H.L., S.S.A.); and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York (G.G.T.)
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Steven S. An
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (R.C., J.L.B.); Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Airways Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania (C.K.W., J.Z., R.A.P.); Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (H.L., S.S.A.); and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York (G.G.T.)
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Gregory G. Tall
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (R.C., J.L.B.); Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Airways Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania (C.K.W., J.Z., R.A.P.); Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (H.L., S.S.A.); and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York (G.G.T.)
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Reynold A. Panettieri Jr.
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (R.C., J.L.B.); Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Airways Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania (C.K.W., J.Z., R.A.P.); Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (H.L., S.S.A.); and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York (G.G.T.)
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Jeffrey L. Benovic
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (R.C., J.L.B.); Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Airways Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania (C.K.W., J.Z., R.A.P.); Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (H.L., S.S.A.); and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York (G.G.T.)
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Abstract

Gαqβγ heterotrimer (Gq), an important mediator in the pathology of airway disease, plays a central role in bronchoconstriction and airway remodeling, including airway smooth muscle growth and inflammation. Current therapeutic strategies to treat airway disease include the use of muscarinic and leukotriene receptor antagonists; however, these pharmaceuticals demonstrate a limited clinical efficacy as multiple Gq-coupled receptor subtypes contribute to these pathologies. Thus, broadly inhibiting the activation of Gq may be an advantageous therapeutic approach. Here, we investigated the effects of broadly inhibiting Gq activation in vitro and ex vivo using receptor-dependent and receptor-independent strategies. P4pal-10 is a protease activated receptor 4–derived pepducin that exhibits efficacy toward multiple Gq-coupled receptors. Mechanistic studies demonstrated that P4pal-10 selectively inhibits all G protein coupling to several Gq-coupled receptors, including protease activated receptor 1, muscarinic acetylcholine M3, and histamine H1 receptors, while demonstrating no direct effect on Gq. We also evaluated the ability of FR900359, also known as UBO-QIC, to directly inhibit Gq activation. FR900359 inhibited spontaneous Gαq nucleotide exchange, while having little effect on Gαsβγ, Gαiβγ, or Gα12/13βγ heterotrimer activity. Both P4pal-10 and FR900359 inhibited Gq-mediated intracellular signaling and primary human airway smooth muscle growth, whereas only FR900359 effectively interdicted agonist-promoted airway contraction in human precision cut lung slices. These studies serve as a proof of concept that the broad-based inhibition of Gq activation may be a useful therapeutic approach to treat multiple common pathologies of airway disease.

Footnotes

    • Received June 9, 2015.
    • Accepted October 9, 2015.
  • This research was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants R37-GM047417, R01-GM068857, R01-GM088242, and T32-GM100836], National Institutes of Health National Heart, Lung, and Blood Institute [Grants P01-HL114471 and R01-HL107361] and National Institutes of Health National Institute of Environmental Health Sciences [Grant P30-ES013508].

  • dx.doi.org/10.1124/mol.115.100339.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 89 (1)
Molecular Pharmacology
Vol. 89, Issue 1
1 Jan 2016
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Research ArticleArticle

Interdicting Gq Activation in Airway Disease

Richard Carr, Cynthia Koziol-White, Jie Zhang, Hong Lam, Steven S. An, Gregory G. Tall, Reynold A. Panettieri and Jeffrey L. Benovic
Molecular Pharmacology January 1, 2016, 89 (1) 94-104; DOI: https://doi.org/10.1124/mol.115.100339

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Research ArticleArticle

Interdicting Gq Activation in Airway Disease

Richard Carr, Cynthia Koziol-White, Jie Zhang, Hong Lam, Steven S. An, Gregory G. Tall, Reynold A. Panettieri and Jeffrey L. Benovic
Molecular Pharmacology January 1, 2016, 89 (1) 94-104; DOI: https://doi.org/10.1124/mol.115.100339
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