title: Interdicting Gq Activation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms.
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.
authors.affiliation: 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.).
authors.forename: Richard
authors.initials: R
authors.lastname: Carr
authors.affiliation: 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.).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Koziol-White
authors.affiliation: 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.).
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 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.).
authors.forename: Hong
authors.initials: H
authors.lastname: Lam
authors.affiliation: 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.).
authors.forename: Steven S
authors.initials: SS
authors.lastname: An
authors.affiliation: 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.).
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Tall
authors.affiliation: 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.).
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.affiliation: 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.) jeffrey.benovic@jefferson.edu.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Benovic
mesh_terms: D002478:Cells, Cultured; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D009924:Organ Culture Techniques; D012120:Respiration Disorders / Q000188:drug therapy / Q000378:metabolism
chemical_list: D009842:Oligopeptides; C524864:palmitoyl-seryl-glycyl-arginyl-arginyl-tyrosyl-glycyl-histidyl-alanyl-leucyl-arginine; D043802:GTP-Binding Protein alpha Subunits, Gq-G11